FIELD OF THE INVENTION

The present invention provides lipids and lipid nanoparticle formulations comprising these lipids, alone or in combination with other lipids. These lipid nanoparticles may be formulated with nucleic acids to facilitate their intracellular delivery both in vitro and for in vivo therapeutic applications. The present invention also provides methods of chemical synthesis of these lipids, lipid nanoparticle preparation and formulation with nucleic acids.

BACKGROUND OF THE INVENTION

Therapeutic nucleic acids including small interfering RNA (siRNA), micro RNA (miRNA), antisense oligonucleotides, messenger RNA (mRNA), ribozymes, pDNA and immune stimulating nucleic acids act via a variety of mechanisms. Specific proteins can be downregulated by siRNA or miRNA through RNA interference (RNAi). Hematopoietic cells, such as leukocytes in general, and primary T lymphocytes and B -cells in particular, are notoriously hard to transfect with small interfering RNAs (siRNAs). Modulating immune cells function, such as T cells and B cells, by downregulating specific genes using RNA interference (RNAi) holds tremendous potential in advancing targeted therapies in many immune -related disorders including cancer, inflammation, autoimmunity and viral infections. The therapeutic applications of RNAi are extremely broad, since siRNA and miRNA constructs can be synthesized with any nucleotide sequence directed against a target protein. To date, siRNA constructs have shown the ability to specially silence target proteins in both in vitro and in vivo models. These are currently being evaluated in clinical studies.

Messenger RNA (mRNA) is the family of large RNA molecules which transport the genetic information from DNA to ribosome. Some nucleic acids, such as mRNA or plasmids, can be used to effect expression of specific cellular products. Such nucleic acids would be useful in the treatment to the of diseases related deficiency of a protein or enzyme. However, there are many problems associated with nucleic acids in therapeutic contexts. One of the major problems with therapeutic nucleic acids is the stability of the phosphodiester inter nucleotide link and its susceptibility to nucleases. Apart from that these nucleic acids have limited ability to cross the cell membrane.

Various lipids, e.g., cationic lipids, have proved to be excellent carriers of nucleic acids to treat different diseases in gene therapy applications. Lipid nanoparticles formed from cationic lipids and other co-lipids such as cholesterol, DSPC and PEGylated lipids encapsulated oligonucleotides which protect them from degradation and facilitate the cellular uptake.

WO 2018087753 discloses a cationic lipid comprising a functional group represented by the structure: -W-(T=O) _m -X-(CH ₂ ) _z -Y, wherein X and Y are each independently O, N or NH, wherein X and Y cannot both be O; W is a bond, O, NH or S; T is C or S; m is 0 or 1; and z is 0 or 2, wherein said functional group is linked to at least one saturated or unsaturated fatty acid residue.

Nevertheless, there remains a need in the art for suitable and efficient delivery platforms for delivery of oligonucleotides.

SUMMARY OF THE INVENTION

The present invention relates to novel lipids which can be used in lipid nanoparticle preparation. These lipid nanoparticles protect nucleic acids from degradation, clearance from circulation and intracellular release. In addition, the nucleic acid encapsulated lipid nanoparticles advantageously are well-tolerated and provide an adequate therapeutic index, such that patient treatment at an effective dose of the nucleic acid is not associated with unacceptable toxicity and/or risk to the patient. The present invention also provides the methods of chemical synthesis of these lipids, lipid nanoparticle preparation and formulations with nucleic acids.

In some embodiments, the present invention relates to novel lipids, and formulations of such lipids with siRNA and pDNA. These lipid nanoparticles (LNPs) were further characterized by DLS and assessed for their in vitro activity in various cancer cell lines.

According to some embodiments, there is provided a lipid represented by the structure of Formula (II): wherein each one of R ¹ and R ¹³ is independently selected from the group consisting of: OH, C _1-3 alkyl-OH, C _4-14 alkyl and C _4-14 alkenyl;

R ¹² is selected from the group consisting of: C _1-13 alkyl; C _2-15 alkenyl, C _1-6 alkyl-CO ₂ -C _0-3 alkylene-N(C _1-8 alkyl) ₂ and C _1-6 alkyl-CO ₂ - C _0-3 alkylene-NH-C _1-8 alkyl; R ¹⁴ is selected from the group consisting of: C _1-13 alkyl; C _2-15 alkenyl and each L is an alkylene ester linker represented by: L ^a -X ^a -L ^b ;

X ^a is selected from the group consisting of: -O ₂ C-, -CO ₂ -C _2-4 alkylene-O ₂ C-, O ₂ C-C _2-4 alkylene-O ₂ C- -CO ₂ -C _2-4 alkylene-CO ₂ - and O ₂ C-C _2-4 alkylene-CO ₂ -;

L ^a is selected from the group consisting of: C _1-3 alkylene, C _4-12 alkylene, C _2-10 alkenylene and absent; and

L ^b is selected from the group consisting of: C _1-3 alkylene, C _2-10 alkenylene and C _4-12 alkylene.

According to some embodiments, R ¹ is selected from the group consisting of: OH, C _2-3 alkyl-OH, and C _8-14 alkyl. Each possibility represents a separate embodiment of the invention.

According to some embodiments, R ¹² is selected from the group consisting of: C _9-15 alkenyl, C _5-11 alkyl, C _3-6 alkyl-CO ₂ -C _0-2 alkylene-N(C _2-8 alkyl) ₂ . Each possibility represents a separate embodiment of the invention.

It is to be understood that the phrase “each L is selected from the group consisting of’ refers to the situation wherein R ¹⁴ may be so that two separate L substituents appear in the structure of Formula (II), i.e., one L of the main formula and a second L of R ¹⁴ . It is intended to mean that in such cases, each of these L, L ^a , X ^a and L ^b substituents may be independently selected from the corresponding selection group of the appropriate embodiment. In other words, in cases that L appears twice, the two sets of L ^a , X ^a and L ^b substituents may be the same or different.

According to some embodiments, R ¹³ is selected from the group consisting of: OH, CH ₂ -OH, and C _4-12 alkyl. Each possibility represents a separate embodiment of the invention.

According to some embodiments, R ¹⁴ is selected from the group consisting of: C _9-15 alkenyl, C _1-9 alkyl and Each possibility represents a separate embodiment of the invention.

According to some embodiments, X ^a is selected from the group consisting of: -O ₂ C- and -CO ₂ - C _2-4 alkylene-O ₂ C- According to some embodiments, L ^a is absent or selected from the group consisting of: C _2-3 alkylene and C _6-11 alkylene. According to some embodiments, L ^b is selected from the group consisting of: C _1-3 alkylene and C _4-12 alkylene.

According to some embodiments, the lipid is selected from the group consisting of: DSL1-1, DSL1-2, DSL1-3, DSL1-4, DSL1-5, DSL3c-l, DSL2-1, DSL2-2, DSL2-49, DSL2-50, DSL4-1 and DSL4-2. Each possibility represents a separate embodiment of the invention. According to some embodiments, the lipid is selected from the group consisting of: DSL1-3 and DSL2-50.

The chemical structures of each of the specific compound are detailed below in the “Exemplary Compounds” Section and in the claims.

According to some embodiments, there is provided a lipid represented by the structure of Formula (I): wherein

L is L ^a -X ^a -L ^b ;

X ^a is selected from the group consisting of: -O ₂ C-, -O-, -CO ₂ -L ^C -O ₂ C-, -O ₂ C-L ^C -CO ₂ -, -CO ₂ -L ^C -CO ₂ -, L ^C -CO ₂ -, -L ^C -O ₂ C-, -CO ₂ -NH- and -CO-NH-;

L ^a is selected from the group consisting of: C _4-20 alkylene, C _4-20 alkenylene and C _0-4 alkylene;

L ^b is selected from the group consisting of: C _4-20 alkylene, C _4-20 alkenylene and C _0-4 alkylene;

L ^c is selected from the group consisting of: C _1-6 alkylene-(O-C _1-6 alkylene) _f - C _2-6 alkenylene-(O-C _1-6 alkylene) _g -, C _1-6 alkylene-S-C _1-6 alkylene, C _1-6 alkylene-S-S-C _1-6 alkylene, C _0-4 alkylene-aryl-C _0-4 alkylene, and C _1-4 alkylene; each one of f and g is 0, 1, 2, 3, 4 or 5; R ¹ is selected from the group consisting of: C _0-10 alkylene- Y ^a , C _2-6 alkenylene- Y ^a , C _1-4 alkyl, C _5-25 alkyl, C _5-25 alkenyl, C _5-25 alkynyl, C _5-15 alkylene-CO ₂ -C _5-15 alkyl, C _5-15 alkylene-CO ₂ -

-C _5-15 alkenyl, C _5-15 alkylene-O ₂ C-C _5-15 alkyl, C _5-15 alkylene-O ₂ C-C _5-15 alkenyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkenylene-O ₂ C-C _5-15 alkyl, and C _5-15 alkenylene-O ₂ C-C _5-15 alkenyl;

R ² is selected from the group consisting of: C _5-25 alkyl, C _5-25 alkenyl, C _5-25 alkynyl,

C _5-15 alkylene-CO ₂ -C _5-15 alkyl, C _5-15 alkylene-CO ₂ -C _5-15 alkenyl,

C _5-15 alkylene-O ₂ C-C _5-15 alkyl, C _5-15 alkylene-O ₂ C-C _5-15 alkenyl,

C _5-15 alkenylene-CO ₂ -C _5-15 alkyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkenyl,

C _5-15 alkenylene-O ₂ C-C _5-15 alkyl, C _5-15 alkenylene-O ₂ C-C _5-15 alkenyl, C _2-15 alkylene-CO ₂ -C _0-4 alkylene-N(C _1-12 alkyl) ₂ , C _2-15 alkylene-CO ₂ -CH ₂ CH ₂ OCH ₂ CH ₂ -N(C _1-12 alkyl) ₂ , C _2-15 alkylene-CO ₂ -C _0-4 alkylene-NH-C _1-12 alkyl, C _2-15 alkylene-CO ₂ -C _0-4 alkylene-N(C _5-25 alkenyl) ₂ , C _2-15 alkylene-CO ₂ -C _0-4 alkylene-NH-C _5-25 alkenyl, C _2-15 alkylene-CO-NH-C _0-8 alkylene-N(C _1-12 alkyl) ₂ and C _5-15 alkylene-CO ₂ H;

R ³ is selected from the group consisting of: H, C _5-25 alkyl, C _5-25 alkenyl, C _5-25 alkynyl,

C _5-15 alkylene-CO ₂ -C _5-15 alkyl, C _5-15 alkylene-CO ₂ -C _5-15 alkenyl,

C _5-15 alkylene-O ₂ C-C _5-15 alkyl, C _5-15 alkylene-O ₂ C-C _5-15 alkenyl,

C _5-15 alkenylene-CO ₂ -C _5-15 alkyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkenyl,

C _5-15 alkenylene-O ₂ C-C _5-15 alkyl, C _5-15 alkenylene-O ₂ C-C _5-15 alkenyl, C _0-6 alkylene- Y ^d , C _2-6 alkenylene-Y ^d and C _1-4 alkyl;

R ⁴ is selected from the group consisting of: C _5-25 alkyl, C _5-25 alkenyl, C _5-25 alkynyl,

C _5-15 alkylene-CO ₂ -C _5-15 alkyl, C _5-15 alkylene-CO ₂ -C _5-15 alkenyl,

C _5-15 alkylene-O ₂ C-C _5-15 alkyl, C _5-15 alkylene-O ₂ C-C _5-15 alkenyl,

C _5-15 alkenylene-CO ₂ -C _5-15 alkyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkenyl,

C _5-15 alkenylene-O ₂ C-C _5-15 alkyl, C _5-15 alkenylene-O ₂ C-C _5-15 alkenyl and C _5-15 alkylene-CO ₂ - C _5-15 alkylene-N(R ⁵ )R ⁶ ;

R ⁵ is selected from the group consisting of: C _1-4 alkyl, C _0-10 alkylene-OH, C _0-10 alkylene-halogen;

R ⁶ is selected from the group consisting of: C _5-25 alkyl, C _5-25 alkenyl;

Y ^a is selected from the group consisting of: O-Y ^b , halogen, PO ₃ H ₂ , PO ₃ (C _1-4 alkyl) ₂ , PO ₃ H(C _1-4 alkyl), NH ₂ , pyrrolidinyl, piperidinyl, piperzinyl, SH, NMe ₂ , NMe ₃ ⁺ and NH-Y ^b ; Y ^b is selected from the group consisting of: H, C _1-4 alkyl, C _1-4 alkylene-OH, C _1-4 alkylene-(O- C _1-4 alkylene) _1-3 -OH, PO ₃ H ₂ , PO ₃ (C _1-4 alkyl) ₂ , PO ₃ H(C _1-4 alkyl), CO-C _1-4 alkyl-Y ^c , CO-aryl, SO ₃ H, SO ₃ - (C _1-4 alkyl) and SO ₃ -aryl;

Y ^c is selected from the group consisting of: H, NH ₂ , NH(CH ₂ ), N(CH ₂ ) ₂ , pyrrolidinyl piperidinyl and piperazinyl each pyrrolidinyl piperidinyl and piperazinyl is optionally substituted with a C _1-4 alkyl;

Y ^d is selected from the group consisting of: O-Y ^e , halogen, PO ₃ H ₂ , PO ₃ (C _1-4 alkyl) ₂ , PO ₃ H(C _1-4 alkyl), NH ₂ , SH, pyrrolidinyl, piperidinyl piperazinyl, NMe ₂ , NMe ₃ ⁺ and NH-Y ^e ;

Y ^e is selected from the group consisting of: H, C _1-4 alkyl, C _1-4 alkylene-OH, PO ₃ H ₂ , PO ₃ (C _1-4 alkyl) ₂ , PO ₃ H(C _1-4 alkyl), CO-C _1-4 alkyl-Y ^f , CO-aryl, SO ₃ H, SO ₃ - (C _1-4 alkyl) and SO ₃ -aryl; and

Y ^f is selected from the group consisting of: H, NH ₂ , NH(CH ₃ ), N(CH ₂ ) ₂ , pyrrolidinyl piperidinyl and piperazinyl, each pyrrolidinyl piperidinyl and piperazinyl is optionally substituted with a C _1-4 alkyl; including salts, hydrates, solvates, polymorphs, optical isomers, geometrical isomers, enantiomers, diastereomers, and mixtures thereof.

It is to be understood than when L ^c is C _1-6 alkylene-(O-C _1-6 alkylene)f- and f is 0, then L ^c is C _1-6 alkylene-, and when L ^c is C _2-6 alkenylene-(O-C _1-6 alkylene) _g - and g is 0, then L ^c is C _2-6 alkenylene. Similarly, it is to be understood that recitations of C ₀ alkylene (e.g., in C _0-4 alkylene as an option of L ^a ) means that this is absent, leaving a single bond between the previous and next moieties. One example is L ^a of compound DSL2-1, which is described below (Exemplary Compounds section) as absent.

According to some embodiments, R ² is selected from the group consisting of: C _5-25 alkyl, C _5-25 alkenyl, C _5-15 alkylene-CO ₂ -C _5-15 alkyl, C _5-15 alkylene-CO ₂ -C _5-15 alkenyl,

C _5-15 alkylene-O ₂ C-C _5-15 alkyl, C _5-15 alkylene-O ₂ C-C _5-15 alkenyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkenylene-O ₂ C-C _5-15 alkyl,

C _5-15 alkenylene-O ₂ C-C _5-15 alkenyl, C _2-15 alkylene-CO ₂ -C _0-4 alkylene-N(C _1-12 alkyl) ₂ , C _2-15 alkylene-CO ₂ -C _0-4 alkylene-NH-C ₁ -n alkyl, C _2-15 alkylene-CO ₂ -C _0-4 alkylene-N(C _5-25 alkenyl) ₂ , C _2-15 alkylene-CO ₂ -C _0-4 alkylene-NH-C _5-25 alkenyl, C _2-15 alkylene-CO-NH-C _0-4 alkylene-N(C _1-12 alkyl) ₂ , and C _5-15 alkylene-CO ₂ H; and R ⁴ is selected from the group consisting of: C _8-25 alkyl, C _5-25 alkenyl, C _5-15 alkylene-CO ₂ -C _5-15 alkyl, C _5-15 alkylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkylene-O ₂ C-C _5-15 alkyl, C _5-15 alkylene-O ₂ C-C _5-15 alkenyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkyl, C _5-15 alkenylene — CO ₂ -C _5-15 alkenyl, C _5-15 alkenylene-O ₂ C-C _5-15 alkyl, C _5-15 alkenylene- -O ₂ C-C _5-15 alkenyl, and C _5-15 alkylene-CO ₂ -C _5-15 alkylene-N(R ⁵ )R ⁶ .

According to some embodiments, X ^a is selected from the group consisting of: -O ₂ C-, -O-, -CO ₂ - L ^c - O ₂ C- , - O ₂ C- L ^c - CO ₂ - , - L ^c - O ₂ C- , -CO ₂ -NH- and -CO-NH-; L ^a is selected from the group consisting of: C _4-20 alkylene, and C _0-4 alkylene; L ^b is selected from the group consisting of: C _4-20 alkylene, and C _0-4 alkylene; L ^c is selected from the group consisting of: C _1-6 alkylene-O-C _1-6 alkylene-, C _1-6 alkylene-S-S-C _1-6 alkylene, and C _1-4 alkylene; R ¹ is selected from the group consisting of: C _0-10 alkylene- Y ^a , C _1-4 alkyl, and C _5-25 alkyl, C _5-15 alkylene-CO ₂ -C _5-15 alkyl; R ² is selected from the group consisting of: C _5-25 alkyl, C _5-25 alkenyl, C _5-15 alkylene-CO ₂ -C _5-15 alkyl, C _5-15 alkylene-CO ₂ -C _5-15 alkenyl, C _2-15 alkylene-CO ₂ -C _0-4 alkylene-N(C _1-12 alkyl) ₂ , C _2-15 alkylene-CO ₂ -C _0-4 alkylene-NH-C _1-12 alkyl, C _2-15 alkylene-CO ₂ -C _0-4 alkylene-N(C _5-25 alkenyl) ₂ , C _2-15 alkylene-CO ₂ -C _0-4 alkylene-NH-C _5-25 alkenyl, C _2-15 alkylene-CO-NH-C _0-8 alkylene-N(C _1-12 alkyl) ₂ and C _5-15 alkylene-CO ₂ H; R ³ is selected from the group consisting of: H, C ₅ " ₂₅ alkyl, C _5-25 alkenyl, C _0-6 alkylene- Y ^d , and C _1-4 alkyl; R ⁴ is selected from the group consisting of: C _5-25 alkyl, C _5-25 alkenyl, C _5-15 alkylene-CO ₂ -C _5-15 alkenyl, and C _5-15 alkylene- -CO ₂ -C _5-15 alkylene-N(R ⁵ )R ⁶ ; R ⁵ is selected from the group consisting of: C _1-4 alkyl, C _0-10 alkylene-OH, and C _0-10 alkylene-halogen, R ⁶ is selected from the group consisting of: C _5-25 alkyl, and C _5-25 alkenyl; Y ^a is selected from the group consisting of: O-Y ^b , halogen, PO ₃ H ₂ , NH ₂ , and NMe2; Y ^b is selected from the group consisting of: H, C _1-4 alkylene-OH, C _1-4 alkylene- (O-C _1-4 alkylene) _1-3 -OH, and CO-C _1-4 alkyl- Y ^c ; Y ^c is N(CH ₃ ) ₂ ; Y ^d is selected from the group consisting of: O-Y ^e , halogen, and NH ₂ ; Y ^e is selected from the group consisting of: H, and CO- C _1-4 alkyl-Y ^f ; and Y ^f is selected from the group consisting of: N(CH ₃ ) ₂ , and piperazinyl, which is optionally substituted with a C _1-4 alkyl.

According to some embodiments, X ^a is selected from the group consisting of: -O ₂ C-, and -CO ₂ - L ^C -O ₂ C-; L ^a is selected from the group consisting of: C _4-20 alkylene, and C _0-4 alkylene; L ^b is selected from the group consisting of: C _4-20 alkylene, and C _0-4 alkylene; L ^c is C _1-4 alkylene; R ¹ is selected from the group consisting of: C _0-10 alkylene- Y ^a , and C _5-25 alkyl; R ² is selected from the group consisting of: C _5-25 alkyl, C _5-25 alkenyl, and

C _2-15 alkylene-CO ₂ -C _0-4 alkylene-N(C _1-12 alkyl) ₂ ; R ³ is selected from the group consisting of: C _{5- 25} alkyl, and C _0-6 alkylene- Y ^d ; R ⁴ is selected from the group consisting of: C _5-25 alkyl, C _5-25 alkenyl, and C _5-15 alkylene-CO ₂ -C _5-15 alkylene-N(R ⁵ )R ⁶ ; R ⁵ is C _0-10 alkylene-OH; R ⁶ is C _5-25 alkenyl; Y ^a is O-Y ^b ; Y ^b is H; Y ^d is O-Y ^e ; and Y ^e is H.

According to some embodiments, R ¹ is OH or CH ₂ CH ₂ -R ²¹ ; R ² comprises at least 6 carbon atoms and is represented by CH ₂ CH ₂ -R ²² ; R ³ is CH ₂ CH ₂ -R ²³ ; R ⁴ comprises at least 6 carbon atoms and is represented by CH ₂ CH ₂ -R ²⁴ ; none of R ¹ , R ² , R ³ , and R ⁴ is H; so the lipid is further represented by the structure of Formula (I’):

R ²¹ is selected from the group consisting of: C _0-8 alkylene- Y ^a , C _2-4 alkenylene- Y ^a , C _1-2 alkyl, C _3-25 alkyl, C _5-23 alkenyl, C _3-23 alkynyl, C _3-13 alkylene-CO ₂ -C _5-15 alkyl, C _3-13 alkylene-CO ₂ - -C _5-15 alkenyl, C _3-13 alkylene-O ₂ C-C _5-15 alkyl, C _3-13 alkylene-O ₂ C-C _5-15 alkenyl, C _3-13 alkenylene-CO ₂ -C _5-15 alkyl, C _3-13 alkenylene-CO ₂ -C _5-15 alkenyl, C _3-13 alkenylene-O ₂ C-C _5-15 alkyl, and C _3-13 alkenylene-O ₂ C-C _5-15 alkenyl; R ²² is selected from the group consisting of: C _4-23 alkyl, C _4-23 alkenyl, C _4-23 alkynyl, C _3-13 alkylene-CO ₂ -C _5-15 alkyl, C _3-13 alkylene-CO ₂ -C _5-15 alkenyl, C _3-13 alkylene-O ₂ C-C _5-15 alkyl, C _3-13 alkylene-O ₂ C-C _5-15 alkenyl, C _3-13 alkenylene- -CO ₂ -C _5-15 alkyl, C _3-13 alkenylene-CO ₂ -C _5-15 alkenyl, C _3-13 alkenylene-O ₂ C-C _5-15 alkyl, C _3-13 alkenylene-O ₂ C-C _5-15 alkenyl, C _0-13 alkylene-CO ₂ -C _0-4 alkylene-N(C _1-12 alkyl) ₂ , C _0-13 alkylene- -CO ₂ -C _0-4 alkylene-NH-C _1-12 alkyl, C _0-13 alkylene-CO ₂ -C _0-4 alkylene-N(C _5-25 alkenyl) ₂ , C _0-13 alkylene-CO ₂ -C _0-4 alkylene-NH-C _5-25 alkenyl, C _0-13 alkylene-CO-NH-C _0-8 alkylene-N(C _1-12 alkyl) ₂ and C _3-13 alkylene-CO ₂ H; R ²³ is selected from the group consisting of: H, C _3-23 alkyl, C _3-23 alkenyl, C _3-23 alkynyl, C _3-13 alkylene-CO ₂ -C _5-15 alkyl, C _3-13 alkylene-CO ₂ -C _5-15 alkenyl, C _3-13 alkylene-O ₂ C-C _5-15 alkyl, C _3-13 alkylene-O ₂ C-C _5-15 alkenyl, C _3-13 alkenylene-CO ₂ -C _5-15 alkyl, C _3-13 alkenylene-CO ₂ -C _5-15 alkenyl, C _3-13 alkenylene-O ₂ C-C _5-15 alkyl, C _3-13 alkenylene- -O ₂ C-C _5-15 alkenyl, C _0-4 alkylene- Y ^d , C _0-4 alkenylene- Y ^d and C _1-2 alkyl; R ²⁴ is selected from the group consisting of: C _3-23 alkyl, C _3-23 alkenyl, C _3-23 alkynyl, C _3-13 alkylene-CO ₂ -C _5-15 alkyl, C3- 13 alkylene-CO ₂ -C _5-15 alkenyl, C _3-13 alkylene-O ₂ C-C _5-15 alkyl, C _3-13 alkylene-O ₂ C-C _5-15 alkenyl, C _3-13 alkenylene-CO ₂ -C _5-15 alkyl, C _3-13 alkenylene-CO ₂ -C _5-15 alkenyl, C _3-13 alkenylene-O ₂ C-C _5-15 alkyl, C _3-13 alkenylene-O ₂ C-C _5-15 alkenyl and C _3-13 alkylene-CO ₂ - C _5-15 alkylene-N(R ⁵ )R ⁶ .

According to some embodiments, R ²² is represented by CH ₂ CH ₂ -R ³² ; R ²⁴ is represented by CH ₂ CH ₂ -R ³⁴ ; so the lipid is further represented by the structure of Formula (I”):

R ³² is selected from the group consisting of: C _2-21 alkyl, C _2-21 alkenyl, C _2-21 alkynyl, C _1-11 alkylene-CO ₂ -C _5-15 alkyl, C _1-11 alkylene-CO ₂ -C _5-15 alkenyl, C _1-11 alkylene-O ₂ C-C _5-15 alkyl, C _1-11 alkylene-O ₂ C-C _5-15 alkenyl, C _2-11 alkenylene-CO ₂ -C _5-15 alkyl, C _2-11 alkenylene-CO ₂ - -C _5-15 alkenyl, C _2-11 alkenylene-O ₂ C-C _5-15 alkyl, C _2-11 alkenylene-O ₂ C-C _5-15 alkenyl, C _0-11 alkylene-CO ₂ -C _0-4 alkylene-N(C _1-12 alkyl) ₂ , C _0-11 alkylene-CO ₂ -C _0-4 alkylene-NH-C _1-12 alkyl, C _0-13 alkylene-CO ₂ -C _0-4 alkylene-N(C _5-25 alkenyl) ₂ , C _0-11 alkylene-CO ₂ -C _0-4 alkylene-NH- -C _5-25 alkenyl, C _0-11 alkylene-CO-NH-C _0-4 alkylene-N(C _1-12 alkyl) ₂ and C _1-11 alkylene-CO ₂ H: and R ³⁴ is selected from the group consisting of: C _1-21 alkyl, C _2-21 alkenyl, C _2-21 alkynyl, C _1-11 alkylene-CO ₂ -C _5-15 alkyl, C _1-11 alkylene-CO ₂ -C _5-15 alkenyl, C _1-11 alkylene-O ₂ C-C _5-15 alkyl, — C _1-11 alkylene-O ₂ C-C _5-15 alkenyl, C _2-11 alkenylene-CO ₂ -C _5-15 alkyl, C _2-11 alkenylene-CO ₂ - -C _5-15 alkenyl, C _2-11 alkenylene-O ₂ C-C _5-15 alkyl, C _2-11 alkenylene-O ₂ C-C _5-15 alkenyl and C _1-11 alkylene-CO ₂ -C _5-15 alkylene-N(R ⁵ )R ⁶ .

According to some embodiments, R ³² is represented by CH ₂ (CH ₂ ) ₆ -R ⁴² ; R ³⁴ is represented by CH ₂ (CH ₂ )-R ⁴⁴ ; so the lipid is further represented by the structure of Formula (I’”):

R ⁴² is selected from the group consisting of: H, C _1-17 alkyl, C _2-17 alkenyl, C _2-17 alkynyl, C _0-7 alkylene-CO ₂ -C _5-15 alkyl, C _0-7 alkylene-CO ₂ -C _5-15 alkenyl, C _0-7 alkylene-O ₂ C-C _5-15 alkyl, C _0-7 alkylene-O ₂ C-C _5-15 alkenyl, C _2-7 alkenylene-CO ₂ -C _5-15 alkyl, C _2-7 alkenylene-CO ₂ -C _5-15 alkenyl, C _2-7 alkenylene-O ₂ C-C _5-15 alkyl, C _2-7 alkenylene-O ₂ C-C _5-15 alkenyl, C _0-11 alkylene- -CO ₂ -C _0-4 alkylene-N(C _1-12 alkyl)2, C _0-7 alkylene-CO ₂ -C _0-4 alkylene-NH-C _1-12 alkyl, C _0-7 alkylene-CO ₂ -C _0-4 alkylene-N(C _5-25 alkenyl) ₂ , C _0-7 alkylene-CO ₂ -C _0-4 alkylene-NH-C _5-25 alkenyl, C _0-7 alkylene-CO-NH-C _0-4 alkylene-N(C _1-12 alkyl) ₂ and C _0-7 alkylene-CO ₂ H; and R ⁴⁴ is selected from the group consisting of: H, C _1-17 alkyl, C _2-17 alkenyl, C _2-17 alkynyl, C _0-7 alkylene- -CO ₂ -C _5-15 alkyl, C _0-7 alkylene-CO ₂ -C _5-15 alkenyl, C _0-7 alkylene-O ₂ C-C _5-15 alkyl, C _0-7 alkylene-O ₂ C-C _5-15 alkenyl, C _2-7 alkenylene-CO ₂ -C _5-15 alkyl, C _2-7 alkenylene-CO ₂ -C _5-15 alkenyl, C _2-7 alkenylene-O ₂ C-C _5-15 alkyl, C _2-7 alkenylene-O ₂ C-C _5-15 alkenyl and C _0-7 alkylene- CO ₂ -C _5-15 alkylene-N(R ⁵ )R ⁶ .

According to some embodiments, R ¹ and R ² collectively have at least 9 carbon atoms, and R ³ and R ⁴ collectively have at least 9 carbon atoms. According to some embodiments, each one of L ^a and L ^b is C _0-4 alkylene or C _4-20 alkylene and at least one of L ^a and L ^b is C _3-15 alkylene. According to some embodiments, each one of L ^a and L ^b is C _0-20 alkylene and at least one of L ^a and L ^b is C _3-15 alkylene. According to some embodiments, each one of L ^a and L ^b is individually a C3-20 alkylene. According to some embodiments, R ¹ is selected from the group consisting of: C _5-15 alkyl, C _5-15 alkenyl, C _5-10 alkylene-CO ₂ -C _5-10 alkyl, C _1-3 alkylene-OH, C _1-3 alkylene-O-CH ₂ CH ₂ -OH, OH, C _1-3 alkylene-halogen, C _1-3 alkylene-PO ₃ H ₂ , methyl, ethyl, propyl and C _1-3 alkylene-NH ₂ ; R ² is selected from the group consisting of: C _5-15 alkyl, C _5-15 alkenyl, C _2-12 alkylene-CO ₂ H, C _5-10 alkylene-CO ₂ -C _5-10 alkenyl, C _5-10 alkylene-CO ₂ -C _5-10 alkyl and L-N(R3)-R ₄ ; R ³ is selected from the group consisting of: H, C _5-15 alkyl and C _5-15 alkenyl, C _1-3 alkylene-OH, OH, C _1-3 alkylene- -halogen, C _1-3 alkylene-PO ₃ H ₂ , methyl, ethyl, propyl, and C _1-3 alkylene-NH ₂ ; and R ⁴ is selected from the group consisting of: C _8-18 alkyl, C _8-18 alkenyl, and C _5-10 alkylene-CO ₂ -C _5-10 alkenyl. According to some embodiments, R ¹ is selected from the group consisting of: C _1-3 alkylene-OH, OH, C _1-3 alkylene-halogen, C _1-3 alkylene-PO ₃ H ₂ , methyl, ethyl, propyl and C _1-3 alkylene-NH ₂ ; R ² is selected from the group consisting of: C _8-18 alkyl, C _8-18 alkenyl, C _5-10 alkylene-CO ₂ -C _5-10 alkenyl and L-N(R3)-R ₄ ; R ³ is selected from the group consisting of: C _1-3 alkylene-OH, OH, C _1-3 alkylene-halogen, C _1-3 alkylene-PO ₃ H ₂ , methyl, ethyl, propyl, and C _1-3 alkylene-NH ₂ ; and R ⁴ is selected from the group consisting of: C _8-18 alkyl, C _8-18 alkenyl, and C _5-10 alkylene-CO ₂ - -C _5-10 alkenyl.

According to some embodiments, R ¹ is selected from the group consisting of: C _8-18 alkyl, C _8-18 alkenyl; C _1-3 alkylene-OH, C _1-3 alkylene-O-CH ₂ CH ₂ -OH, C _1-3 alkylene-Cl, C _1-3 alkylene-NH ₂ , OH and C _1-3 alkylene-PO ₃ H ₂ ; R ² is selected from the group consisting of: C _5-15 alkyl, C _5-15 alkenyl, C _2-12 alkylene-CO ₂ H, L-N(R3)-R ₄ , and C _5-10 alkylene-CO ₂ - -C _5-10 alkenyl; R ³ is selected from the group consisting of: H, C _5-15 alkyl and C _5-15 alkenyl; and R ⁴ is selected from the group consisting of: C _5-15 alkyl, C _5-15 alkenyl.

According to some embodiments, R ¹ is selected from the group consisting of: C _5-15 alkyl and C _8-18 alkenyl and C _5-10 alkylene-CO ₂ -C _5-10 alkyl; R ² is selected from the group consisting of: C _8-18 alkyl, C _8-18 alkenyl and C _5-10 alkylene-CO ₂ -C _5-10 alkyl; R ³ is selected from the group consisting of: H and C _8-18 alkyl and C _8-18 alkenyl; and R ⁴ is a C _8-18 alkyl.

According to some embodiments, L is L ¹ -X ¹ - L ² ; X ¹ is selected from the group consisting of: -O ₂ C-, -CO ₂ -L ³ -O ₂ C-, -O ₂ C-L ³ -CO ₂ -, -CO ₂ -L ³ -CO ₂ -, L ³ -CO ₂ - and L ³ -O ₂ C-; each one of L ¹ and L ² is independently selected from the group consisting of: C _4-20 alkylene and C _4-20 alkenylene; L ³ is selected from the group consisting of: C _1-6 alkylene-(O-C _1-6 alkylene) _n -, C _2-6 alkenylene-(O-C _1-6 alkylene) _m -, C _1-6 alkylene-S-C _1-6 alkylene and C _1-6 alkylene-S-S-C _1-6 alkylene; each one of n and m is 0, 1, 2, 3, 4 or 5; R ¹ is selected from the group consisting of: C _0-6 alkylene-Y ¹ , C _2-6 alkenylene-Y ¹ and C _1-4 alkyl; R ² is selected from the group consisting of: C _5-25 alkyl, C _5-25 alkenyl, C _5-15 alkylene-CO ₂ -C _5-15 alkyl, C _5-15 alkylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkylene-O ₂ C-C _5-15 alkyl, C _5-15 alkylene-O ₂ C-C _5-15 alkenyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkenylene-O ₂ C-C _5-15 alkyl, C _5-15 alkenylene- -O ₂ C-C _5-15 alkenyl, C _2-15 alkylene-CO ₂ -C _0-4 alkylene-N(C _1-12 alkyl) ₂ , and C _5-15 alkylene-O ₂ C- C _5-15 alkylene-N(C _1-12 alkyl) ₂ ; R ³ is selected from the group consisting of: C _0-6 alkylene-Y ¹ , C _2-6 alkenylene-Y ¹ , and C _1-4 alkyl; R ⁴ is selected from the group consisting of: C _5-25 alkyl, C _5-25 alkenyl, C _5-15 alkylene-CO ₂ -C _5-15 alkyl, C _5-15 alkylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkylene-O ₂ C- -C _5-15 alkyl, C _5-15 alkylene-O ₂ C-C _5-15 alkenyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkenylene-O ₂ C-C _5-15 alkyl and C _5-15 alkenylene-O ₂ C- -C _5-15 alkenyl; each Y ¹ is selected from the group consisting of: O-Y ² , halogen, PO ₃ H ₂ , PO ₃ (C _1-4 alkyl) ₂ , PO ₃ H(C _1-4 alkyl), NH ₂ , NMe2, and NH-Y ² ; and Y ² is selected from the group consisting of: H, C _1-4 alkyl, C _1-4 alkylene-OH, PO ₃ H ₂ , PO ₃ (C _1-4 alkyl) ₂ , PO ₃ H(C _1-4 alkyl), CO- -C _1-4 alkyl, CO-aryl, SO ₃ H, SO ₃ -(C _1-4 alkyl) and SO ₃ -aryl; or

L is L ⁴ -X ² -L ⁵ ; X ² is selected from the group consisting of: -O ₂ C-, -CO ₂ -L ⁶ -O ₂ C- -O ₂ C-L ⁶ -CO ₂ -, -CO ₂ -L ⁶ -CO ₂ -, L ⁶ -CO ₂ -, L ⁶ -O ₂ C- and -CO-NH-; L ⁴ is a C _0-4 alkylene; L ⁵ is selected from the group consisting of: C ₂ -20 alkylene and C _4-20 alkenylene; L ⁶ is selected from the group consisting of: C _1-6 alkylene-(O-C _1-6 alkylene)j-, C _2-6 alkenylene-(O-C _1-6 alkylene)k-, C _1-6 alkylene-S-C _1-6 alkylene and C _1-6 alkylene-S-S-C _1-6 alkylene; each one of j and k is 0, 1, 2, 3, 4 or 5; R ¹ is selected from the group consisting of: C _0-10 alkylene- Y ³ , C _2-6 alkenylene- Y ³ and C _1-4 alkyl; R ² is selected from the group consisting of: C _5-25 alkyl, C _5-25 alkenyl, C _5-15 alkylene-CO ₂ -C _5-15 alkyl, C _5-15 alkylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkylene-O ₂ C-C _5-15 alkyl, C _5-15 alkylene-O ₂ C-C _5-15 alkenyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkyl, C _5-15 alkenylene-CO ₂ - -C _5-15 alkenyl, C _5-15 alkenylene-O ₂ C-C _5-15 alkyl, C _5-15 alkenylene-O ₂ C-C _5-15 alkenyl, C _5-15 alkylene-CO ₂ H, C _2-15 alkylene-CO ₂ -C _0-4 alkylene-N(C _1-12 alkyl) ₂ , C _2-15 alkylene-CO ₂ -C _0-4 alkylene-NH-C _5-25 alkenyl, C _2-15 alkylene-CO ₂ -C _0-4 alkylene-N(C _5-25 alkenyl) ₂ , C _2-15 alkylene- — CO— NH— C _0-4 alkylene-N(C _1-12 alkyl) ₂ and C _2-15 alkylene-CO ₂ -C _0-4 alkylene-NH-C _1-12 alkyl; R ³ is selected from the group consisting of: H, C _5-25 alkyl, C _5-25 alkenyl, C _5-15 alkylene-CO ₂ - -C _5-15 alkyl, C _5-15 alkylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkylene-O ₂ C-C _5-15 alkyl, C _5-15 alkylene- -O ₂ C-C _5-15 alkenyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkyl, C _5-15 alkenylene-CO ₂ - -C _5-15 alkenyl, C _5-15 alkenylene-O ₂ C-C _5-15 alkyl and C _5-15 alkenylene-O ₂ C-C _5-15 alkenyl; R ⁴ is selected from the group consisting of: C _5-25 alkyl, C _5-25 alkenyl, C _5-15 alkylene-CO ₂ -C _5-15 alkyl, C _5-15 alkylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkylene-O ₂ C-C _5-15 alkyl, C _5-15 alkylene-O ₂ C-C _5-15 alkenyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkenylene-O ₂ C-C _5-15 alkyl, and C _5-15 alkenylene-O ₂ C-C _5-15 alkenyl; Y ³ is selected from the group consisting of: O-Y ⁴ , halogen, PO ₃ H ₂ , PO ₃ (C _1-4 alkyl) ₂ , PO ₃ H(C _1-4 alkyl), NH ₂ , and NH- -Y ⁴ ; Y ⁴ is selected from the group consisting of: H, C _1-4 alkyl, C _1-4 alkylene-OH, C _1-4 alkylene- (O-C _1-4 alkylene) _1-3 -OH, PO ₃ H ₂ , PO ₃ (C _1-4 alkyl) ₂ , PO ₃ H(C _1-4 alkyl), CO-C _1-4 alkyl, CO-aryl, CO-C _1-4 alkyl-N(CH ₃ ) ₂ , SO ₃ H, SO ₃ -(C _1-4 alkyl), NMe ₂ , CO-C _1-4 alkyl-NM ₂ and SO ₃ -aryl; or

L is L ⁷ -X ³ -L ⁸ ; X ³ is selected from the group consisting of: -O ₂ C-, -CO ₂ -NH-, -CO ₂ -L ⁹ -O ₂ C- -O ₂ C-L ⁹ -CO ₂ -, -CO ₂ -L ⁹ -CO ₂ - and L ⁹ -CO ₂ -, L ⁹ -O ₂ C-; L ⁷ is a C _0-4 alkylene; L ⁸ is a C _0-4 alkylene or C _4-20 alkylene; L ⁹ is selected from the group consisting of: C _0-4 alkylene-aryl-C _0-4 alkylene, C _1-4 alkylene, C _1-6 alkylene-(O-C _1-6 alkylene)h-, C _2-6 alkenylene-(O-C _1-6 alkylene);-, C _1-6 alkylene-S-C _1-6 alkylene, and C _1-6 alkylene-S-S-C _1-6 alkylene; each one of h and i is 0, 1, 2, 3, 4 or 5; R ¹ is selected from the group consisting of: C _5-25 alkyl, C _5-25 alkenyl and C _0-10 alkylene-O-CO-C _1-4 alkyl-N(CH ₃ ) ₂ ; each one of R ² and R ⁴ is independently selected from the group consisting of: C _5-25 alkyl and C _5-25 alkenyl; and R ³ is selected from the group consisting of: H, C _5-25 alkyl, and C _5-25 alkenyl.

According to some embodiments, L is L ¹ -X ¹ -L ² ; X ¹ is selected from the group consisting of: -O ₂ C-, -CO ₂ -L ³ -O ₂ C-, -O ₂ C-L ³ -CO ₂ -, -CO ₂ -L ³ -CO ₂ -, L ³ -CO ₂ - and L ³ -O ₂ C-; each one of L ¹ and L ² is selected from the group consisting of: C _4-20 alkylene and C _4-20 alkenylene; L ³ is selected from the group consisting of: C _1-6 alkylene-(O-C _1-6 alkylene) _n -, C _2-6 alkenylene-(O- -C _1-6 alkylene) _m -, C _1-6 alkylene-S-C _1-6 alkylene and C _1-6 alkylene-S-S-C _1-6 alkylene; each one of n and m is 0, 1, 2, 3, 4 or 5; R ¹ is selected from the group consisting of: C _0-6 alkylene-Y ¹ , C _2-6 alkenylene-Y ¹ and C _1-4 alkyl; R ² is selected from the group consisting of: C _5-25 alkyl, C _5-25 alkenyl, C _5-15 alkylene-CO ₂ -C _5-15 alkyl, C _5-15 alkylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkylene-O ₂ C- -C _5-15 alkyl, C _5-15 alkylene-O ₂ C-C _5-15 alkenyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkenylene-O ₂ C-C _5-15 alkyl, C _5-15 alkenylene-O ₂ C-C _5-15 alkenyl, C _2-15 alkylene-CO ₂ — C _0-4 alkylene-N(C _1-12 alkyl) ₂ , and C _5-15 alkylene-O ₂ C-C _5-15 alkylene-N(C _1-12 alkyl) ₂ ; R ³ is selected from the group consisting of: C _0-6 alkylene-Y ¹ , C _2-6 alkenylene-Y ¹ , and C _1-4 alkyl; R ⁴ is selected from the group consisting of: C _5-25 alkyl, C _5-25 alkenyl, C _5-15 alkylene-CO ₂ -C _5-15 alkyl, C _5-15 alkylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkylene-O ₂ C- -C _5-15 alkyl, C _5-15 alkylene-O ₂ C-C _5-15 alkenyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkenylene-O ₂ C-C _5-15 alkyl, C _5-15 alkenylene-O ₂ C-C _5-15 alkenyl and C _5-15 alkylene-CO ₂ -C _5-15 alkylene-N(R ⁵ )R ⁶ ; each Y ¹ is selected from the group consisting of: O-Y ² , halogen, PO ₃ H ₂ , PO ₃ (C _1-4 alkyl) ₂ , PO ₃ H(C _1-4 alkyl), NH ₂ , NMe2, and NH- -Y ² ; and Y ² is selected from the group consisting of: H, C _1-4 alkyl, C _1-4 alkylene-OH, PO ₃ H ₂ , PO ₃ (C _1-4 alkyl) ₂ , PO ₃ H(C _1-4 alkyl), CO-C _1-4 alkyl, CO-aryl, SO ₃ H, SO ₃ -(C _1-4 alkyl) and SO ₃ - -aryl. According to some embodiments, X ¹ is selected from the group consisting of: -O ₂ C- and -CO ₂ -L ³ -O ₂ C-; each one of L ¹ and L ² is C _5-15 alkylene; L ³ is C _1-4 alkylene-; R ¹ is C _0-4 alkylene- -Y ¹ ; R ² is selected from the group consisting of: C ₉ -20 alkyl and C ₉ -20 alkenyl; R ³ is C _1-4 alkylene- Y ¹ ; R ⁴ is selected from the group consisting of: C _5-25 alkyl, C _5-25 alkenyl, C _5-15 alkylene-CO ₂ - -C _5-15 alkylene-N(R ⁵ )R ⁶ ; and each Y ¹ is OH.

It is to be understood that the phrase “each Y ¹ is selected from the group consisting of’ refers to the situation wherein R ¹ may be C _0-6 alkylene-Y ¹ or C _2-6 alkenylene-Y ¹ , and R ³ may be C _0-6 alkylene-Y ¹ , C _2-6 alkenylene-Y ¹ , and it is intended to mean that in cases that Y ¹ appears in both R ¹ and R ³ , each of these Y ¹ substituents may be independently selected from the Y ¹ group. In other words, in cases that Y ¹ appears in both R ¹ and R ³ , the two Y ¹ substituents may be the same or different.

According to some embodiments, L is L- ¹ X ¹ -L ² , and is selected from the group consisting of: C _6-15 alkylene-O ₂ C-C _6-15 alkylene, C _4-15 alkylene-CO ₂ -C _1-3 alkylene-(O-C _º-3 alkylene) _n -O ₂ C-C4- 15 alkylene, and C _4-15 alkylene-CO ₂ -C _1-4 alkylene-S-S-C _1-4 alkylene-O ₂ C-C4-i5 alkylene; wherein n is 0 1 or 2.

According to some embodiments, R ¹ is selected from the group consisting of: CH ₂ CH ₂ PO ₃ H ₂ , CH ₂ CH ₂ CI, CH ₂ CH ₂ OH, CH ₃ , OH and C _1-3 alkyl. According to some embodiments, R ² is selected from the group consisting of: C _8-16 alkyl, C _8-20 alkenyl and L-N(R ³ )-R ⁴ . According to some embodiments, R ² is the same as R ⁴ . According to some embodiments, R ³ is selected from the group consisting of: CH ₂ CH ₂ PO ₃ H ₂ , CH ₂ CH ₂ CI, CH ₂ CH ₂ OH, CH ₃ , OH and C _1-3 alkyl. According to some embodiments, R ¹ is the same as R ³ . According to some embodiments, R ⁴ is selected from the group consisting of: C _8-16 alkyl, C _8-20 alkenyl, and C _8-12 alkylene-CO ₂ -C _8-12 alkenyl.

According to some embodiments, L is L ⁴ -X ² -L ⁵ ; X ² is selected from the group consisting of: -O ₂ C-, -CO ₂ -L ⁶ -O ₂ C-, -O ₂ C-L ⁶ -CO ₂ -, -CO ₂ -L ⁶ -CO ₂ -, L ⁶ -CO ₂ -, L ⁶ -O ₂ C- and -CO-NH-; L ⁴ is a C _0-4 alkylene; L ⁵ is selected from the group consisting of: C ₂ -20 alkylene and C _4-20 alkenylene; L ⁶ is selected from the group consisting of: C _1-6 alkylene-(O-C _1-6 alkylene)j-, C _2-6 alkenylene-(O-C _1-6 alkylene)k-, C _1-6 alkylene-S-C _1-6 alkylene and C _1-6 alkylene-S-S-C _1-6 alkylene; each one of j and k is 0, 1, 2, 3, 4 or 5; R ¹ is selected from the group consisting of: C _0-10 alkylene- Y ³ , C _2-6 alkenylene- Y ³ and C _1-4 alkyl; R ² is selected from the group consisting of: C _5-25 alkyl, C _5-25 alkenyl, C _5-15 alkylene-CO ₂ -C _5-15 alkyl, C _5-15 alkylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkylene-O ₂ C-C _5-15 alkyl, C _5-15 alkylene-O ₂ C-C _5-15 alkenyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkenylene-O ₂ C-C _5-15 alkyl, C _5-15 alkenylene-O ₂ C- -C _5-15 alkenyl, C _5-15 alkylene-CO ₂ H, C _2-15 alkylene-CO ₂ -C _0-4 alkylene-N(C _1-12 alkyl) ₂ , C _2-15 alkylene-CO ₂ -C _0-4 alkylene-NH-C _5-25 alkenyl, C _2-15 alkylene-CO ₂ -C _0-4 alkylene-N(C _5-25 alkenyl) ₂ , C _2-15 alkylene-CO-NH-C _0-4 alkylene-N(C _1-12 alkyl) ₂ and C _2-15 alkylene-CO ₂ -C _0-4 alkylene-NH-C 1 -12 alkyl; R ³ is selected from the group consisting of: H, C _5-25 alkyl, C _5-25 alkenyl, C _5-15 alkylene-CO ₂ -C _5-15 alkyl, C _5-15 alkylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkylene-O ₂ C-C _5-15 alkyl, C _5-15 alkylene-O ₂ C-C _5-15 alkenyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkyl, C _5-15 alkenylene- CO ₂ -C _5-15 alkenyl, C _5-15 alkenylene-O ₂ C-C _5-15 alkyl and C _5-15 alkenylene-O ₂ C-C _5-15 alkenyl; R ⁴ is selected from the group consisting of: C _5-25 alkyl, C _5-25 alkenyl, C _5-15 alkylene-CO ₂ -C _5-15 alkyl, C _5-15 alkylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkylene-O ₂ C-C _5-15 alkyl, C _5-15 alkylene-O ₂ C- -C _5-15 alkenyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkenylene-O ₂ C-C _5-15 alkyl, and C _5-15 alkenylene-O ₂ C-C _5-15 alkenyl; Y ³ is selected from the group consisting of: O-Y ⁴ , halogen, PO ₃ H ₂ , PO ₃ (C _1-4 alkyl) ₂ , PO ₃ H(C _1-4 alkyl), NH ₂ , and NH- Y ⁴ ; and Y ⁴ is selected from the group consisting of: H, C _1-4 alkyl, C _1-4 alkylene-OH, C _1-4 alkylene-(O-C _1-4 alkylene) _1-3 -OH, PO ₃ H ₂ , PO ₃ (C _1-4 alkyl) ₂ , PO ₃ H(C _1-4 alkyl), CO-C _1-4 alkyl, CO-aryl, CO-C _1-4 alkyl-N(CH ₃ ) ₂ , SO ₃ H, SO ₃ -(C _1-4 alkyl), NMe ₂ , CO-C _1-4 alkyl-NM ₂ and SO ₃ - aryl.

According to some embodiments, X ² is -O ₂ C-; L ⁴ is a C _0-4 alkylene or C _4-20 alkylene; L ⁵ is a C _4-20 alkylene; R ¹ is C _0-10 alkylene- Y ³ ; R ² is selected from the group consisting of: C _5-25 alkyl, C _5-25 alkenyl and C _2-15 alkylene-CO ₂ -C _0-4 alkylene-N(C _1-12 alkyl) ₂ ; R ³ is a C _5-25 alkyl; R ⁴ is a C _5-25 alkyl; Y ³ is O-Y ^b ; and Y ⁴ is H.

According to some embodiments, L is L ⁴ -X ² -L ⁵ ; X ² is selected from the group consisting of: -O ₂ C-, -CO ₂ -L ⁶ -O ₂ C-, -O ₂ C-L ⁶ -CO ₂ -, -CO ₂ -L ⁶ -CO ₂ -, L ⁶ -CO ₂ -, L ⁶ -O ₂ C- and -CO-NH-; L ⁴ is a C _0-4 alkylene; L ⁵ is selected from the group consisting of: C _4-20 alkylene and C _4-20 alkenylene; L ⁶ is selected from the group consisting of: C _1-6 alkylene-(O-C _1-6 alkylene)j-, C _2-6 alkenylene-(O-C _1-6 alkylene)k-, C _1-6 alkylene-S-C _1-6 alkylene and C _1-6 alkylene-S-S-C _1-6 alkylene; each one of j and k is 0, 1, 2, 3, 4 or 5; R ¹ is selected from the group consisting of: C _0-10 alkylene- Y ³ , C _2-6 alkenylene- Y ³ and C _1-4 alkyl; R ² is selected from the group consisting of: C _5-25 alkyl, C _5-25 alkenyl, C _5-15 alkylene-CO ₂ -C _5-15 alkyl, C _5-15 alkylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkylene-O ₂ C-C _5-15 alkyl, C _5-15 alkylene-O ₂ C-C _5-15 alkenyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkenylene-O ₂ C-C _5-15 alkyl, C _5-15 alkenylene-O ₂ C- -C _5-15 alkenyl, C _5-15 alkylene-CO ₂ H and L-N(R ³ )-R ⁴ ; R ³ is selected from the group consisting of: H, C _5-25 alkyl, C _5-25 alkenyl, C _5-15 alkylene-CO ₂ -C _5-15 alkyl, C _5-15 alkylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkylene-O ₂ C-C _5-15 alkyl, C _5-15 alkylene-O ₂ C-C _5-15 alkenyl, C _5-15 alkenylene- -CO ₂ -C _5-15 alkyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkenylene-O ₂ C-C _5-15 alkyl and C _5-15 alkenylene-O ₂ C-C _5-15 alkenyl; R ⁴ is selected from the group consisting of: C _5-25 alkyl, C _{5- 25} alkenyl, C _5-15 alkylene-CO ₂ -C _5-15 alkyl, C _5-15 alkylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkylene- -O ₂ C-C _5-15 alkyl, C _5-15 alkylene-O ₂ C-C _5-15 alkenyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkenylene-O ₂ C-C _5-15 alkyl, and C _5-15 alkenylene-O ₂ C- -C _5-15 alkenyl; Y ³ is selected from the group consisting of: O-Y ⁴ , halogen, PO ₃ H ₂ , PO ₃ (C _1-4 alkyl) ₂ , PO ₃ H(C _1-4 alkyl), NH ₂ , and NH-Y ⁴ ; Y ⁴ is selected from the group consisting of: H, C _1-4 alkyl, C _1-4 alkylene-OH, PO ₃ H ₂ , PO ₃ (C _1-4 alkyl) ₂ , PO ₃ H(C _1-4 alkyl), CO-C _1-4 alkyl, CO-aryl, SO ₃ H, SO ₃ -(C _1-4 alkyl) and SO ₃ -aryl. According to some embodiments, L selected from the group consisting of: -O ₂ C-C _6-12 alkylene, C _1-3 alkylene-CO ₂ -C _1-3 alkylene-S-S-C _1-3 alkylene-O ₂ C- -C _4-10 alkylene, C _1-3 alkylene-CO ₂ -C _6-12 alkylene, C _1-3 alkylene-O-C _1-3 alkylene-O ₂ C-C _6-12 alkylene, and C _1-3 alkylene-NHCO-C _6-12 alkylene. According to some embodiments, R ¹ is selected from the group consisting of: CH ₂ CH ₂ OH, CH ₂ CH ₂ OCH ₂ CH ₂ OH, CH ₂ CH ₂ CI, OH, CH ₂ CH ₂ PO ₃ H ₂ , and CH ₂ CH ₂ NH ₂ . According to some embodiments, R ² is selected from the group consisting of: C _8-16 alkyl, C _8-20 alkenyl, C _6-12 alkylene-CO ₂ -C _6-12 alkenyl, C _6-12 alkylene-CO ₂ H, and L-N(R ³ )-R ⁴ . According to some embodiments, R ³ is selected from the group consisting of: H, C _6-16 alkyl, and C _6-16 alkenyl. According to some embodiments, R ³ is the same as R ⁴ . According to some embodiments, R ⁴ is selected from the group consisting of: C _6-16 alkyl, C _6-16 alkenyl.

According to some embodiments, L is L ⁷ -X ³ -L ⁸ ; X ³ is selected from the group consisting of: -O ₂ C-, -CO ₂ -NH-, -CO ₂ -L ⁹ -O ₂ C-, -O ₂ C-L ⁹ -CO ₂ -, -CO ₂ -L ⁹ -CO ₂ - and L ⁹ -CO ₂ -, L ⁹ -O ₂ C-; L ⁷ is a C _0-4 alkylene; L ⁸ is a C _0-4 alkylene or C _4-20 alkylene; L ⁹ is selected from the group consisting of: C _0-4 alkylene-aryl-C _0-4 alkylene, C _1-4 alkylene, C _1-6 alkylene-(O-C _1-6 alkylene)h-, C _2-6 alkenylene-(O-C _1-6 alkylene);-, C _1-6 alkylene-S-C _1-6 alkylene, and C _1-6 alkylene-S-S-C _1-6 alkylene; each one of h and i is 0, 1, 2, 3, 4 or 5; R ¹ is selected from the group consisting of: C _5-25 alkyl, C _5-25 alkenyl and C _0-10 alkylene-O-CO-C _1-4 alkyl-N(CH ₃ ) ₂ ; each one of R ² and R ⁴ is independently selected from the group consisting of: C _5-25 alkyl and C _5-25 alkenyl; and R ³ is selected from the group consisting of: H, C _5-25 alkyl, and C _5-25 alkenyl. According to some embodiments, X ³ is-O ₂ C-; L ⁷ is a C _0-4 alkylene; L ⁸ is a C _0-4 alkylene; R ¹ is C _5-25 alkyl; and each one of R ¹ , R ² , R ³ and R ⁴ is a C _5-25 alkyl.

According to some embodiments, L is L ⁷ -X ³ -L ⁸ ; X ³ is selected from the group consisting of: -O ₂ C-, -CO ₂ -L ⁹ -O ₂ C-, -O ₂ C-L ⁹ -CO ₂ -, -CO ₂ -L ⁹ -CO ₂ - and L ⁹ -CO ₂ -, L ⁹ -O ₂ C-; L ⁷ is a C _0-4 alkylene; L ⁸ is a C _0-4 alkylene; L ⁹ is selected from the group consisting of: C _0-4 alkylene-aryl-C _0- 4 alkylene, C _1-4 alkylene, C _1-6 alkylene-(O-C _1-6 alkylene)h-, C _2-6 alkenylene-(O-C _1-6 alkylene);- , C _1-6 alkylene-S-C _1-6 alkylene and C _1-6 alkylene-S-S-C _1-6 alkylene; each one of h and i is 0, 1, 2, 3, 4 or 5; and each one of R ¹ , R ² and R ³ is independently selected from the group consisting of: C _5-25 alkyl, C _5-25 alkenyl, C _5-15 alkylene-CO ₂ -C _5-15 alkyl, C _5-15 alkylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkylene-O ₂ C-C _5-15 alkyl, C _5-15 alkylene-O ₂ C-C _5-15 alkenyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkenylene-O ₂ C-C _5-15 alkyl, and C _5-15 alkenylene-O ₂ C-C _5-15 alkenyl; and R ⁴ is selected from the group consisting of: H, C _5-25 alkyl, C _5-25 alkenyl, C _5-15 alkylene-CO ₂ -C _5-15 alkyl, C _5-15 alkylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkylene- O ₂ C-C _5-15 alkyl, C _5-15 alkylene-O ₂ C-C _5-15 alkenyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkenylene-O ₂ C-C _5-15 alkyl, and C _5-15 alkenylene-O ₂ C- -C _5-15 alkenyl.

According to some embodiments, L is selected from the group consisting of C _1-4 alkylene-CO ₂ - C _1-4 alkylene, C _1-4 alkylene-CO ₂ -, O ₂ C-C _1-3 alkylene-C ₆ H4-C _0-4 alkylene-CO ₂ , C _1-4 alkylene- -O-C _1-4 alkylene-O ₂ C-C _1-4 alkylene, C _1-4 alkylene-O ₂ C-C _1-6 alkylene-CO ₂ -C _1-4 alkylene, O ₂ C-C _1-4 alkylene-S-S-C _1-4 alkylene-CO ₂ , and O ₂ C-C _1-6 alkylene-CO ₂ .

According to some embodiments, R ¹ is selected from the group consisting of: C _8-15 alkyl, C _8-20 alkenyl, and C _6-12 alkylene-O ₂ C-C _9-18 alkylene. According to some embodiments, R ² is selected from the group consisting of: C _8-15 alkyl, C _8-20 alkenyl, and C _6-12 alkylene-O ₂ C-Co-is alkylene.

According to some embodiments, R ³ is selected from the group consisting of: C _8-15 alkyl and C _8-20 alkenyl. According to some embodiments, R ⁴ is selected from the group consisting of: H, C _5-15 alkyl and C _8-20 alkenyl. According to some embodiments, R ⁴ is selected from the group consisting of: C _8-15 alkyl and C _8-20 alkenyl.

According to some embodiments, at least two of R ¹ , R ² , R ³ , and R ⁴ represent the same substituent. According to some embodiments, each of R ¹ , R ² , R ³ , and R ⁴ represents a different substituent.

According to some embodiments, the lipid is selected from the group consisting of: DSL1-1, DSL1-2, DSL1-3, DSL1-4, DSL1-5, DSL1-6, DSL1-7, DSL1-8, DSL1-9, DSL1-10, DSL1-11,

DSL1-12, DSL1-13, DSL1-14, DSL1-15, DSL1-16, DSL1-17, DSL1-18, DSL1-19, DSL1-20, DSL1-21, DSL1-22, DSL1-23, DSL1-24, DSL1-25, DSL1-26, DSL1-27, DSL1-28, DSL1-29, DSL1-30, DSL1-31, DSL1-32, DSL1-33, DSL1-34, DSL1-35, DSL1-36, DSL1-37, DSL1-38, DSL1-39, DSL1-40, DSL1-41, DSL1-42, DSL1-43, DSLl-4,4 DSL1-45, DSL1-46, DSL1-47, DSL1-48, DSL1-49, DSL1-50, DSL1-51, DSL1-52, DSL1-53, DSL1-54, DSL1-55, DSL1-56, DSL1-57, DSL1-58, DSL1-59, DSL1-60, DSL3c-l, DSL3c-2, DSL3c-3, DSL3c-4, DSL3c-5, DSL3c-6, DSL3c-7 and DSL3c-8, DSL2-1, DSL2-2, DSL2-3, DSL2-4, DSL2-5, DSL2-6, DSL2- 7, DSL2-8, DSL2-9, DSL2-10, DSL2-11, DSL2-12, DSL2-13, DSL2-14, DSL2-15, DSL2-16, DSL2-17, DSL2-18, DSL2-19, DSL2-20, DSL2-21, DSL2-22, DSL2-23, DSL2-24, DSL2-25,

DSL2-26, DSL2-27, DSL2-28, DSL2-29, DSL2-30, DSL2-31, DSL2-32, DSL2-33, DSL2-34, DSL2-35, DSL2-36, DSL2-37, DSL2-38, DSL2-39, DSL2-40, DSL2-41, DSL2-42, DSL2-43, DSL2-44, DSL2-45,DSL2-46, DSL2-47, DSL2-48, DSL2-49, DSL2-50, DSL2-51, DSL2-52, DSL2-53, DSL2-54, DSL2-55, DSL2-56, DSL2-57, DSL2-58, DSL2-59, DSL2-60, DSL2-61, DSL2-62, DSL2-63, DSL2-64, DSL2-65, DSL2-66, DSL2-67, DSL2-68, DSL2-69, DSL2-70, DSL2-71, DSL2-72, DSL4-1, DSL4-2, DSL4-3, DSL4-4, DSL4-5, DSL4-6, DSL4-7, DSL4-8, DSL4-9, DSL4-10, DSL4-11, DSL4-12, DSL4-13, DSL4-14 and DSL4-15. The chemical structures of each of the specific compound are detailed below in the “Exemplary Compounds” Section and in the claims.

According to some embodiments, the lipid is selected from the group consisting of: DSL1-1, DSL1-2, DSL1-3, DSL1-4, DSL1-5, DSL1-6, DSL1-7, DSL1-8, DSL1-9, DSL1-10, DSL1-11, DSL1-12, DSL1-13, DSL1-14, DSL1-15, DSL1-16, DSL1-17, DSL1-18, DSL1-19, DSL1-20, DSL1-21, DSL1-22, DSL1-23, DSL1-24, DSL1-25, DSL1-26, DSL1-27, DSL1-28, DSL1-29, DSL1-30, DSL1-31, DSL1-32, DSL1-33, DSL1-34, DSL1-35, DSL1-36, DSL1-37, DSL1-38, DSL1-39, DSL1-40, DSL1-41, DSL1-42, DSL1-43, DSLl-4,4 DSL1-45, DSL1-46, DSL1-47, DSL1-48, DSL1-49, DSL1-50, DSL1-51, DSL1-52, DSL1-53, DSL1-54, DSL3c-l, DSL3c-2, DSL3c-3, DSL3c-4, DSL3c-5, DSL3c-6, DSL3c-7 and DSL3c-8, DSL2-1, DSL2-2, DSL2-3, DSL2-4, DSL2-5, DSL2-6, DSL2-7, DSL2-8, DSL2-9, DSL2-10, DSL2-11, DSL2-12, DSL2-13, DSL2-14, DSL2-15, DSL2-16, DSL2-17, DSL2-18, DSL2-19, DSL2-20, DSL2-21, DSL2-22, DSL2-23, DSL2-24, DSL2-25, DSL2-26, DSL2-27, DSL2-28, DSL2-29, DSL2-30, DSL2-31, DSL2-32, DSL2-33, DSL2-34, DSL2-35, DSL2-36, DSL2-37, DSL2-38, DSL2-39, DSL2-40, DSL2-41, DSL2-42, DSL2-43, DSL2-44, DSL2-45,DSL2-46, DSL2-47, DSL2-48, DSL4-1, DSL4-2, DSL4-3, DSL4-4, DSL4-5, DSL4-6, DSL4-7, DSL4-8, DSL4-9, DSL4-10, DSL4-11, DSL4-12, DSL4-13, DSL4-14 and DSL4-15. According to some embodiments, the lipid is selected from the group consisting of: DSL1-1, DSL1-2, DSL1-3, DSL1-4, DSL1-5, DSL1-6, DSL1-7, DSL1-8, DSL1-9, DSL1-10, DSL1-11, DSL1-12, DSL1-13, DSL1-14, DSL1-15, DSL1- 16, DSL1-17, DSL1-18, DSL1-19, DSL1-20, DSL1-21, DSL1-22, DSL1-23, DSL1-24, DSL1-25, DSL1-26, DSL1-27, DSL1-28, DSL1-29, DSL1-30, DSL1-31, DSL1-32, DSL1-33, DSL1-34, DSL1-35, DSL1-36, DSL1-37, DSL1-38, DSL1-39, DSL1-40, DSL1-41, DSL1-42, DSL1-43, DSLl-4,4 DSL1-45, DSL1-46, DSL1-47, DSL1-48, DSL1-49, DSL1-50, DSL1-51, DSL1-52, DSL1-53, DSL1-54, DSL2-55, DSL2-56, DSL2-57, DSL2-58, DSL2-59, DSL2-60, DSL3c-l, DSL3c-2, DSL3c-3, DSL3c-4, DSL3c-5, DSL3c-6, DSL3c-7 and DSL3c-8. According to some embodiments, the lipid is selected from the group consisting of: DSL1-1, DSL1-2, DSL1-3, DSL1- 4, DSL1-5, DSL1-6, DSL1-7, DSL1-8, DSL1-9, DSL1-10, DSL1-11, DSL1-12, DSL1-13, DSL1- 14, DSL1-15, DSL1-16, DSL1-17, DSL1-18, DSL1-19, DSL1-20, DSL1-21, DSL1-22, DSL1-23, DSL1-24, DSL1-25, DSL1-26, DSL1-27, DSL1-28, DSL1-29, DSL1-30, DSL1-31, DSL1-32, DSL1-33, DSL1-34, DSL1-35, DSL1-36, DSL1-37, DSL1-38, DSL1-39, DSL1-40, DSL1-41, DSL1-42, DSL1-43, DSLl-4,4 DSL1-45, DSL1-46, DSL1-47, DSL1-48, DSL1-49, DSL1-50, DSL1-51, DSL1-52, DSL1-53, DSL1-54, DSL3c-l, DSL3c-2, DSL3c-3, DSL3c-4, DSL3c-5, DSL3c-6, DSL3c-7 and DSL3c-8. According to some embodiments, the lipid is selected from the group consisting of: DSL1-1, DSL1-2, DSL1-3, DSL1-4, DSL1-5, DSL1-6, DSL1-7, DSL1-8, DSL1-9, DSL1-10, DSL1-11, DSL1-12, DSL1-13, DSL1-14, DSL1-15, DSL1-16, DSL1-17, DSL1-18, DSL1-19, DSL1-20, DSL1-21, DSL1-22, DSL1-23, DSL1-24, DSL1-25, DSL1-26, DSL1-27, DSL1-28, DSL1-29, DSL1-30, DSL1-31, DSL1-32, DSL1-33, DSL1-34, DSL1-35, DSL1-36, DSL1-37, DSL1-38, DSL1-39, DSL1-40, DSL1-41, DSL1-42, DSL1-43, DSLl-4,4 DSL1-45, DSL1-46, DSL1-47, DSL1-48, DSL1-49, DSL1-50 and DSL1-51, DSL1-52, DSL1-53, DSL1-54, DSL1-55, DSL1-56, DSL1-57, DSL1-58, DSL1-59 and DSL1-60. According to some embodiments, the lipid is selected from the group consisting of: DSL1-1, DSL1-2, DSL1-3, DSL1- 4, DSL1-5, DSL1-6, DSL1-7, DSL1-8, DSL1-9, DSL1-10, DSL1-11, DSL1-12, DSL1-13, DSL1- 14, DSL1-15, DSL1-16, DSL1-17, DSL1-18, DSL1-19, DSL1-20, DSL1-21, DSL1-22, DSL1-23, DSL1-24, DSL1-25, DSL1-26, DSL1-27, DSL1-28, DSL1-29, DSL1-30, DSL1-31, DSL1-32, DSL1-33, DSL1-34, DSL1-35, DSL1-36, DSL1-37, DSL1-38, DSL1-39, DSL1-40, DSL1-41, DSL1-42, DSL1-43, DSLl-4,4 DSL1-45, DSL1-46, DSL1-47, DSL1-48, DSL1-49, DSL1-50 and DSL1-51, DSL1-52, DSL1-53 and DSL1-54. According to some embodiments, the lipid is selected from the group consisting of: DSL3c-l, DSL3c-2, DSL3c-3, DSL3c-4, DSL3c-5, DSL3c- 6, DSL3c-7 and DSL3c-8. According to some embodiments, the lipid is selected is selected from the group consisting of: DSL2-1, DSL2-2, DSL2-3, DSL2-4, DSL2-5, DSL2-6, DSL2-7, DSL2- 8, DSL2-9, DSL2-10, DSL2-11, DSL2-12, DSL2-13, DSL2-14, DSL2-15, DSL2-16, DSL2-17, DSL2-18, DSL2-19, DSL2-20, DSL2-21, DSL2-22, DSL2-23, DSL2-24, DSL2-25, DSL2-26, DSL2-27, DSL2-28, DSL2-29, DSL2-30, DSL2-31, DSL2-32, DSL2-33, DSL2-34, DSL2-35, DSL2-36, DSL2-37, DSL2-38, DSL2-39, DSL2-40, DSL2-41, DSL2-42, DSL2-43, DSL2-44, DSL2-45,DSL2-46, DSL2-47, DSL2-48, DSL2-49, DSL2-50, DSL2-51, DSL2-52, DSL2-53, DSL2-54, DSL2-55, DSL2-56, DSL2-57, DSL2-58, DSL2-59, DSL2-60, DSL2-61, DSL2-62, DSL2-63, DSL2-64, DSL2-65, DSL2-66, DSL2-67, DSL2-68, DSL2-69, DSL2-70, DSL2-71, DSL2-72. According to some embodiments, the lipid is selected is selected from the group consisting of: DSL2-1, DSL2-2, DSL2-3, DSL2-4, DSL2-5, DSL2-6, DSL2-7, DSL2-8, DSL2-9, DSL2-10, DSL2-11, DSL2-12, DSL2-13, DSL2-14, DSL2-15, DSL2-16, DSL2-17, DSL2-18, DSL2-19, DSL2-20, DSL2-21, DSL2-22, DSL2-23, DSL2-24, DSL2-25, DSL2-26, DSL2-27, DSL2-28, DSL2-29, DSL2-30, DSL2-31, DSL2-32, DSL2-33, DSL2-34, DSL2-35, DSL2-36, DSL2-37, DSL2-38, DSL2-39, DSL2-40, DSL2-41, DSL2-42, DSL2-43, DSL2-44, DSL2- 45,DSL2-46, DSL2-47 and DSL2-48. According to some embodiments, the lipid is selected from the group consisting of: DSL4-1, DSL4-2, DSL4-3, DSL4-4, DSL4-5, DSL4-6, DSL4-7, DSL4- 8, DSL4-9, DSL4-10, DSL4-11, DSL4-12, DSL4-13, DSL4-14 and DSL4-15. According to some embodiments, the lipid is selected from the group consisting of: DSL1-1, DSL1-2, DSL1-3, DSL1- 4, DSL1-5, DSL2-1, DSL2-2, DSL4-1, DSL4-2, DSL3c-l, DSL2-49 and DSL2-50. According to some embodiments, the lipid is selected from the group consisting of: DSL1-1, DSL1-2, DSL1-3, DSL1-4, DSL1-5, DSL2-1, DSL2-2, DSL4-2, DSL3c-l, DSL2-49 and DSL2-50.

According to some embodiments, the present invention provides a particle comprising the lipid according to the present invention and a membrane stabilizing lipid. According to some embodiments, the particle comprises the membrane stabilizing lipid and a lipid membrane comprising the lipid.

According to some embodiments, the membrane stabilizing lipid is selected from the group consisting of cholesterol, phospholipids, cephalins, sphingolipids and glycoglycerolipids. According to some embodiments, the membrane stabilizing lipid comprises cholesterol. According to some embodiments, the particle further comprising one or more additional components selected from the group consisting of a PEG-lipid conjugate, a neutral lipid and a charged lipid. According to some embodiments, the additional component comprises l,2-Distearoyl-sn-glycero-3- phosphocholine (DSPC). According to some embodiments, the additional component comprises 1,2-Dimyristoyl-sn-glyceryl-methoxy polyethylene glycol (DMG-PEG). According to some embodiments, the particle comprises the lipid, cholesterol, l,2-Distearoyl-sn-glycero-3- phosphocholine (DSPC) and 1,2-Dimyristoyl-sn-glyceryl-methoxy polyethylene glycol (DMG- PEG). According to some embodiments, the particle is conjugated to a targeting moiety.

According to some embodiments, the particle further comprises a nucleic acid. According to some embodiments, the nucleic acid is encapsulated within a particle comprising the lipid. According to some embodiments, the nucleic acid is selected from the group consisting of small interfering RNA (siRNA), micro RNA (miRNA), antisense oligo nucleotides, messenger RNA (mRNA), ribozymes, pDNA, CRISPR mRNA, gRNA, circular RNA and immune stimulating nucleic acids. According to some embodiments, the particle further comprises a therapeutic agent. According to some embodiments, the therapeutic agent is encapsulated within a particle comprising the lipid. According to some embodiments, the therapeutic agent is RNA comprising an open reading frame encoding a polypeptide that comprises a SARS-CoV-2 spike protein or an immunogenic fragment or variant thereof. Each possibility represents a separate embodiment of the invention. According to some embodiments, the therapeutic agent is RNA comprising an open reading frame encoding a polypeptide that comprises a SARS-CoV-2 spike protein, an immunogenic fragment of SARS- CoV-2 or a SARS-CoV-2 variant. Each possibility represents a separate embodiment of the invention. According to some embodiments, the therapeutic agent is RNA comprising an open reading frame encoding a polypeptide that comprises a SARS-CoV-2 spike protein.

According to some embodiments, there is provided a composition comprising a plurality of particles as discloses herein and a pharmaceutically acceptable carrier, diluent or excipient. According to some embodiments, the composition is a liposomal composition.

According to some embodiments, there is provided a method of gene silencing, comprising the step of contacting a cell with a composition according to the present invention.

According to some embodiments, there is provided a method of gene silencing, comprising the step of contacting a cell with a composition comprising a plurality of particles according to the present invention and a pharmaceutically acceptable carrier, diluent or excipient. According to some embodiments, the cell is a cancer cell.

In other embodiments, the compositions of the present invention may be used as a delivery system to administer a therapeutic agent to its target location in the body. According to some embodiments, there is provided method for administering a therapeutic agent, the method comprising the step of preparing a composition comprising a lipid according to the present invention, and a therapeutic agent, and administering the composition to a subject in need thereof. According to some embodiments, the method further comprises encapsulating the therapeutic agent within a particle comprising the lipid. According to some embodiments, the therapeutic agent is RNA comprising an open reading frame encoding a polypeptide that comprises a SARS-CoV-2 spike protein or an immunogenic fragment or variant thereof. Each possibility represents a separate embodiment of the invention. According to some embodiments, the therapeutic agent is RNA comprising an open reading frame encoding a polypeptide that comprises a SARS-CoV-2 spike protein or an immunogenic fragment or variant thereof. Each possibility represents a separate embodiment of the invention. According to some embodiments, the therapeutic agent is RNA comprising an open reading frame encoding a polypeptide that comprises a SARS-CoV-2 spike protein, an immunogenic fragment of SARS-CoV-2 or a SARS-CoV-2 variant. Each possibility represents a separate embodiment of the invention.

The lipids of the present invention can be used alone or in combination with other lipid components such as neutral lipids, charged lipids, steroids (including, for example, sterols) and/or their analogs, and/or polymer conjugated lipids to form lipid nanoparticles for the delivery of therapeutic agents. In some instances the lipid nanoparticles are used to deliver nucleic acids for the treatment of various diseases or conditions, in particular leukocyte associated conditions such as inflammation and/or lack of sufficient protein.

Thus, in some embodiments, the present invention relates to a method of treating a leukocyte associated condition, the method comprising the step of administering to a subject in need thereof a composition according to the present invention. The leukocyte associated condition may be selected from the group consisting of cancer, infection, autoimmune diseases, neurodegenerative diseases and inflammation. According to some embodiments, there is provided a method of treating a leukocyte associated condition, the method comprising the step of administering to a subject in need thereof a composition comprising a plurality of particles according to the present invention and a pharmaceutically acceptable carrier, diluent or excipient.

Further embodiments and the full scope of applicability of the present invention will become apparent from the detailed description given hereinafter. However, it should be understood that the detailed description and specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

Figures 1A-B - 9A-F represent the 1H NMR spectra (A) and ESI-MS (B) of: DSL1-1 (Figure 1 A and IB); DSL1-2 (Figures 2A and 2B); DSL1-3 (Figures 3A and 3B); DSL1-4 (Figures 4A and 4B); DSL1-5 (Figures 5A and 5B); DSE2-1 (Figures 6A and 6B); DSE2-2 (Figures 7A and 7B); DSL4-1 (Figures 8A and 8B); DSL4-2 (Figures 9A and 9B), DSL3c-l (Figures 9C - 1H NMR spectra and 9D - ESI-MS) and DSL1-50 (Figures 9E - 1H NMR spectra and 9F - ESI-MS).

Figures 10A-10G depict transmission electron microscopy (TEM) images of LNPs made of ionizable lipids DSL1-1 (Figure 10A), DSL1-2 (Figure 10B), DSL1-5 (Figure 10C), DSL2-50 (Figure 10D), DSL1-3, (Figure 10E), DSL3c-l (Figure 10F) or DSL2-49 (Figure 10G). The images relate to organs from mice after intravenous administration of the lipids. The organs are lung, liver, spleen and kidney in this order (lung - top, and kidney - bottom).

Figures 11A-11K depict IVIS images of organs from mice after intravenous administration of mLUC-LNPs comprising DSL1-1 (Figure 11A), DSL1-2 (Figure 11B), DSL1-5 (Figure 11C), DSL1-4 (Figure 11 D), DSL1-3 (Figure 11E), DSL4-2 (Figure 11F), DSL3c-l (Figure 11G), DSL2-2 (Figure 11H), DSL2-1 (Figure 111), DSL2-49 (Figure 11 J) or DSL2-50 (Figure 11K) as the ionizable lipid. The organs are lung, liver, spleen and kidney in this order (lung - top, and kidney - bottom). Figure 11 L depicts IVIS. images of organs from mice administered intravenously with DSL1-3 LNPs comprising either 1.5% (second and third panels) or 2.5% PEG (fourth and fifth panels), untreated mice (first from left panel). The organs are lung, liver, spleen and kidney in this order (lung - top, and kidney - bottom).

Figures 11M -11P depict IVIS images of organs from mice administered with LNPs along with either DOPE or DSPC co-lipids. Figure 11M - DSL1-4 LNPs with DOPE (left panel) or DSPC (right panel); Figure 1 IN - DSL 1-5 LNPs with DOPE (left panel) or DSPC (right panel); Figure 110 - DSL2-2 LNPs with DOPE (left panel) or DSPC (right panel); Figure 1 IP - DSL2-50 LNPs with DOPE (left panel) or DSPC (right panel). The organs are lung, liver, spleen and kidney in this order (lung - top, and kidney - bottom). Figure 11 Q depicts IVIS images of organs from mice administered with LNPs at different mole ratios: top left - DSL 1-5 at 30% mole ratio; top right - DSL 1-5 at 40% mole ratio; bottom left DSL2-50 at 30% mole ratio; bottom right - DSL2-50 at 40% mole ratio. The organs are lung, liver, spleen and kidney in this order (lung - top, and kidney - bottom). Figure 11 R depicts IVIS images of organs from mice administered with mRNA-LNPs composed of DSL2-50, either intravenously (left panel) or intra-muscularly (right panel). The organs in the left panel are lung, liver, spleen and kidney in this order (lung - top, and kidney - bottom). The organs in the right panel are lung, liver, spleen, kidney and muscle in this order (lung - top, and muscle - bottom).

Figure 12 is a bar graph showing quantitative analysis of Luciferase expression in the spleen and liver of mice after intravenous administration of LNPs comprising DSL1-1, DSL1-2, DSL1-3, DSL1-4, DSL1-5, DSL2-1, DSL2-2, DSL4-2, DSL3c-l, DSL2-49 and DSL2-50.

Figures 13A and 13B are bar graphs demonstrating FACS analysis of tdTomato expression in peritoneal macrophages (Figure 13A) and splenocytes (Figure 13B) isolated from untreated (Mock, dotted bar) Ai9 mice or Ai9 mice following intravenous administration of mCRE-LNPs comprising DSL1-1 (black dots on while background), DSL 1-2 (while dots on black background) or DSL 1-3 (diagonal bar).

Figure 14 is a bar graph demonstrating FACS analysis of tdTomato expression in different type of immune cells from spleens isolated from untreated (Mock) Ai9 mice or Ai9 mice following intravenous administration of mCRE-LNPs comprising DSL 1-3.

Figures 15A and 15B are bar graphs showing quantitative analysis of tdTomato expression in the spleen (Figure 15 A) and liver (Figure 15B) of Ai9 mice following intravenous administration of MC3 mCRE-LNPs LNPs or DSL 1-2 mCRE-LNPs, compared to untreated (Mock) mice.

Figures 16A-16B show analysis of Luciferase expression as seen in IVIS images of organs from mice administered with DSL2-50 LNPs encapsulated with Luciferase mRNA prepared on day ‘0’ (Figure 16A, left panel)) and after day ‘210’ (Figure 16A, right panel). The lung, liver, spleen and kidney are arranged in this order (lung - top, and kidney - bottom). Figure 16B is a histogram analysis of Luciferase expression on days 0 (vertical bars) or 210 (checkered bars) in mouse lung, liver, spleen and kidney.

Figures 16C-16D show analysis of mCherry expression as seen in IVIS images of organs from mice administered with DSL-50 LNPs encapsulated with mCherry mRNA prepared on day ‘0’ (Figure 16C, middle panel), control (Figure 16C, left panel) and 90 days after preparation (Figure 16C, right panel). The organs in Figure 16C are lung, liver, spleen and kidney in this order (lung - top, and kidney - bottom). Figure 16D is a histogram analysis of mCherry expression, compared to controls (Mock, hatched bars) on days 0 (dotted bars) or 90 (horizontal bars) in mouse lung, liver, spleen and kidney.

Figure 17 shows in vivo safety analysis of mRNA-LNPs (DSL2-50 or DSL1-3) after IV administration. After 2hr and 24hr blood was collected and serum samples were analyzed for levels of the liver enzymes alkaline phosphatase (Aik Phos), serum glutamic-oxaloacetic transaminase (SGOT) or serum glutamic pyruvic transaminase (SGPT).

Figures 18A-18B depict mRNA delivery capability of a single LNP. Figure 18A shows IVIS images of mice livers following treatment with DSL2-50 LNPs (two right column) or Moderna’s lipid SMI 02 as control (two left columns), encapsulated with luciferase (mLuc, bottom panel) or mO ₂ erry (top panel). Figure 18B shows a histogram analysis of Luciferase and mO ₂ erry expression in mice livers.

Figures 19A-19B illustrate the evaluation of mRNA-LNPs for COVID-19 vaccine delivery in BALB/c mice, as evaluated by ELISA of SARS-CoV-2 spike-specific antibody titers (Figure 19A) in sera of mice treated with DSL1-3, 2-2, 2-50 or Moderna’s SMI 02 encapsulated RBD-hFc mRNA. Figure 19B depicts ELISPOT assay for evaluation of COVID-19 specific T-cell response in splenocytes. Circles denote pre boost markers, triangles - post boost.

Figures 20A-20B depict evaluation of mRNA-LNPs for CO VID-19 vaccine delivery in C57BL6 mice, as evaluated by ELISA SARS-CoV-2 spike-specific antibody titers (Figure 20 A) in sera of mice DSL1-3, 2-2, 2-50 or Moderna’s SMI 02 encapsulated RBD-hFc mRNA. Figure 20B depicts ELISPOT assay for evaluation of COVID-19 specific T-cell response in splenocytes. Circles denote pre boost markers, triangles - post boost.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

The present invention based on the discovery of lipids useful in preparing lipid nanoparticles to deliver active agents in vitro and in vivo. The lipids of the present invention are useful in delivery of nucleic acids such as siRNA, miRNA and mRNA etc.

Lipids

As contemplated herein, the present invention relates to a lipid represented by the structure of Formula (I): including salts, hydrates, solvates, polymorphs, optical isomers, geometrical isomers, enantiomers, diastereomers, and mixtures thereof. According to some embodiments, L is L ^a -X ^a -L ^b . It is to be understood that when describing that L ^a -X ^a -L ^b , the order of substituents is only limited to X ^a being in the center, flanked by L ^a and L ^b . it does not intended to mean that L ^a is bonded to N(R ^X )R ² and L ^b is bonded to N(R ³ )R ⁴ or vice versa. Thus, L is selected from the group consisting of: Each possibility represents a separate embodiment of the invention.

According to some embodiments, X ^a is selected from the group consisting of: -O ₂ C-, -O-, -CO ₂ - L ^C -O ₂ C-, -O ₂ C-L ^C -CO ₂ -, -CO ₂ -L ^C -CO ₂ -, L ^C -CO ₂ -, L ^C -O ₂ C-, -CO ₂ -NH- and -CO-NH-. According to some embodiments, X ^a is O ₂ C-. According to some embodiments, X ^a is -CO ₂ -L ^C - -O ₂ C-. According to some embodiments, X ^a is -O ₂ C-L ^C -CO ₂ -. According to some embodiments, X ^a is - CO ₂ - L ^c - CO ₂ - • According to some embodiments, X ^a is L ^C -CO ₂ - According to some embodiments, X ^a is L ^c -O ₂ C- According to some embodiments, X ^a is -CO-NH-. According to some embodiments, X ^a is -CO ₂ -NH-.

According to some embodiments, L ^a is selected from the group consisting of: C _4-20 alkylene, C _4-20 alkenylene and C _0-4 alkylene. According to some embodiments, L ^a is C _4-20 alkylene. According to some embodiments, L ^a is C _4-10 alkylene. According to some embodiments, L ^a is C _10-20 alkylene. According to some embodiments, L ^a is C _4-20 alkenylene. According to some embodiments, L ^a is C _4-10 alkenylene. According to some embodiments, L ^a is C _10-20 alkenylene. According to some embodiments, L ^a is C _0-4 alkylene.

According to some embodiments, L ^b is selected from the group consisting of: C _4-20 alkylene, C _4-20 alkenylene and C _0-4 alkylene. According to some embodiments, L ^b is C _4-20 alkylene. According to some embodiments, L ^b is C _4-10 alkylene. According to some embodiments, L ^b is C _10-20 alkylene. According to some embodiments, L ^b is C _4-20 alkenylene. According to some embodiments, L ^b is C _4-10 alkenylene. According to some embodiments, L ^b is C _10-20 alkenylene. According to some embodiments, L ^b is C _0-4 alkylene.

According to some embodiments, L ^c is selected from the group consisting of: C _1-6 alkylene-(O- -C _1-6 alkylene)f-,C _2-6 alkenylene-(O-C _1-6 alkylene) _g -, C _1-6 alkylene-S-C _1-6 alkylene, C _1-6 alkylene-S-S-C _1-6 alkylene, C _0-4 alkylene-aryl-C _0-4 alkylene, and C _1-4 alkylene. According to some embodiments, L ^c is C _1-6 alkylene-(O-C _1-6 alkylene)^. According to some embodiments, L ^c is C _1-6 alkylene. According to some embodiments, L ^c is C _2-6 alkenylene-(O-C _1-6 alkylene) _g - According to some embodiments, L ^c is C _1-6 alkylene-S-C _1-6 alkylene. According to some embodiments, L ^c is C _1-6 alkylene-S-S-C _1-6 alkylene. According to some embodiments, L ^c is C _1-4 alkylene-S-S-C _1-4 alkylene. According to some embodiments, L ^c is C _1-2 alkylene-S-S- — C _1-2 alkylene. According to some embodiments, L ^c is C _0-4 alkylene-aryl-C _0-4 alkylene. According to some embodiments, L ^c is C _1-4 alkylene-aryl-C _1-4 alkylene. According to some embodiments, L ^c is C _0-2 alkylene-aryl-C _0-2 alkylene. According to some embodiments, L ^c is C _1-4 alkylene. According to some embodiments, each one of f and g is 0, 1, 2, 3, 4 or 5. According to some embodiments, f is 0, 1 or 2. According to some embodiments, f is 0. According to some embodiments, f is 1. According to some embodiments, g is 0, 1 or 2. According to some embodiments, g is 0. According to some embodiments, g is 1.

According to some embodiments, R ¹ is selected from the group consisting of: C _0-10 alkylene- Y ^a , C _2-6 alkenylene- Y ^a , C _1-4 alkyl, C _5-25 alkyl, C _5-25 alkenyl, C _5-25 alkynyl,C _5-15 alkylene-CO ₂ -C _5-15 alkyl, C _5-15 alkylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkylene-O ₂ C-C _5-15 alkyl, C _5-15 alkylene-O ₂ C- -C _5-15 alkenyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkenylene-O ₂ C-C _5-15 alkyl, and C _5-15 alkenylene-O ₂ C-C _5-15 alkenyl. According to some embodiments, R ¹ is C _0-10 alkylene- Y ^a . According to some embodiments, R ¹ is Y ^a . According to some embodiments, R ¹ is C _1-2 alkylene- Y ^a . According to some embodiments, R ¹ is C _5-10 alkylene- -Y ^a . According to some embodiments, R ¹ is C _2-6 alkenylene- Y ^a . According to some embodiments, R ¹ is C _1-4 alkyl. According to some embodiments, R ¹ is C _5-25 alkyl. According to some embodiments, R ¹ is C _5-15 alkyl. According to some embodiments, R ¹ is C ₁₂ - ₂₅ alkyl. According to some embodiments, R ¹ is C _5-25 alkenyl. According to some embodiments, R ¹ is C _5-10 alkenyl. According to some embodiments, R ¹ is C1 _0-25 alkenyl. According to some embodiments, R ¹ is C _5-15 alkylene-CO ₂ -C _5-15 alkyl. According to some embodiments, R ¹ is C _5-15 alkylene-CO ₂ - -C _5-15 alkenyl. According to some embodiments, R ¹ is C _5-15 alkylene-O ₂ C-C _5-15 alkyl. According to some embodiments, R ¹ is C _5-15 alkylene-O ₂ C-C _5-15 alkenyl. According to some embodiments, R ¹ is C _5-15 alkenylene-CO ₂ -C _5-15 alkyl. According to some embodiments, R ¹ is C _5-15 alkenylene- CO ₂ -C _5-15 alkenyl. According to some embodiments, R ¹ is C _5-15 alkenylene-O ₂ C-C _5-15 alkyl. According to some embodiments, R ¹ is C _5-15 alkenylene-O ₂ C-C _5-15 alkenyl. According to some embodiments, R ² is selected from the group consisting of: R ² is selected from the group consisting of: C _5-25 alkyl, C _5-25 alkenyl, C _5-25 alkynyl,C _5-15 alkylene-CO ₂ -C _5-15 alkyl, C _5-15 alkylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkylene-O ₂ C-C _5-15 alkyl, C _5-15 alkylene-O ₂ C-C _5-15 alkenyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkenylene-O ₂ C-C _5-15 alkyl, C _5-15 alkenylene-O ₂ C-C _5-15 alkenyl, C _2-15 alkylene-CO ₂ -C _0-4 alkylene-N(C _1-12 alkyl) ₂ , C _2-15 alkylene-CO ₂ -CH ₂ CH ₂ OCH ₂ CH ₂ -N(C _1-12 alkyl) ₂ , C _2-15 alkylene-CO ₂ -C _0-4 alkylene-NH-C _1-12 alkyl, C _2-15 alkylene-CO ₂ -C _0-4 alkylene-N(C _5-25 alkenyl) ₂ , C _2-15 alkylene-CO ₂ -C _0-4 alkylene-NH-C _5-25 alkenyl, C _2-15 alkylene-CO-NH-C _0-8 alkylene-N(C _1-12 alkyl) ₂ and C _5-15 alkylene-CO ₂ H.

According to some embodiments, R ² is selected from the group consisting of: C _5-25 alkyl, C _5-25 alkenyl, C _5-25 alkynyl, C _5-15 alkylene-CO ₂ -C _5-15 alkyl, C _5-15 alkylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkylene-O ₂ C-C _5-15 alkyl, C _5-15 alkylene-O ₂ C-C _5-15 alkenyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkenylene-O ₂ C-C _5-15 alkyl, C _5-15 alkenylene-O ₂ C- -C _5-15 alkenyl, C _5-15 alkylene-CO ₂ H and L-N(R3)-R ₄ .

According to some embodiments, R ² is C _5-25 alkyl. According to some embodiments, R ² is C _5-10 alkyl. According to some embodiments, R ² is C _10-18 alkyl. According to some embodiments, R ² is C _18-25 alkyl. According to some embodiments, R ² is C _5-25 alkenyl. According to some embodiments, R ² is C _5-10 alkenyl. According to some embodiments, R ² is C _10-18 alkenyl. According to some embodiments, R ² is C _18-25 alkenyl. According to some embodiments, R ² is C _5-15 alkylene-CO ₂ -C _5-15 alkyl. According to some embodiments, R ² is C _5-15 alkylene-CO ₂ - -C _5-15 alkenyl. According to some embodiments, R ² is C _5-15 alkylene-O ₂ C-C _5-15 alkyl. According to some embodiments, R ² is C _5-15 alkylene-O ₂ C-C _5-15 alkenyl. According to some embodiments, R ² is C _5-15 alkenylene-CO ₂ -C _5-15 alkyl. According to some embodiments, R ² is C _5-15 alkenylene- -CO ₂ -C _5-15 alkenyl. According to some embodiments, R ² is C _5-15 alkenylene-O ₂ C-C _5-15 alkyl. According to some embodiments, R ² is C _5-15 alkenylene-O ₂ C-C _5-15 alkenyl. According to some embodiments, R ² is C _5-15 alkylene-CO ₂ H. According to some embodiments, R ² is L-N(R3)-R ₄ . According to some embodiments, R ² is C _2-15 alkylene-CO ₂ -C _0-4 alkylene-N(C _1-12 alkyl) ₂ . According to some embodiments, R ² is C _2-15 alkylene-CO ₂ -CH ₂ CH ₂ OCH ₂ CH ₂ -N(C _1-12 alkyl) ₂ . According to some embodiments, R ² is C _2-15 alkylene-CO ₂ -C _0-4 alkylene-NH- -C _1-12 alkyl. According to some embodiments, R ² is C _2-15 alkylene-CO ₂ -C _0-4 alkylene-N(C _5-25 alkenyl) ₂ . According to some embodiments, R ² is C _2-15 alkylene-CO ₂ -C _0-4 alkylene-NH-C _5-25 alkenyl. According to some embodiments, R ² is C _2-15 alkylene-CO-NH-C _0-8 alkylene-N(C _1-12 alkyl) ₂ .

According to some embodiments, R ³ is selected from the group consisting of: H, C _5-25 alkyl, C _5-25 alkenyl, C _5-25 alkynyl, C _5-15 alkylene-CO ₂ -C _5-15 alkyl, C _5-15 alkylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkylene-O ₂ C-C _5-15 alkyl, C _5-15 alkylene-O ₂ C-C _5-15 alkenyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkenylene-O ₂ C-C _5-15 alkyl, C _5-15 alkenylene- O ₂ C-C _5-15 alkenyl, C _0-6 alkylene- Y ^d , C _2-6 alkenylene- Y ^d and C _1-4 alkyl.

According to some embodiments, R ³ is selected from the group consisting of: H, C _5-25 alkyl, C _5-25 alkenyl, C _5-25 alkynyl, C _5-15 alkylene-CO ₂ -C _5-15 alkyl, C _5-15 alkylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkylene-O ₂ C-C _5-15 alkyl, C _5-15 alkylene-O ₂ C-C _5-15 alkenyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkenylene-O ₂ C-C _5-15 alkyl, C _5-15 alkenylene- -O ₂ C-C _5-15 alkenyl, C _0-6 alkylene- Y ^a , C _2-6 alkenylene- Y ^a and C _1-4 alkyl. According to some embodiments, R ³ is selected from the group consisting of: C _5-25 alkyl, C _5-25 alkenyl, C _5-15 alkylene-CO ₂ -C _5-15 alkyl, C _5-15 alkylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkylene-O ₂ C-C _5-15 alkyl, C _5-15 alkylene-O ₂ C-C _5-15 alkenyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkyl, C _5-15 alkenylene-CO ₂ - -C _5-15 alkenyl, C _5-15 alkenylene-O ₂ C-C _5-15 alkyl, C _5-15 alkenylene-O ₂ C-C _5-15 alkenyl, C _0-6 alkylene- Y ^a , C _2-6 alkenylene- Y ^a and C _1-4 alkyl. According to some embodiments, R ³ is H. According to some embodiments, R ³ is C _5-25 alkyl. According to some embodiments, R ³ is C _5-10 alkyl. According to some embodiments, R ³ is C _10-18 alkyl. According to some embodiments, R ³ is C _18-25 alkyl. According to some embodiments, R ³ is C _5-25 alkenyl. According to some embodiments, R ³ is C _5-10 alkenyl. According to some embodiments, R ³ is C _10-18 alkenyl. According to some embodiments, R ³ is C _18-25 alkenyl. According to some embodiments, R ³ is C _5-15 alkylene-CO ₂ -C _5-15 alkyl. According to some embodiments, R ³ is C _5-15 alkylene-CO ₂ - -C _5-15 alkenyl. According to some embodiments, R ³ is C _5-15 alkylene-O ₂ C-C _5-15 alkyl. According to some embodiments, R ³ is C _5-15 alkylene-O ₂ C-C _5-15 alkenyl. According to some embodiments, R ³ is C _5-15 alkenylene-CO ₂ -C _5-15 alkyl. According to some embodiments, R ³ is C _5-15 alkenylene- -CO ₂ -C _5-15 alkenyl. According to some embodiments, R ³ is C _5-15 alkenylene-O ₂ C-C _5-15 alkyl. According to some embodiments, R ³ is C _5-15 alkenylene-O ₂ C-C _5-15 alkenyl. According to some embodiments, R ³ is C _0-6 alkylene- Y ^a . According to some embodiments, R ³ is C _0-6 alkylene- Y ^d . According to some embodiments, R ³ is C _2-6 alkenylene- Y ^d . According to some embodiments, R ³ is C _0-10 alkylene- Y ^a . According to some embodiments, R ³ is Y ^a . According to some embodiments, R ³ is Y ^d . According to some embodiments, R ³ is C _1-2 alkylene-Y ^a . According to some embodiments, R ³ is C _2-6 alkenylene- Y ^a . According to some embodiments, R ³ is C _1-4 alkyl. According to some embodiments, R ³ is not H.

According to some embodiments, R ⁴ is selected from the group consisting of: C _5-25 alkyl, C _5-25 alkenyl, C _5-25 alkynyl,C _5-15 alkylene-CO ₂ -C _5-15 alkyl, C _5-15 alkylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkylene-O ₂ C-C _5-15 alkyl, C _5-15 alkylene-O ₂ C-C _5-15 alkenyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkenylene-O ₂ C-C _5-15 alkyl, C _5-15 alkenylene-O ₂ C- -C _5-15 alkenyl and C _5-15 alkylene-CO ₂ -C _5-15 alkylene-N(R ⁵ )R ⁶ .

According to some embodiments, R ⁴ is selected from the group consisting of: C _5-25 alkyl, C _5-25 alkenyl, C _5-25 alkynyl, C _5-15 alkylene-CO ₂ -C _5-15 alkyl, C _5-15 alkylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkylene-O ₂ C-C _5-15 alkyl, C _5-15 alkylene-O ₂ C-C _5-15 alkenyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkenylene-O ₂ C-C _5-15 alkyl, and C _5-15 alkenylene- -O ₂ C-C _5-15 alkenyl.

According to some embodiments, R ⁴ is C _5-25 alkyl. According to some embodiments, R ⁴ is C _5-10 alkyl. According to some embodiments, R ⁴ is C _10-18 alkyl. According to some embodiments, R ⁴ is C _18-25 alkyl. According to some embodiments, R ⁴ is C _5-25 alkenyl. According to some embodiments, R ⁴ is C _5-10 alkenyl. According to some embodiments, R ⁴ is C _10-18 alkenyl. According to some embodiments, R ⁴ is C _18-25 alkenyl. According to some embodiments, R ⁴ is C _5-15 alkylene-CO ₂ -C _5-15 alkyl. According to some embodiments, R ⁴ is C _5-15 alkylene-CO ₂ - -C _5-15 alkenyl. According to some embodiments, R ⁴ is C _5-15 alkylene-O ₂ C-C _5-15 alkyl. According to some embodiments, R ⁴ is C _5-15 alkylene-O ₂ C-C _5-15 alkenyl. According to some embodiments, R ⁴ is C _5-15 alkenylene-CO ₂ -C _5-15 alkyl. According to some embodiments, R ⁴ is C _5-15 alkenylene- -CO ₂ -C _5-15 alkenyl. According to some embodiments, R ⁴ is C _5-15 alkenylene-O ₂ C-C _5-15 alkyl. According to some embodiments, R ⁴ is C _5-15 alkenylene-O ₂ C-C _5-15 alkenyl. According to some embodiments, R ⁴ is C _5-15 alkylene-CO ₂ -C _5-15 alkylene-N(R ⁵ )R ⁶ .

According to some embodiments, R ⁵ is selected from the group consisting of: C _1-4 alkyl, C _0-10 alkylene-OH, and C _0-10 alkylene-halogen. According to some embodiments, R ⁵ is C _1-4 alkyl. According to some embodiments, R ⁵ is C _0-10 alkylene-OH. According to some embodiments, R ⁵ is C _0-10 alkylene-halogen.

According to some embodiments, R ⁶ is selected from the group consisting of: C _5-25 alkyl, C _5-25 alkenyl. According to some embodiments, R ⁶ is C _5-25 alkyl. According to some embodiments, R ⁶ is C _5-25 alkenyl. According to some embodiments, Y ^a is selected from the group consisting of: O-Y ^b , halogen, PO ₃ H ₂ , PO ₃ (C _1-4 alkyl) ₂ , PO ₃ H(C _1-4 alkyl), pyrrolidinyl, piperidinyl piperazinyl, NH ₂ , SH, NMe2, NMe ₃ ⁺ and NH-Y ^b . According to some embodiments, Y ^a is O-Y ^b . According to some embodiments, Y ^a is a halogen. According to some embodiments, the halogen is selected from the group consisting of: fluorine, chlorine and bromine. According to some embodiments, the halogen is selected from the group consisting of: fluorine and chlorine. According to some embodiments, the halogen is chlorine. According to some embodiments, Y ^a is selected from the group consisting of PO ₃ H ₂ , PO ₃ (C _1-4 alkyl) ₂ , PO ₃ H(C _1-4 alkyl). According to some embodiments, Y ^a is PO ₃ H ₂ . According to some embodiments, Y ^a is PO ₃ (C _1-4 alkyl) ₂ . According to some embodiments, Y ^a is PO ₃ H(C _1-4 alkyl). According to some embodiments, Y ^a is SH. According to some embodiments, Y ^a is NH ₂ . According to some embodiments, Y ^a is NH(CH ₃ ). According to some embodiments, Y ^a is N(CH ₃ ) ₂ . According to some embodiments, Y ^a is pyrrolidine. According to some embodiments, Y ^a is piperidine. According to some embodiments, Y ^a is piperazine. According to some embodiments, Y ^a is NH-Y ^b .

According to some embodiments, Y ^b is selected from the group consisting of: H, C _1-4 alkyl, C _1-4 alkylene-OH, C _1-4 alkylene-(O-C _1-4 alkylene) 1.3-OH, PO ₃ H ₂ , PO ₃ (C _1-4 alkyl) ₂ , PO ₃ H(C _1-4 alkyl), CO-C _1-4 alkyl-Y ^c , CO-aryl, SO ₃ H, SO ₃ -(C _1-4 alkyl) and SO ₃ -aryl. According to some embodiments, Y ^b is selected from the group consisting of: H, C _1-4 alkyl, C _1-4 alkylene-OH, PO ₃ H ₂ , PO ₃ (C _1-4 alkyl) ₂ , PO ₃ H(C _1-4 alkyl), CO-C _1-4 alkyl- Y ^c , CO-aryl, SO ₃ H, SO ₃ -(C _1-4 alkyl), SO ₃ - aryl,. According to some embodiments, Y ^b is selected from the group consisting of: C _1-4 alkyl, C ₁ - 4 alkylene-OH, PO ₃ H ₂ , PO ₃ (C _1-4 alkyl) ₂ , PO ₃ H(C _1-4 alkyl), CO-C _1-4 alkyl, CO-aryl, SO ₃ H, SO ₃ - (C _1-4 alkyl) and SO ₃ -aryl.

According to some embodiments, Y ^b is C _1-4 alkyl. According to some embodiments, Y ^b is C _1-4 alkylene-OH. According to some embodiments, Y ^b is PO ₃ H ₂ . According to some embodiments, Y ^b is PO ₃ (C _1-4 alkyl) ₂ . According to some embodiments, Y ^b is PO ₃ H(C _1-4 alkyl). According to some embodiments, Y ^b is CO-C _1-4 alkyl. According to some embodiments, Y ^b is CO-aryl. According to some embodiments, the aryl is a phenyl, optionally substituted by at least one alkyl, haloalkyl or halogen. According to some embodiments, Y ^b is SO ₃ H. According to some embodiments, Y ^b is SO ₃ -(C _1-4 alkyl). According to some embodiments, Y ^b is SO ₃ -aryl. According to some embodiments, Y ^b is C _1-4 alkylene-(O-C _1-4 alkylene) 1.3-OH. According to some embodiments, Y ^c is selected from the group consisting of: H, NH ₂ , NH(CH ₃ ), N(CH ₃ ) ₂ , pyrrolidinyl piperidinyl and piperazinyl, each pyrrolidinyl piperidinyl and piperazinyl is optionally substituted with a C _1-4 alkyl. Each possibility represents a separate embodiment of the invention.

According to some embodiments, each of the pyrrolidinyl piperidinyl and piperazinyl in either Y ^a or Y ^c is bonded through the respective nitrogen atom, ach possibility represents a separate embodiment of the invention.

According to some embodiments, Y ^d is selected from the group consisting of: O-Y ^e , halogen, PO ₃ H ₂ , PO ₃ (C _1-4 alkyl) ₂ , PO ₃ H(C _1-4 alkyl), NH ₂ , SH, pyrrolidinyl, piperidinyl piperazinyl, NMe2, NMe ₃ ⁺ and NH-Y ^e . According to some is O-Y ^e . According to some embodiments, Y ^d is a halogen. According to embodiments, Y ^d some embodiments, Y ^d is PO ₃ H ₂ , PO ₃ (C _1-4 alkyl) ₂ . According to some embodiments, Y ^d is PO ₃ H(C _1-4 alkyl). According to some embodiments, Y ^d is NH ₂ . According to some embodiments, Y ^d is SH. According to some embodiments, Y ^d is pyrrolidinyl. According to some embodiments, Y ^d is piperidinyl. According to some embodiments, Y ^d is piperazinyl. According to some embodiments, Y ^d is NMe2. According to some embodiments, Y ^d is NMe ₃ ⁺ . According to some embodiments, Y ^d is NH-Y ^e .

According to some embodiments, Y ^e is selected from the group consisting of: H, C _1-4 alkyl, C _1-4 alkylene-OH, PO ₃ H ₂ , PO ₃ (C _1-4 alkyl) ₂ , PO ₃ H(C _1-4 alkyl), CO-C _1-4 alkyl- Y ^f , CO-aryl, SO ₃ H, SO ₃ - (C _1-4 alkyl) and SO ₃ -aryl. According to some embodiments, Y ^e is H. According to some embodiments, Y ^e is C _1-4 alkyl. According to some embodiments, Y ^e is C _1-4 alkylene-OH. According to some embodiments, Y ^e is PO ₃ H ₂ . According to some embodiments, Y ^e is PO ₃ (C _1-4 alkyl) ₂ . According to some embodiments, Y ^e is PO ₃ H(C _1-4 alkyl). According to some embodiments, Y ^e is CO-C _1-4 alkyl-Y ^f . According to some embodiments, Y ^e is CO-aryl. According to some embodiments, Y ^e is SO ₃ H. According to some embodiments, Y ^e is SO ₃ -(C _1-4 alkyl). According to some embodiments, Y ^e is SO ₃ -aryl.

According to some embodiments, Y ^f is selected from the group consisting of: H, NH ₂ , NH(CH ₃ ), N(CH ₃ ) ₂ , pyrrolidinyl piperidinyl and piperazinyl, each pyrrolidinyl piperidinyl and piperazinyl is optionally substituted with a C _1-4 alkyl. Each possibility represents a separate embodiment of the invention. According to some embodiments, any one of the alkenyl groups of R ^1-4 , (e.g., C _5-25 alkenyl) is a dienyl (e.g., C _5-25 dienyl). According to some embodiments, any one of the alkenyl groups of R ¹ ’ ⁴ , (e.g., C _5-25 alkenyl) is a mono-enyl (e.g., C _5-25 mono-enyl).

According to some embodiments, R ² is selected from the group consisting of: C _5-25 alkyl, C _5-25 alkenyl, C _5-15 alkylene-CO ₂ -C _5-15 alkyl, C _5-15 alkylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkylene-O ₂ C- -C _5-15 alkyl, C _5-15 alkylene-O ₂ C-C _5-15 alkenyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkenylene-O ₂ C-C _5-15 alkyl, C _5-15 alkenylene-O ₂ C-C _5-15 alkenyl, C _2-15 alkylene-CO ₂ -C _0-4 alkylene-N(C _1-12 alkyl) ₂ , C _2-15 alkylene-CO ₂ -C _0-4 alkylene- -NH-C _1-12 alkyl, C _2-15 alkylene-CO ₂ -C _0-4 alkylene-N(C _5-25 alkenyl) ₂ , C _2-15 alkylene-CO ₂ -C _0-4 alkylene-NH-C _5-25 alkenyl, C _2-15 alkylene— CO— NH—C _0-4 alkylene— N(C _1-12 alkyl) ₂ , and C _5-15 alkylene-CO ₂ H; and R ⁴ is selected from the group consisting of: C _5-25 alkyl, C _5-25 alkenyl, C _5-15 alkylene-CO ₂ -C _5-15 alkyl, C _5-15 alkylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkylene-O ₂ C-C _5-15 alkyl, C _5-15 alkylene-O ₂ C-C _5-15 alkenyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkyl, C _5-15 alkenylene-CO ₂ - -C _5-15 alkenyl, C _5-15 alkenylene-O ₂ C-C _5-15 alkyl, C _5-15 alkenylene-O ₂ C-C _5-15 alkenyl, and C _5-15 alkylene-CO ₂ -C _5-15 alkylene-N(R ⁵ )R ⁶ . According to some embodiments, R ² is selected from the group consisting of: C _5-25 alkyl, C _5-25 alkenyl, C _5-15 alkylene-CO ₂ -C _5-15 alkyl, C _5-15 alkylene- -CO ₂ -C _5-15 alkenyl, C _5-15 alkylene-O ₂ C-C _5-15 alkyl, C _5-15 alkylene-O ₂ C-C _5-15 alkenyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkenylene-O ₂ C-C _5-15 alkyl, C _5-15 alkenylene-O ₂ C-C _5-15 alkenyl, C _5-15 alkylene-CO ₂ H and L-N(R ₃ )-R ₄ ; and R ⁴ is selected from the group consisting of: C _5-25 alkyl, C _5-25 alkenyl, C _5-15 alkylene-CO ₂ -C _5-15 alkyl, C _5-15 alkylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkylene-O ₂ C-C _5-15 alkyl, C _5-15 alkylene-O ₂ C-C _5-15 alkenyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkenylene-O ₂ C-C _5-15 alkyl, and C _5-15 alkenylene-O ₂ C-C _5-15 alkenyl.

One of the features of the lipids of the present invention is that each of the nitrogen atoms in Formula I includes at least one lipid moiety. According to some embodiments, R ¹ and R ² collectively have at least 9 carbon atoms. According to some embodiments, R ³ and R ⁴ collectively have at least 9 carbon atoms. According to some embodiments, R ¹ and R ² collectively have at least 9 carbon atoms, and R ³ and R ⁴ collectively have at least 9 carbon atoms. According to some embodiments, R ¹ and R ² collectively have at least 10 carbon atoms. According to some embodiments, R ³ and R ⁴ collectively have at least 10 carbon atoms. According to some embodiments, R ¹ and R ² collectively have at least 10 carbon atoms, and R ³ and R ⁴ collectively have at least 10 carbon atoms. According to some embodiments, R ¹ and R ² collectively have at least 11 carbon atoms. According to some embodiments, R ³ and R ⁴ collectively have at least 11 carbon atoms. According to some embodiments, R ¹ and R ² collectively have at least 11 carbon atoms, and R ³ and R ⁴ collectively have at least 11 carbon atoms. According to some embodiments, R ¹ and R ² collectively have at least 12 carbon atoms. According to some embodiments, R ³ and R ⁴ collectively have at least 12 carbon atoms. According to some embodiments, R ¹ and R ² collectively have at least 12 carbon atoms, and R ³ and R ⁴ collectively have at least 12 carbon atoms. According to some embodiments, R ¹ and R ² collectively have at least 13 carbon atoms. According to some embodiments, R ³ and R ⁴ collectively have at least 13 carbon atoms. According to some embodiments, R ¹ and R ² collectively have at least 13 carbon atoms, and R ³ and R ⁴ collectively have at 13 carbon atoms.

According to some embodiments, each one of L ^a and L ^b is C _0-4 alkylene or C _4-20 alkylene and at least one of L ^a and L ^b is C _3-15 alkylene. According to some embodiments, each one of L ^a and L ^b is C _0- 20 alkylene and at least one of L ^a and L ^b is C _3-15 alkylene. According to some embodiments, each one of L ^a and L ^b is C _0-2 0 alkylene. According to some embodiments, at least one of L ^a and L ^b is C _3-15 alkylene. According to some embodiments, each one of L ^a and L ^b is C _0-2 0 alkylene and at least one of L ^a and L ^b is C _3-15 alkylene. According to some embodiments, each one of L ^a and L ^b is C ₀ -15 alkylene. According to some embodiments, at least one of L ^a and L ^b is C _5-15 alkylene.

According to some embodiments, each one of L ^a and L ^b is C ₀ -15 alkylene and at least one of L ^a and L ^b is C _5-15 alkylene.

According to some embodiments, each one of L ^a and L ^b is C3-20 alkylene. According to some embodiments, each one of L ^a and L ^b is C _3-15 alkylene.

According to some embodiments, L ^a and L ^b collectively have at least 5 carbon atoms. According to some embodiments, L ^a and L ^b collectively have at least 6 carbon atoms. According to some embodiments, L ^a and L ^b collectively have at least 7 carbon atoms. According to some embodiments, L ^a and L ^b collectively have at least 8 carbon atoms. According to some embodiments, L ^a and L ^b collectively have at least 9 carbon atoms. According to some embodiments, L ^a and L ^b collectively have at least 10 carbon atoms. According to some embodiments, L ^a and L ^b collectively have at least 11 carbon atoms. According to some embodiments, L ^a and L ^b collectively have at least 12 carbon atoms. According to some embodiments, R ¹ is selected from the group consisting of: C _5-15 alkyl, C _5-15 alkenyl, C _5-10 alkylene-CO ₂ -C _5-10 alkyl, C _1-3 alkylene-OH, C _1-3 alkylene-O-CH ₂ CH ₂ -OH, OH, C _1-3 alkylene-halogen, C _1-3 alkylene-PO ₃ H ₂ , methyl, ethyl, propyl and C _1-3 alkylene-NH ₂ ; R ² is selected from the group consisting of: C _5-15 alkyl, C _5-15 alkenyl, C _2-12 alkylene-CO ₂ H, C _5-10 alkylene-CO ₂ -C _5-10 alkenyl, C _5-10 alkylene-CO ₂ -C _5-10 alkyl and L-N(R3)-R ₄ ; R ³ is selected from the group consisting of: H, C _5-15 alkyl and C _5-15 alkenyl, C _1-3 alkylene-OH, OH, C _1-3 alkylenehalogen, C _1-3 alkylene-PO ₃ H ₂ , methyl, ethyl, propyl, and C _1-3 alkylene-NH ₂ ; and R ⁴ is selected from the group consisting of: C _5-15 alkyl, C _5-15 alkenyl, and C _5-10 alkylene-CO ₂ -C _5-10 alkenyl.

According to some embodiments, X ^a is selected from the group consisting of: -O ₂ C-, -O-, -CO ₂ - - L ^c - O ₂ C- , - O ₂ C- L ^c - CO ₂ - , - L ^c - O ₂ C- , -CO ₂ -NH- and -CO-NH-; L ^a is selected from the group consisting of: C _4-20 alkylene, and C _0-4 alkylene; L ^b is selected from the group consisting of: C _4-20 alkylene, and C _0-4 alkylene; L ^c is selected from the group consisting of: C _1-6 alkylene-O-C _1-6 alkylene-, C _1-6 alkylene-S-S-C _1-6 alkylene, and C _1-4 alkylene; R ¹ is selected from the group consisting of: C _0-10 alkylene- Y ^a , C _1-4 alkyl, and C _5-25 alkyl, C _5-15 alkylene-CO ₂ -C _5-15 alkyl; R ² is selected from the group consisting of: C _5-25 alkyl, C _5-25 alkenyl, C _5-15 alkylene-CO ₂ -C _5-15 alkyl, C _5-15 alkylene-CO ₂ -C _5-15 alkenyl, C _2-15 alkylene-CO ₂ -C _0-4 alkylene-N(C _1-12 alkyl) ₂ , C _2-15 alkylene-CO ₂ -C _0-4 alkylene-NH-C _1-12 alkyl, C _2-15 alkylene-CO ₂ -C _0-4 alkylene-N(C _5-25 alkenyl) ₂ , C _2-15 alkylene-CO ₂ -C _0-4 alkylene-NH-C _5-25 alkenyl, C _2-15 alkylene-CO-NH-C _0-8 alkylene-N(C _1-12 alkyl) ₂ and C _5-15 alkylene-CO ₂ H; R ³ is selected from the group consisting of: H, C ₅ " ₂₅ alkyl, C _5-25 alkenyl, C _0-6 alkylene- Y ^d , and C _1-4 alkyl; R ⁴ is selected from the group consisting of: C _5-25 alkyl, C _5-25 alkenyl, C _5-15 alkylene-CO ₂ -C _5-15 alkenyl, and C _5-15 alkylene- CO ₂ -C _5-15 alkylene-N(R ⁵ )R ⁶ ; R ⁵ is selected from the group consisting of: C _1-4 alkyl, C _0-10 alkylene-OH, and C _0-10 alkylene-halogen, R ⁶ is selected from the group consisting of: C _5-25 alkyl, and C _5-25 alkenyl; Y ^a is selected from the group consisting of: O-Y ^b , halogen, PO ₃ H ₂ , NH ₂ , and NMe2; Y ^b is selected from the group consisting of: H, C _1-4 alkylene-OH, C _1-4 alkylene-(O-C _1-4 alkylene) _1-3 -OH, and CO-C _1-4 alkyl-Y ^c ; Y ^c is N(CH ₃ ) ₂ ; Y ^d is selected from the group consisting of: O-Y ^e , halogen, and NH ₂ ; Y ^e is selected from the group consisting of: H, and CO-C _1-4 alkyl- -Y ^f ; and Y ^f is selected from the group consisting of: N(CH ₃ ) ₂ , and piperazinyl, which is optionally substituted with a C _1-4 alkyl.

According to some embodiments, X ^a is selected from the group consisting of: -O ₂ C-, and -CO ₂ - -L ^C -O ₂ C-; L ^a is selected from the group consisting of: C _4-20 alkylene, and C _0-4 alkylene; L ^b is selected from the group consisting of: C _4-20 alkylene, and C _0-4 alkylene; L ^c is C _1-4 alkylene; R ¹ is selected from the group consisting of: C _0-10 alkylene- Y ^a , and C _5-25 alkyl; R ² is selected from the group consisting of: C _5-25 alkyl, C _5-25 alkenyl, and C _2-15 alkylene-CO ₂ -C _0-4 alkylene-N(C _1-12 alkyl) ₂ ; R ³ is selected from the group consisting of: C _5-25 alkyl, and C _0-6 alkylene- Y ^d ; R ⁴ is selected from the group consisting of: C _5-25 alkyl, C _5-25 alkenyl, and C _5-15 alkylene-CO ₂ -C _5-15 alkylene- -N(R ⁵ )R ⁶ ; R ⁵ is C _0-10 alkylene-OH; R ⁶ is C _5-25 alkenyl; Y ^a is O-Y ^b ; Y ^b is H; Y ^d is O-Y ^e ; and Y ^e is H.

Formula (T)

According to some embodiments, R ² is represented by CH ₂ CH ₂ -R ²² ; R ³ is represented by CH ₂ CH ₂ -R ²³ and R ⁴ is represented by CH ₂ CH ₂ -R ²⁴ ; so the lipid is further represented by the structure of Formula (F). According to some embodiments, R ¹ is OH or CH ₂ CH ₂ -R ²¹ ; R ² comprises at least 6 carbon atoms and is represented by CH ₂ CH ₂ -R ²² ; R ³ is CH ₂ CH ₂ -R ²³ ; R ⁴ comprises at least 6 carbon atoms and is represented by CH ₂ CH ₂ -R ²⁴ ; none of R ¹ , R ² , R ³ , and R ⁴ is H; so the lipid is further represented by the structure of Formula (F).

The structure of Formula (F) is presented below:

As can be understood by the person having ordinary skill in the art Formula (F) is a substructure of formula (I) which is presented herein. Thus, embodiments relating to L and to R ¹ as presented with respect to Formula (I) may similarly be used to describe Formula (F). Also, one of the options of R ¹ is CH ₂ CH ₂ -R ²¹ , as described above, thus as understood by the person having ordinary skill in the art, each of the options presented above for R ¹ , which comprise a terminal ethylene group, may be converted into a respective set of CH ₂ CH ₂ -R ²¹ and R ²¹ . For example, R ¹ is described above as optionally C _5-25 alkyl - this embodiment may be converted to R ²¹ described as C3-22 alkyl (given that the first two carbon atoms of the R ¹ are each CH ₂ ). Also, R ¹ is described above as optionally C _0-10 alkylene- Y ^a - this embodiment may be converted to R ²¹ described as C _0-8 alkylene-Y ^a (given that the first two carbon atoms of the R ¹ are each CH ₂ ). Similarly, R ² is represented by CH ₂ CH ₂ -R ²² ; R ³ is represented by CH ₂ CH ₂ -R ²³ and R ⁴ is represented by CH ₂ CH ₂ -R ²⁴ . So, similar conversions may be made to interpret R ^22-24 , in view of the embodiments previously described for R ² ’ ⁴ .

According to some embodiments, R ¹ is OH or CH ₂ CH ₂ -R ²¹ . According to some embodiments, R ¹ is OH. According to some embodiments, R ¹ is CH ₂ CH ₂ -R ²¹ . According to some embodiments, R ² comprises at least 6 carbon atoms. According to some embodiments, R ² comprises at least 7, 8, 9, 10, 11 or 12 carbon atoms. Each possibility represents a separate embodiment of the invention. According to some embodiments, R ²² comprises at least 4 carbon atoms. According to some embodiments, R ²² comprises at least 5, 6, 7, 8, 9, or 10 carbon atoms. Each possibility represents a separate embodiment of the invention. According to some embodiments, R ⁴ comprises at least 6 carbon atoms. According to some embodiments, R ⁴ comprises at least 7, 8, 9, 10, 11 or 12 carbon atoms. Each possibility represents a separate embodiment of the invention. According to some embodiments, R ²⁴ comprises at least 4 carbon atoms. According to some embodiments, R ²⁴ comprises at least 5, 6, 7, 8, 9, or 10 carbon atoms. According to some embodiments, none of R ¹ , R ² , R ³ , and R ⁴ is H.

According to some embodiments, R ²¹ is selected from the group consisting of: C _0-8 alkylene- Y ^a , C _2-4 alkenylene- Y ^a , C _1-2 alkyl, C3- ₂₅ alkyl, C ₅ -23 alkenyl, C _3-23 alkynyl, C _3-13 alkylene-CO ₂ -C _5-15 alkyl, C _3-13 alkylene-CO ₂ -C _5-15 alkenyl, C _3-13 alkylene-O ₂ C-C _5-15 alkyl, C _3-13 alkylene-O ₂ C- -C _5-15 alkenyl, C _3-13 alkenylene-CO ₂ -C _5-15 alkyl, C _3-13 alkenylene-CO ₂ -C _5-15 alkenyl, C _3-13 alkenylene-O ₂ C-C _5-15 alkyl, and C _3-13 alkenylene-O ₂ C-C _5-15 alkenyl. According to some embodiments, R ²¹ is C _0-8 alkylene- Y ^a . According to some embodiments, R ²¹ is C _2-4 alkenylene- -Y ^a . According to some embodiments, R ²¹ is C _1-2 alkyl. According to some embodiments, R ²¹ is C3- ₂₅ alkyl. According to some embodiments, R ²¹ is C _5- 23 alkenyl. According to some embodiments, R ²¹ is C _3-23 alkynyl. According to some embodiments, R ²¹ is C _3-13 alkylene-CO ₂ - -C _5-15 alkyl. According to some embodiments, R ²¹ is C _3-13 alkylene-CO ₂ -C _5-15 alkenyl. According to some embodiments, R ²¹ is C _3-13 alkylene-O ₂ C-C _5-15 alkyl. According to some embodiments, R ²¹ is C _3-13 alkylene-O ₂ C-C _5-15 alkenyl. According to some embodiments, R ²¹ is C _3-13 alkenylene-CO ₂ -C _5-15 alkyl. According to some embodiments, R ²¹ is C _3-13 alkenylene-CO ₂ - -C _5-15 alkenyl. According to some embodiments, R ²¹ is C _3-13 alkenylene-O ₂ C-C _5-15 alkyl.

According to some embodiments, R ²¹ is and C _3-13 alkenylene-O ₂ C-C _5-15 alkenyl. According to some embodiments, R ²² is selected from the group consisting of: C _4-23 alkyl, C _4-23 alkenyl, C _4-23 alkynyl, C _3-13 alkylene-CO ₂ -C _5-15 alkyl, C _3-13 alkylene-CO ₂ -C _5-15 alkenyl, C _3-13 alkylene-O ₂ C-C _5-15 alkyl, C _3-13 alkylene-O ₂ C-C _5-15 alkenyl, C _3-13 alkenylene-CO ₂ -C _5-15 alkyl, C _3-13 alkenylene-CO ₂ -C _5-15 alkenyl, C _3-13 alkenylene-O ₂ C-C _5-15 alkyl, C _3-13 alkenylene-O ₂ C- -C _5-15 alkenyl, C _0-13 alkylene-CO ₂ -C _0-4 alkylene-N(C _1-12 alkyl) ₂ , C _0-13 alkylene-CO ₂ -C _0-4 alkylene-NH-C 1 -12 alkyl, C _0-13 alkylene— CO ₂ —C _0-4 alkylene— N(C _5-25 alkenyl) ₂ , C _0-13 alkylene— -CO ₂ -C _0-4 alkylene-NH-C _5-25 alkenyl, C _0-13 alkylene-CO-NH-C _0-8 alkylene-N(C _1-12 alkyl) ₂ and C _3-13 alkylene-CO ₂ H. According to some embodiments, R ²² is C _4-23 alkyl. According to some embodiments, R ²² is C _4-23 alkenyl. According to some embodiments, R ²² is C _4-23 alkynyl. According to some embodiments, R ²² is C _3-13 alkylene-CO ₂ -C _5-15 alkyl. According to some embodiments, R ²² is C _3-13 alkylene-CO ₂ -C _5-15 alkenyl. According to some embodiments, R ²² is C _3-13 alkylene-O ₂ C-C _5-15 alkyl. According to some embodiments, R ²² is C _3-13 alkylene-O ₂ C- -C _5-15 alkenyl. According to some embodiments, R ²² is C _3-13 alkenylene-CO ₂ -C _5-15 alkyl. According to some embodiments, R ²² is C _3-13 alkenylene-CO ₂ -C _5-15 alkenyl. According to some embodiments, R ²² is C _3-13 alkenylene-O ₂ C-C _5-15 alkyl. According to some embodiments, R ²² is C _3-13 alkenylene-O ₂ C-C _5-15 alkenyl. According to some embodiments, R ²² is C _0-13 alkylene-CO ₂ - -C _0-4 alkylene — N(C _1-12 alkyl) ₂ . According to some embodiments, R ²² is C _0-13 alkylene-CO ₂ - -C _0-4 alkylene-NH-C _1-12 alkyl. According to some embodiments, R ²² is C _0-13 alkylene— CO ₂ — -C _0-4 alkylene-N(C _5-25 alkenyl) ₂ . According to some embodiments, R ²² is C _0-13 alkylene-CO ₂ - -C _0-4 alkylene-NH-C _5-25 alkenyl. According to some embodiments, R ²² is C _0-13 alkylene-CO- NH-C _0-8 alkylene-N(C _1-12 alkyl) ₂ . According to some embodiments, R ²² is C _3-13 alkylene-CO ₂ H. R ²³ is selected from the group consisting of: H, C _3-23 alkyl, C _3-23 alkenyl, C _3-23 alkynyl, C _3-13 alkylene-CO ₂ -C _5-15 alkyl, C _3-13 alkylene-CO ₂ -C _5-15 alkenyl, C _3-13 alkylene-O ₂ C-C _5-15 alkyl, C _3-13 alkylene-O ₂ C-C _5-15 alkenyl, C _3-13 alkenylene-CO ₂ -C _5-15 alkyl, C _3-13 alkenylene-CO ₂ - -C _5-15 alkenyl, C _3-13 alkenylene-O ₂ C-C _5-15 alkyl, C _3-13 alkenylene-O ₂ C-C _5-15 alkenyl, C _0-4 alkylene- Y ^d , C _0-4 alkenylene- Y ^d and C _1-2 alkyl. According to some embodiments, R ²³ is H. According to some embodiments, R ²³ is C _3-23 alkyl. According to some embodiments, R ²³ is C _3-23 alkenyl. According to some embodiments, R ²³ is C _3-23 alkynyl. According to some embodiments, R ²³ is C _3-13 alkylene-CO ₂ -C _5-15 alkyl. According to some embodiments, R ²³ is C _3-13 alkylene-CO ₂ -C _5-15 alkenyl. According to some embodiments, R ²³ is C _3-13 alkylene-O ₂ C- C _5-15 alkyl. According to some embodiments, R ²³ is C _3-13 alkylene-O ₂ C-C _5-15 alkenyl. According to some embodiments, R ²³ is C _3-13 alkenylene-CO ₂ -C _5-15 alkyl. According to some embodiments, R ²³ is C _3-13 alkenylene-CO ₂ -C _5-15 alkenyl. According to some embodiments, R ²³ is C _3-13 alkenylene-O ₂ C-C _5-15 alkyl. According to some embodiments, R ²³ is C _3-13 alkenylene-O ₂ C- -C _5-15 alkenyl. According to some embodiments, R ²³ is C _0-4 alkylene- Y ^d . According to some embodiments, R ²³ is C _0-4 alkenylene- Y ^d . According to some embodiments, R ²³ is C _1-2 alkyl. Y ^d is as described in various embodiments of the present invention, e.g., when relating to Formula (I). According to some embodiments, R ²⁴ is selected from the group consisting of: C _3-23 alkyl, C _3-23 alkenyl, C _3-23 alkynyl, C _3-13 alkylene-CO ₂ -C _5-15 alkyl, C _3-13 alkylene-CO ₂ -C _5-15 alkenyl, C _3-13 alkylene-O ₂ C-C _5-15 alkyl, C _3-13 alkylene-O ₂ C-C _5-15 alkenyl, C _3-13 alkenylene-CO ₂ -C _5-15 alkyl, C _3-13 alkenylene-CO ₂ -C _5-15 alkenyl, C _3-13 alkenylene-O ₂ C — C _5-15 alkyl, C _3-13 alkenylene-O ₂ C- -C _5-15 alkenyl and C _3-13 alkylene-CO ₂ -C _5-15 alkylene-N(R ⁵ )R ⁶ .

According to some embodiments. According to some embodiments, R ²⁴ is R ²⁴ is C _3-23 alkyl. According to some embodiments, R ²⁴ is C _3-23 alkenyl. According to some embodiments, R ²⁴ is C3- 23 alkynyl. According to some embodiments, R ²⁴ is C _3-13 alkylene-CO ₂ -C _5-15 alkyl. According to some embodiments, R ²⁴ is C _3-13 alkylene-CO ₂ -C _5-15 alkenyl. According to some embodiments, R ²⁴ is C _3-13 alkylene-O ₂ C-C _5-15 alkyl. According to some embodiments, R ²⁴ is C _3-13 alkylene- O ₂ C-C _5-15 alkenyl. According to some embodiments, R ²⁴ is C _3-13 alkenylene-CO ₂ -C _5-15 alkyl. According to some embodiments, R ²⁴ is C _3-13 alkenylene-CO ₂ -C _5-15 alkenyl. According to some embodiments, R ²⁴ is C _3-13 alkenylene-O ₂ C — C _5-15 alkyl. According to some embodiments, R ²⁴ is C _3-13 alkenylene-O ₂ C-C _5-15 alkenyl. According to some embodiments, R ²⁴ is C _3-13 alkylene-CO ₂ - -C _5-15 alkylene-N(R ⁵ )R ⁶ .

Formula (I”)

According to some embodiments, R ²² is represented by CH ₂ CH ₂ -R ³² . According to some embodiments, R ²⁴ is represented by CH ₂ CH ₂ -R ³⁴ . According to some embodiments, R ²² is represented by CH ₂ CH ₂ -R ³² and R ²⁴ is represented by CH ₂ CH ₂ -R ³⁴ , so the lipid is further represented by the structure of Formula (I”)- According to some embodiments, R ² is represented by CH ₂ (CH ₂ ) ₃ -R ³² . According to some embodiments, R ⁴ is represented by CH ₂ (CH ₂ )3-R ³⁴ . According to some embodiments, R ² is represented by CH ₂ (CH ₂ )3-R ³² and R ⁴ is represented by CH ₂ (CH ₂ ) ₃ -R ³⁴ , SO the lipid is further represented by the structure of Formula (I”). In addition, as detailed above for Formula (I’), R ¹ may be OH or CH ₂ CH ₂ -R ²¹ and R ³ may be CH ₂ CH ₂ -R ²³ , according to some embodiments. Thus, any reference to R ¹ , R ²¹ , R ³ and R ²³ , may similarly apply to the respective substituent in Formula (I”).

The structure of Formula (I”) is presented below:

As can be understood by the person having ordinary skill in the art Formula (I”) is a substructure of Formulas (I) and (F) which are presented herein. Thus, embodiments relating to L and to R ¹ as presented with respect to Formulas (I) and/or (F) may similarly be used to describe Formula (I”). Also, one of the options of R ¹ is CH ₂ CH ₂ -R ²¹ , as described above, thus as understood by the person having ordinary skill in the art, each of the options presented above for R ¹ , which comprise a terminal ethylene group, may be converted into a respective set of CH ₂ CH ₂ -R ²¹ and R ²¹ . For example, R ¹ is described above as optionally C _5-25 alkyl - this embodiment may be converted to R ²¹ described as C3-22 alkyl (given that the first two carbon atoms of the R ¹ are each CH ₂ ). Also, R ¹ is described above as optionally C _0-10 alkylene- Y ^a - this embodiment may be converted to R ²¹ described as C _0-8 alkylene- Y ^a (given that the first two carbon atoms of the R ¹ are each CH ₂ ).

Likewise, according to some embodiments, R ²² is represented by CH ₂ CH ₂ -R ³² and/or R ² is represented by CH ₂ (CH ₂ )3-R ³² - thus, similar conversions may be made to interpret R ³² , in view of the embodiments previously described for R ² (e.g., when relating to Formula (I)) and/or R ²² (e.g., when relating to Formula (I’)). For example, R ² is described above as optionally C _5-15 alkylene-CO ₂ -C _5-15 alkyl - this embodiment may be converted to (a) R ²² described as C _3-13 alkylene-CO ₂ -C _5-15 alkyl (given that the first two carbon atoms of the R ² are each CH ₂ ); and/or (b) R ³² described as C _1-11 alkylene-CO ₂ -C _5-15 alkyl (given that the first two carbon atoms of the R ²² are each CH ₂ , i.e., the first four carbon atoms of the R ² are each CH ₂ ). Similarly, according to some embodiments, R ²⁴ is represented by CH ₂ CH ₂ -R ³⁴ and/or R ⁴ is represented by CH ₂ (CH ₂ )3-R ³⁴ - thus, similar conversions may be made to interpret R ³⁴ , in view of the embodiments previously described for R ⁴ and/or R ²⁴ . Lastly, R ²³ of Formula (I”) is as described for R ²³ of Formula (I’).

According to some embodiments, R ¹ is OH or CH ₂ CH ₂ -R ²¹ . According to some embodiments, R ¹ is OH. According to some embodiments, R ¹ is CH ₂ CH ₂ -R ²¹ . According to some embodiments, R ² comprises at least 6 carbon atoms. According to some embodiments, R ² comprises at least 7, 8, 9, 10, 11 or 12 carbon atoms. Each possibility represents a separate embodiment of the invention. According to some embodiments, R ³² comprises at least 2 carbon atoms. According to some embodiments, R ³² comprises at least 3, 4, 5, 6, 7 or 8 carbon atoms. Each possibility represents a separate embodiment of the invention. According to some embodiments, R ⁴ comprises at least 6 carbon atoms. According to some embodiments, R ⁴ comprises at least 7, 8, 9, 10, 11 or 12 carbon atoms. Each possibility represents a separate embodiment of the invention. According to some embodiments, R ³⁴ comprises at least 2 carbon atoms. According to some embodiments, R ³⁴ comprises at least 3, 4, 5, 6, 7 or 8 carbon atoms. According to some embodiments, none of R ¹ , R ² , R ³ , and R ⁴ is H.

According to some embodiments, R ³² is selected from the group consisting of: C _2-21 alkyl, C _2-21 alkenyl, C _2-21 alkynyl,C _1-11 alkylene-CO ₂ -C _5-15 alkyl, C _1-11 alkylene-CO ₂ -C _5-15 alkenyl, C _1-11 alkylene-O ₂ C-C _5-15 alkyl, C _1-11 alkylene-O ₂ C-C _5-15 alkenyl, C _2-11 alkenylene-CO ₂ -C _5-15 alkyl, C _2-11 alkenylene-CO ₂ -C _5-15 alkenyl, C _2-11 alkenylene-O ₂ C — C _5-15 alkyl, C _2-11 alkenylene-O ₂ C- -C _5-15 alkenyl, C _0-11 alkylene-CO ₂ -C _0-4 alkylene-N(C _1-12 alkyl) ₂ , C _0-11 alkylene-CO ₂ -C _0-4 alkylene-NH-C 1 -12 alkyl, C _0-13 alkylene— CO ₂ — C _0-4 alkylene— N(C _5-25 alkenyl) ₂ , C _0-11 alkylene— -CO ₂ -C _0-4 alkylene-NH-C _5-25 alkenyl, C _0-11 alkylene-CO-NH-C _0-4 alkylene-N(C _1-12 alkyl) ₂ and C _1-11 alkylene-CO ₂ H. According to some embodiments, R ³² is C _2-21 alkyl. According to some embodiments, R ³² is C _2-21 alkenyl. According to some embodiments, R ³² is C _2-21 alkynyl. According to some embodiments, R ³² isC _1-11 alkylene-CO ₂ -C _5-15 alkyl. According to some embodiments, R ³² is C _1-11 alkylene-CO ₂ -C _5-15 alkenyl. According to some embodiments, R ³² is C _1-11 alkylene-O ₂ C-C _5-15 alkyl. According to some embodiments, R ³² is C _1-11 alkylene-O ₂ C- -C _5-15 alkenyl. According to some embodiments, R ³² is C _2-11 alkenylene-CO ₂ -C _5-15 alkyl. According to some embodiments, R ³² is C _2-11 alkenylene-CO ₂ -C _5-15 alkenyl. According to some embodiments, R ³² is C _2-11 alkenylene-O ₂ C-C _5-15 alkyl. According to some embodiments, R ³² is C _2-11 alkenylene-O ₂ C-C _5-15 alkenyl. According to some embodiments, R ³² is C _0-11 alkylene-CO ₂ - -C _0-4 alkylene-N(C _1-12 alkyl) ₂ . According to some embodiments, R ³² is C _0-11 alkylene-CO ₂ -C _0-4 alkylene-NH-C 1 -12 alkyl. According to some embodiments, R ³² is C _0-13 alkylene-CO ₂ -C _0-4 alkylene-N(C _5-25 alkenyl) ₂ . According to some embodiments, R ³² is C _0-11 alkylene-CO ₂ -C _0-4 alkylene-NH-C _5-25 alkenyl. According to some embodiments, R ³² is C _0-11 alkylene-CO-NH-C _0-4 alkylene-N(C _1-12 alkyl) ₂ . According to some embodiments, R ³² is C _1-11 alkylene-CO ₂ H. R ³⁴ is selected from the group consisting of: C _1-2 1 alkyl, C _2-21 alkenyl, C _2-21 alkynyl, C _1-11 alkylene-CO ₂ -C _5-15 alkyl, C _1-11 alkylene-CO ₂ -C _5-15 alkenyl, C _1-11 alkylene-O ₂ C-C _5-15 alkyl, C _1-11 alkylene-O ₂ C-C _5-15 alkenyl, C _2-11 alkenylene-CO ₂ -C _5-15 alkyl, C _2-11 alkenylene-CO ₂ -C _5-15 alkenyl, C _2-11 alkenylene-O ₂ C-C _5-15 alkyl, C _2-11 alkenylene-O ₂ C — C _5-15 alkenyl and C _1-11 alkylene-CO ₂ -C _5-15 alkylene-N(R ⁵ )R ⁶ . According to some embodiments, R ³⁴ is C _1-2 1 alkyl. According to some embodiments, R ³⁴ is C _2-21 alkenyl. According to some embodiments, R ³⁴ is C _2-21 alkynyl. According to some embodiments, R ³⁴ is C _1-11 alkylene-CO ₂ -C _5-15 alkyl. According to some embodiments, R ³⁴ is C _1-11 alkylene-CO ₂ -C _5-15 alkenyl. According to some embodiments, R ³⁴ is C _1-11 alkylene-O ₂ C — C _5-15 alkyl. According to some embodiments, R ³⁴ is C _1-11 alkylene- O ₂ C-C _5-15 alkenyl. According to some embodiments, R ³⁴ is C _2-11 alkenylene-CO ₂ -C _5-15 alkyl. According to some embodiments, R ³⁴ is C _2-11 alkenylene-CO ₂ -C _5-15 alkenyl. According to some embodiments, R ³⁴ is C _2-11 alkenylene-O ₂ C-C _5-15 alkyl. According to some embodiments, R ³⁴ is C _2-11 alkenylene-O ₂ C-C _5-15 alkenyl and C _1-11 alkylene-CO ₂ -C _5-15 alkylene-N(R ⁵ )R ⁶ .

Formula (I’”)

According to some embodiments, R ³² is represented by CH ₂ (CH ₂ )3-R ⁴² . According to some embodiments, R ³⁴ is represented by CH ₂ (CH ₂ )3-R ⁴⁴ . According to some embodiments, R ³² is represented by CH ₂ (CH ₂ )3-R ⁴² and R ³⁴ is represented by CH ₂ (CH ₂ )3-R ⁴⁴ , so the lipid is further represented by the structure of Formula (I’”)- According to some embodiments, R ² is represented by CH ₂ (CH ₂ ) ₇ -R ⁴² . According to some embodiments, R ⁴ is represented by CH ₂ (CH ₂ ) ₇ -R ⁴⁴ . According to some embodiments, R ² is represented by CH ₂ (CH ₂ ) ₇ -R ⁴² and R ⁴ is represented by CH ₂ (CH ₂ ) ₇ -R ⁴⁴ , so the lipid is further represented by the structure of Formula (I’”). In addition, as detailed above for Formulas (F) and (I”), R ¹ may be OH or CH ₂ CH ₂ -R ²¹ and R ³ may be CH ₂ CH ₂ -R ²³ , according to some embodiments. Thus, any reference to R ¹ , R ²¹ , R ³ and R ²³ , may similarly apply to the respective substituent in Formula (I’”).

The structure of Formula (I’”) is presented below As can be understood by the person having ordinary skill in the art Formula (I’ ”) is a substructure of Formulas (I), (F) and (I”), which are presented herein. Thus, embodiments relating to L and to R ¹ as presented with respect to Formulas (I), (F) and/or (I”) may similarly be used to describe Formula (I’”)- Also, one of the options of R ¹ is CH ₂ CH ₂ -R ²¹ , as described above, and it may be interpreted as also described above.

Likewise, according to some embodiments, R ³² is represented by CH ₂ (CH ₂ )3-R ⁴² and/or R ² is represented by CH ₂ (CH ₂ ) ₇ -R ³² - thus, similar conversions may be made to interpret R ⁴² , in view of the embodiments previously described for R ² (e.g., when relating to Formula (I)) and/or R ³² (e.g., when relating to Formula (I”)). For example, R ² is described above as optionally C _5-15 alkylene-CO ₂ -C _5-15 alkyl - this embodiment may be converted to (a) R ²² described as C _3-13 alkylene-CO ₂ -C _5-15 alkyl (given that the first two carbon atoms of the R ² are each CH ₂ ); (b) R ³² described as C _1-11 alkylene-CCL-C _5-15 alkyl (given that the first two carbon atoms of the R ²² are each CH ₂ , i.e., the first four carbon atoms of the R ² are each CH ₂ ); and (c) R ⁴² described as C _0-7 alkylene-CO ₂ -C _5-15 alkyl (given that R ²² is at least C4 alkylene-CO ₂ -C _5-15 alkyl and its first four carbon atoms are each CH ₂ , i.e., R ² is also at least C4 alkylene-CCL-C _5-15 alkyl and its the first eight carbon atoms of the are each CH ₂ ). Similarly, according to some embodiments, R ³⁴ is represented by CH ₂ (CH ₂ )3-R ⁴⁴ and/or R ⁴ is represented by CH ₂ (CH ₂ ) ₈ -R ⁴⁴ - thus, similar conversions may be made to interpret R ⁴⁴ , in view of the embodiments previously described for R ⁴ and/or R ³⁴ . Lastly, R ²³ of Formula (I’”) is as described for R ²³ of Formulas (I’) and/or (I”).

According to some embodiments, R ⁴² is selected from the group consisting of: H, C _1-17 alkyl, C _2-17 alkenyl, C _2-17 alkynyl,C ₀ -7 alkylene-CCL-C _5-15 alkyl, C _0-7 alkylene-CCL-C _5-15 alkenyl, C ₀ - 7 alkylene-O ₂ C-C _5-15 alkyl, C _0-7 alkylene-O ₂ C-C _5-15 alkenyl, C _2-7 alkenylene — CO ₂ -C _5-15 alkyl, C _2-7 alkenylene-CO ₂ -C _5-15 alkenyl, C _2-7 alkenylene-CLC-C _5-15 alkyl, C _2-7 alkenylene-CLC- -C _5-15 alkenyl, C _0-11 alkylene-CO ₂ -C _0-4 alkylene-N(C _1-12 alkyl) ₂ , C _0-7 alkylene-CO ₂ -C _0-4 alkylene-NH-C 1 -12 alkyl, C _0-7 alkylene— CO ₂ —C _0-4 alkylene — N(C _5-25 alkenyl) ₂ , C _0-7 alkylene— -CO ₂ -C _0-4 alkylene-NH-C _5-25 alkenyl, C _0-7 alkylene — CO-NH-C _0-4 alkylene-N(C _1-12 alkyl) ₂ and C _0-7 alkylene-CCLH. According to some embodiments, R ⁴² is H. According to some embodiments, R ⁴² is C _1-17 alkyl. According to some embodiments, R ⁴² is C _2-17 alkenyl. According to some embodiments, R ⁴² is C _2-17 alkynyl. According to some embodiments, R ⁴² is C _0-7 alkylene- -CO ₂ -C _5-15 alkyl. According to some embodiments, R ⁴² is C _0-7 alkylene-CO ₂ -C _5-15 alkenyl. According to some embodiments, R ⁴² is C _0-7 alkylene-O ₂ C-C _5-15 alkyl. According to some embodiments, R ⁴² is C ₀ -7 alkylene-O ₂ C-C _5-15 alkenyl. According to some embodiments, R ⁴² is C _2-7 alkenylene-CO ₂ -C _5-15 alkyl. According to some embodiments, R ⁴² is C _2-7 alkenylene-CO ₂ - -C _5-15 alkenyl. According to some embodiments, R ⁴² is C _2-7 alkenylene-O ₂ C-C _5-15 alkyl. According to some embodiments, R ⁴² is C _2-7 alkenylene-O ₂ C-C _5-15 alkenyl. According to some embodiments, R ⁴² is C _0-11 alkylene-CO ₂ -C _0-4 alkylene-N(C _1-12 alkyl) ₂ . According to some embodiments, R ⁴² is C _0-7 alkylene-CO ₂ -C _0-4 alkylene — NH-C _1-12 alkyl. According to some embodiments, R ⁴² is C _0-7 alkylene-CO ₂ -C _0-4 alkylene-N(C _5-25 alkenyl) ₂ . According to some embodiments, R ⁴² is C _0-7 alkylene-CO ₂ -C _0-4 alkylene-NH-C _5-25 alkenyl. According to some embodiments, R ⁴² is C _0-7 alkylene-CO-NH-C _0-4 alkylene-N(C _1-12 alkyl) ₂ . According to some embodiments, R ⁴² is C _0-7 alkylene-CO ₂ H.

According to some embodiments, R ⁴⁴ is selected from the group consisting of: H, C _1-17 alkyl, C _2-17 alkenyl, C _2-17 alkynyl, C _0-7 alkylene-CO ₂ -C _5-15 alkyl, C _0-7 alkylene-CO ₂ -C _5-15 alkenyl, C _0-7 alkylene-O ₂ C-C _5-15 alkyl, C _0-7 alkylene-O ₂ C-C _5-15 alkenyl, C _2-7 alkenylene-CO ₂ -C _5-15 alkyl, C _2-7 alkenylene-CO ₂ -C _5-15 alkenyl, C _2-7 alkenylene-O ₂ C-C _5-15 alkyl, C _2-7 alkenylene- -O ₂ C-C _5-15 alkenyl and C _0-7 alkylene-CO ₂ -C _5-15 alkylene-N(R ⁵ )R ⁶ . According to some embodiments, R ⁴⁴ is H. According to some embodiments, R ⁴⁴ is C _1-17 alkyl. According to some embodiments, R ⁴⁴ is C _2-17 alkenyl. According to some embodiments, R ⁴⁴ is C _2-17 alkynyl. According to some embodiments, R ⁴⁴ is C _0-7 alkylene-CO ₂ -C _5-15 alkyl. According to some embodiments, R ⁴⁴ is C _0-7 alkylene-CO ₂ -C _5-15 alkenyl. According to some embodiments, R ⁴⁴ is C _0-7 alkylene-O ₂ C-C _5-15 alkyl. According to some embodiments, R ⁴⁴ is C _0-7 alkylene-O ₂ C-C _5-15 alkenyl. According to some embodiments, R ⁴⁴ is C _2-7 alkenylene-CO ₂ -C _5-15 alkyl. According to some embodiments, R ⁴⁴ is C _2-7 alkenylene-CO ₂ -C _5-15 alkenyl. According to some embodiments, R ⁴⁴ is C _2-7 alkenylene-O ₂ C-C _5-15 alkyl. According to some embodiments, R ⁴⁴ is C _2-7 alkenylene- -O ₂ C-C _5-15 alkenyl and C _0-7 alkylene-CO ₂ -C _5-15 alkylene-N(R ⁵ )R ⁶ .

Formulas (la-c)

L, according to some embodiments, is selected from the group consisting of: L ¹ -X ¹ -L ² , L ⁴ — X ² — L ³ , and L ⁷ -X ³ -L ⁸ . Thus, according to some embodiments, the structure of Formula (I) is represented by the structure of Formula (la), the structure of Formula (lb), or the structure of Formula (Ic):

Each one of L ¹ , X ¹ , L ² , L ⁴ , X ² , L ³ , L ⁷ , X ³ , and L ⁸ is described herein.

According to some embodiments, L is L ¹ X ¹ L ² (i.e., Formula (la)), wherein

X ¹ is selected from the group consisting of: -O ₂ C-, -CO ₂ - L ³ -O ₂ C-,-O ₂ C-L ³ -CO ₂ -, -CO ₂ -L ³ - -CO ₂ -, L ³ - CO ₂ - and L ³ -O ₂ C-; each one of L ¹ and L ² is independently selected from the group consisting of: C _4-20 alkylene and C _4-20 alkenylene; L ³ is selected from the group consisting of: C _1-6 alkylene-(O-C _1-6 alkylene) _n -, C _2-6 alkenylene-(O-C _1-6 alkylene) _m -, C _1-6 alkylene-S-C _1-6 alkylene and C _1-6 alkylene-S-S-C _1-6 alkylene; each one of n and m is 0, 1, 2, 3, 4 or 5; R ¹ is selected from the group consisting of: C _0-6 alkylene-Y ¹ , C _2-6 alkenylene-Y ¹ and C _1-4 alkyl; R ² is selected from the group consisting of: C _5-25 alkyl, C _5-25 alkenyl, C _5-15 alkylene-CO ₂ -C _5-15 alkyl, C _5-15 alkylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkylene-O ₂ C-C _5-15 alkyl, C _5-15 alkylene-O ₂ C-C _5-15 alkenyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkenylene-O ₂ C-C _5-15 alkyl and C _5-15 alkenylene-O ₂ C-C _5-15 alkenyl and L-N(R ³ )-R ⁴ ; or R ² is selected from the group consisting of: C _5-25 alkyl, C _5-25 alkenyl, C _5-15 alkylene-CO ₂ -C _5-15 alkyl, C _5-15 alkylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkylene-O ₂ C-C _5-15 alkyl, C _5-15 alkylene-O ₂ C-C _5-15 alkenyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkenylene-O ₂ C-C _5-15 alkyl, C _5-15 alkenylene-O ₂ C-C _5-15 alkenyl, C _2-15 alkylene-CO ₂ -C _0-4 alkylene-N(C _1-12 alkyl) ₂ , and C _5-15 alkylene-O ₂ C-C _5-15 alkylene-N(C _1-12 alkyl) ₂ ; R ³ is selected from the group consisting of: C _0-6 alkylene-Y ¹ , C _2-6 alkenylene-Y ¹ , and C _1-4 alkyl;

R ⁴ is selected from the group consisting of: C _5-25 alkyl, C _5-25 alkenyl, C _5-15 alkylene-CO ₂ -C _5-15 alkyl, C _5-15 alkylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkylene-O ₂ C-C _5-15 alkyl, C _5-15 alkylene-O ₂ C- -C _5-15 alkenyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkenylene-O ₂ C-C _5-15 alkyl and C _5-15 alkenylene-O ₂ C-C _5-15 alkenyl; each Y ¹ is selected from the group consisting of: O-Y ² , halogen, PO ₃ H ₂ , PO ₃ (C _1-4 alkyl) ₂ , PO ₃ H(C _1-4 alkyl), NH ₂ , NMe ₂ , and NH-Y ² ; and Y ² is selected from the group consisting of: H, C _1-4 alkyl, C _1-4 alkylene-OH, PO ₃ H ₂ , PO ₃ (C _1-4 alkyl) ₂ , PO ₃ H(C _1-4 alkyl), CO-C _1-4 alkyl, CO-aryl, SO ₃ H, SO ₃ -(C _1-4 alkyl) and SO ₃ — aryl; or

L is L ⁴ — X ² — L ⁵ (i.e. Formula (Ib)), wherein; X ² is selected from the group consisting of: -O ₂ C-, -CO ₂ -L ⁶ -O ₂ C-, -O ₂ C-L ⁶ -CO ₂ -, -CO ₂ -L ⁶ - -CO ₂ -, L ⁶ - CO ₂ - , L ⁶ - O ₂ C- and -CO-NH-; L ⁴ is a C _0-4 alkylene; L ⁵ is selected from the group consisting of: C ₂ -20 alkylene and C _4-20 alkenylene; L ⁶ is selected from the group consisting of: C _1-6 alkylene-(O-C _1-6 alkylene)j-, C _2-6 alkenylene-(O-C _1-6 alkylene)k-, C _1-6 alkylene-S-C _1-6 alkylene and C _1-6 alkylene-S-S-C _1-6 alkylene;each one of j and k is 0, 1, 2, 3, 4 or 5; R ¹ is selected from the group consisting of: C _0-10 alkylene- Y ³ , C _2-6 alkenylene- Y ³ and C _1-4 alkyl; R ² is selected from the group consisting of: C _5-25 alkyl, C _5-25 alkenyl, C _5-15 alkylene-CO ₂ -C _5-15 alkyl, C _5-15 alkylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkylene-O ₂ C-C _5-15 alkyl, C _5-15 alkylene-O ₂ C-C _5-15 alkenyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkenylene-O ₂ C- -C _5-15 alkyl, C _5-15 alkenylene-O ₂ C-C _5-15 alkenyl, C _5-15 alkylene-CO ₂ H and L-N(R ³ )-R ⁴ ; or R ² is selected from the group consisting of: C _5-25 alkyl, C _5-25 alkenyl, C _5-15 alkylene-CO ₂ -C _5-15 alkyl, C _5-15 alkylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkylene-O ₂ C-C _5-15 alkyl, C _5-15 alkylene-O ₂ C-C _5-15 alkenyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkenylene-O ₂ C-C _5-15 alkyl, C _5-15 alkenylene-O ₂ C-C _5-15 alkenyl, C _5-15 alkylene-CO ₂ H, C _2-15 alkylene-CO ₂ -C _0-4 alkylene-N(C _1-12 alkyl) ₂ , C _2-15 alkylene-CO ₂ -C _0-4 alkylene-NH-C _5-25 alkenyl, C _2-15 alkylene-CO ₂ -C _0-4 alkylene-N(C _5-25 alkenyl) ₂ , C _2-15 alkylene-CO-NH-C _0-4 alkylene-N(C _1-12 alkyl) ₂ and C _2-15 alkylene-CO ₂ -C _0-4 alkylene-NH-C _1-12 alkyl; R ³ is selected from the group consisting of: H, C _5-25 alkyl, C _5-25 alkenyl, C _5-15 alkylene-CO ₂ -C _5-15 alkyl, C _5-15 alkylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkylene-O ₂ C-C _5-15 alkyl, C _5-15 alkylene-O ₂ C-C _5-15 alkenyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkenylene-O ₂ C- -C _5-15 alkyl and C _5-15 alkenylene-O ₂ C-C _5-15 alkenyl; R ⁴ is selected from the group consisting of: C _5-25 alkyl, C _5-25 alkenyl, C _5-15 alkylene-CO ₂ -C _5-15 alkyl, C _5-15 alkylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkylene-O ₂ C-C _5-15 alkyl, C _5-15 alkylene-O ₂ C-C _5-15 alkenyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkenylene-O ₂ C-C _5-15 alkyl, and C _5-15 alkenylene-O ₂ C-C _5-15 alkenyl; Y ³ is selected from the group consisting of: O-Y ⁴ , halogen, PO ₃ H ₂ , PO ₃ (C _1-4 alkyl) ₂ , PO ₃ H(C _1-4 alkyl), NH ₂ , and NH-Y ⁴ ; Y ⁴ is selected from the group consisting of: H, C _1-4 alkyl, C _1-4 alkylene-OH, PO ₃ H ₂ , PO ₃ (C _1-4 alkyl) ₂ , PO ₃ H(C _1-4 alkyl), CO- -C _1-4 alkyl, CO-aryl, SO ₃ H, SO ₃ -(C _1-4 alkyl) and SO ₃ -aryl; or Y ⁴ is selected from the group consisting of: H, C _1-4 alkyl, C _1-4 alkylene-OH, C _1-4 alkylene-(O-C _1-4 alkylene) _1-3 -OH, PO ₃ H ₂ , PO ₃ (C _1-4 alkyl) ₂ , PO ₃ H(C _1-4 alkyl), CO-C _1-4 alkyl, CO-aryl, CO-C _1-4 alkyl-N(CH ₃ ) ₂ , SO ₃ H, SO ₃ - (C _1-4 alkyl), NMe2, CO-C _1-4 alkyl-NM2 and SO ₃ -aryl; or L is L ⁷ — X ³ — L ⁸ (i.e. Formula (la)), wherein

X ³ is selected from the group consisting of: -O ₂ C-, -CO ₂ -L ⁹ -O ₂ C-, -O ₂ C-L ⁹ -CO ₂ -, -CO ₂ -L ⁹ - -CO ₂ - and L ⁹ - CO ₂ - , L ⁹ -O ₂ C-; L ⁷ is a C _0-4 alkylene; L ⁸ is a C _0-4 alkylene or C4 -20 alkylene; L ⁹ is selected from the group consisting of: C _0-4 alkylene-aryl-C _0-4 alkylene, C _1-4 alkylene, C _1-6 alkylene-(O-C _1-6 alkylene)h-, C _2-6 alkenylene-(O-C _1-6 alkylene);-, C _1-6 alkylene-S-C _1-6 alkylene and C _1-6 alkylene-S-S-C _1-6 alkylene; each one of h and i is 0, 1, 2, 3, 4 or 5; each one of R ¹ , R ² and R ³ is independently selected from the group consisting of: C _5-25 alkyl, C _5-25 alkenyl, C _5-15 alkylene-CO ₂ -C _5-15 alkyl, C _5-15 alkylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkylene-O ₂ C-C _5-15 alkyl, C _5-15 alkylene-O ₂ C-C _5-15 alkenyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkyl, C _5-15 alkenylene- -CO ₂ -C _5-15 alkenyl, C _5-15 alkenylene-O ₂ C-C _5-15 alkyl, and C _5-15 alkenylene-O ₂ C-C _5-15 alkenyl and R ⁴ is selected from the group consisting of: H, C _5-25 alkyl, C _5-25 alkenyl, C _5-15 alkylene-CO ₂ - -C _5-15 alkyl, C _5-15 alkylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkylene-O ₂ C-C _5-15 alkyl, C _5-15 alkylene- O ₂ C-C _5-15 alkenyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkenylene-O ₂ C-C _5-15 alkyl, and C _5-15 alkenylene-O ₂ C-C _5-15 alkenyl; or R ¹ is selected from the group consisting of: C _5-25 alkyl, C _5-25 alkenyl and C _0-10 alkylene-O-CO-C _1-4 alkyl-N(CH ₃ ) ₂ ; each one of R ² and R ⁴ is independently selected from the group consisting of: C _5-25 alkyl and C _5-25 alkenyl; and R ³ is selected from the group consisting of: H, C _5-25 alkyl, and C _5-25 alkenyl.

Formula (la)

According to some embodiments, L is L ¹ -X ¹ -L ² . Thus, according to some embodiments, the structure of Formula (I) is represented by the structure of Formula (la):

According to some embodiments, L ^a is L ¹ or L ² . According to some embodiments, L ^a is L ¹ . According to some embodiments, L ^a is L ² . According to some embodiments, L ^b is L ¹ or L ² . According to some embodiments, L ^b is L ¹ . According to some embodiments, L ^b is L ² . According to some embodiments, X ^a is X ¹ . Thus, it is to be understood that the definitions detailed above with respect to L ^a , L ^b and X ^a may similarly apply for L ¹ , L ² and X ¹ , when appropriate. According to some embodiments, X ¹ is selected from the group consisting of: -O ₂ C-, -CO ₂ -L ³ - -O ₂ C-, - O ₂ C- L ³ - CO ₂ - , - CO ₂ - L ³ - CO ₂ - , L ³ - CO ₂ - and L ³ -O ₂ C- Each possibility represents a separate embodiment.

According to some embodiments, each one of L ¹ and L ² is selected from the group consisting of: C _4-20 alkylene and C _4-20 alkenylene. Each possibility represents a separate embodiment.

According to some embodiments, L ³ is selected from the group consisting of: C _1-6 alkylene-(O- C _1-6 alkylene) _n -, C _2-6 alkenylene-(O-C _1-6 alkylene) _m -, C _1-6 alkylene-S-C _1-6 alkylene and C _1-6 alkylene-S-S-C _1-6 alkylene. Each possibility represents a separate embodiment. According to some embodiments, each one of n and m in Formula (la) is 0, 1, 2, 3, 4 or 5. Each possibility represents a separate embodiment.

According to some embodiments, R ¹ in Formula (la) is selected from the group consisting of: C _0-6 alkylene-Y ¹ , C _2-6 alkenylene-Y ¹ and C _1-4 alkyl. Each possibility represents a separate embodiment.

According to some embodiments, R ² in Formula (la) is selected from the group consisting of: C _5-25 alkyl, C _5-25 alkenyl, C _5-15 alkylene-CO ₂ -C _5-15 alkyl, C _5-15 alkylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkylene-O ₂ C-C _5-15 alkyl, C _5-15 alkylene-O ₂ C-C _5-15 alkenyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkenylene-O ₂ C-C _5-15 alkyl and C _5-15 alkenylene-O ₂ C-C _5-15 alkenyl and L-N(R ³ )-R ⁴ . Each possibility represents a separate embodiment. According to some embodiments, R ² in Formula (la) is selected from the group consisting of: R ² is selected from the group consisting of: C _5-25 alkyl, C _5-25 alkenyl, C _5-15 alkylene- CO ₂ -C _5-15 alkyl, C _5-15 alkylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkylene-O ₂ C-C _5-15 alkyl, C _5-15 alkylene-O ₂ C-C _5-15 alkenyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkenylene-O ₂ C-C _5-15 alkyl, C _5-15 alkenylene-O ₂ C-C _5-15 alkenyl, C _2-15 alkylene- -CO ₂ -C _0-4 alkylene-N(C _1-12 alkyl) ₂ , and C _5-15 alkylene-O ₂ C-C _5-15 alkylene-N(C _1-12 alkyl) ₂ . Each possibility represents a separate embodiment.

According to some embodiments, R ³ in Formula (la) is selected from the group consisting of: C _0-6 alkylene-Y ¹ , C _2-6 alkenylene-Y ¹ , and C _1-4 alkyl. Each possibility represents a separate embodiment.

According to some embodiments, R ⁴ in Formula (la) is selected from the group consisting of: C _5-25 alkyl, C _5-25 alkenyl, C _5-15 alkylene-CO ₂ -C _5-15 alkyl, C _5-15 alkylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkylene-O ₂ C-C _5-15 alkyl, C _5-15 alkylene-O ₂ C-C _5-15 alkenyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkenylene-O ₂ C-C _5-15 alkyl and C _5-15 alkenylene-O ₂ C-C _5-15 alkenyl. Each possibility represents a separate embodiment. According to some embodiments, R ⁴ in Formula (la) is selected from the group consisting of: C _5-25 alkyl, C _5-25 alkenyl, C _5-15 alkylene-CO ₂ -C _5-15 alkyl, C _5-15 alkylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkylene-O ₂ C- -C _5-15 alkyl, C _5-15 alkylene-O ₂ C-C _5-15 alkenyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkenylene-O ₂ C — C _5-15 alkyl, C _5-15 alkenylene-O ₂ C-C _5-15 alkenyl and C _5-15 alkylene-CO ₂ -C _5-15 alkylene-N(R ⁵ )R ⁶ .

According to some embodiments, each Y ¹ is selected from the group consisting of: O-Y ² , halogen, PO ₃ H ₂ , PO ₃ (C _1-4 alkyl) ₂ , PO ₃ H(C _1-4 alkyl), NH ₂ , and NH-Y ² . Each possibility represents a separate embodiment. According to some embodiments, each Y ¹ is selected from the group consisting of: O-Y ² , halogen, PO ₃ H ₂ , PO ₃ (C _1-4 alkyl) ₂ , PO ₃ H(C _1-4 alkyl), NH ₂ , NMe2, and NH- Y ² . Each possibility represents a separate embodiment of the invention.

According to some embodiments, Y ² is selected from the group consisting of: H, C _1-4 alkyl, C _1-4 alkylene-OH, PO ₃ H ₂ , PO ₃ (C _1-4 alkyl) ₂ , PO ₃ H(C _1-4 alkyl), CO-C _1-4 alkyl, CO-aryl, SO ₃ H, SO ₃ - - (C _1-4 alkyl) and SO ₃ -aryl. Each possibility represents a separate embodiment. According to some embodiments, Y ² is selected from the group consisting of: H, C _1-4 alkyl, C _1-4 alkylene-OH, PO ₃ H ₂ , PO ₃ (C _1-4 alkyl) ₂ , PO ₃ H(C _1-4 alkyl), CO-C _1-4 alkyl, CO-aryl, SO ₃ H, SO ₃ -(C _1-4 alkyl) and SO ₃ - -aryl.

It is to be understood that the definitions detailed above with respect to Y ^a and Y ^b may similarly apply for Y ¹ and Y ² , when appropriate.

According to some embodiments, X ¹ is selected from the group consisting of: -O ₂ C- and -CO ₂ - L ³ -O ₂ C-; each one of L ¹ and L ² is C _5-15 alkylene; L ³ is C _1-4 alkylene-; R ¹ is C _0-4 alkylene-Y ¹ ; R ² is selected from the group consisting of: C ₉ -20 alkyl and C ₉ -20 alkenyl; R ³ is C _1-4 alkylene-Y ¹ ; R ⁴ is selected from the group consisting of: C _5-25 alkyl, C _5-25 alkenyl, C _5-15 alkylene-CO ₂ -C _5-15 alkylene-N(R ⁵ )R ⁶ ; and each Y ¹ is OH.

According to some embodiments, X ¹ is selected from the group consisting of: -O ₂ C-, -CO ₂ -L ³ - -O ₂ C-, - O ₂ C- L ³ - CO ₂ - , - CO ₂ - L ³ - CO ₂ - , L ³ - CO ₂ - and L ³ -O ₂ C-; each one of L ¹ and L ² is selected from the group consisting of: C _4-20 alkylene and C _4-20 alkenylene; L ³ is selected from the group consisting of: C _1-6 alkylene-(O-C _1-6 alkylene) _n -, C _2-6 alkenylene-(O-C _1-6 alkylene) _m -, C _1-6 alkylene-S-C _1-6 alkylene and C _1-6 alkylene-S-S-C _1-6 alkylene; each one of n and m is 0, 1, 2, 3, 4 or 5; R ¹ is selected from the group consisting of: C _0-6 alkylene-Y ¹ , C _2-6 alkenylene-Y ¹ and C _1-4 alkyl; R ² is selected from the group consisting of: C _5-25 alkyl, C _5-25 alkenyl, C _5-15 alkylene- -CO ₂ -C _5-15 alkyl, C _5-15 alkylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkylene-O ₂ C-C _5-15 alkyl, C _5-15 alkylene-O ₂ C-C _5-15 alkenyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkenylene-O ₂ C-C _5-15 alkyl and C _5-15 alkenylene-O ₂ C-C _5-15 alkenyl and L-N(R ³ )- -R ⁴ ; R ³ is selected from the group consisting of: C _0-6 alkylene-Y ¹ , C _2-6 alkenylene-Y ¹ , and C _1-4 alkyl; R ⁴ is selected from the group consisting of: C _5-25 alkyl, C _5-25 alkenyl, C _5-15 alkylene-CO ₂ - -C _5-15 alkyl, C _5-15 alkylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkylene-O ₂ C-C _5-15 alkyl, C _5-15 alkylene- -O ₂ C-C _5-15 alkenyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkyl, C _5-15 alkenylene-CO ₂ -C _5-15 alkenyl, C _5-15 alkenylene-O ₂ C-C _5-15 alkyl and C _5-15 alkenylene-O ₂ C-C _5-15 alkenyl; Y ¹ is selected from the group consisting of: O-Y ² , halogen, PO ₃ H ₂ , PO ₃ (C _1-4 alkyl) ₂ , PO ₃ H(C _1-4 alkyl), NH ₂ , and -NH-Y ² ; and Y ² is selected from the group consisting of: H, C _1-4 alkyl, C _1-4 alkylene-OH, PO ₃ H ₂ , PO ₃ (C _1-4 alkyl) ₂ , PO ₃ H(C _1-4 alkyl), CO-C _1-4 alkyl, CO-aryl, SO ₃ H, SO ₃ -(C _1-4 alkyl) and SO ₃ - aryl.

According to some embodiments, R ¹ is selected from the group consisting of: C _1-3 alkylene-OH, OH, C _1-3 alkylene-halogen, C _1-3 alkylene-PO ₃ H ₂ , methyl, ethyl, propyl and C _1-3 alkylene-NH ₂ ; R ² is selected from the group consisting of: C _5-15 alkyl, C _5-15 alkenyl, C _5-10 alkylene-CO ₂ -C _5-10 alkenyl and L-N(R ³ )-R ⁴ ; R ³ is selected from the group consisting of: C _1-3 alkylene-OH, OH, C _1-3 alkylene-halogen, C _1-3 alkylene-PO ₃ H ₂ , methyl, ethyl, propyl, and C _1-3 alkylene-NH ₂ ; and R ⁴ is selected from the group consisting of: C _5-15 alkyl, C _5-15 alkenyl, and C _5-10 alkylene-CO ₂ - -C _5-10 alkenyl.