This invention relates to nanoparticles or microparticles comprising polymer drug conjugates according to formula I optionally in conjugation with or as a blend with chitosan and/or alginate and/or PEG-PLA and/or PEG-PLGA and/or PEG-PF127 and/or PEG and/or PLA and/or PLGA and/or PF-127.

BACKGROUND OF THE INVENTION

Several viral diseases affect the respiratory system of humans leading to severe pneumonia and in some cases even death. In the last 20 years there has been two major epidemics caused by viruses, specifically SARS-CoV and SARS-CoV-2. The diseases caused by these viruses, namely SARS and Covid-19, lead to several deaths around the globe. At the moment there is no vaccine specific for these viruses and also there is no drug indicated for the treatment.

Even in the present circumstances some previously known molecules indicated for treatment of different unrelated diseases are considered as helpful with minimum clinical data. For example, chloroquine or its derivative hydroxychloroquine and some antiviral drugs are considered as treatment options. However, some of these drugs have serious side effects and can be as fatal as the virus itself.

One downside of these conventional drugs, specifically chloroquine and its derivatives is that they are administered systemically and therefore they are distributed to the entire body and accumulate in organs other then the lungs and even cause heart failure upon prolonged use. The inventors aim to solve the problem of systemic distribution of the candidate molecules and prevent side effects.

BRIEF DESCRIPTION OF THE INVENTION

Present invention relates to a nanoparticle or microparticle comprising a polymer-drug conjugate as shown with formula I, optionally in conjugation with or as a blend with chloroquine, hydroxychloroquine, mefloquine, remdesivir, nafamostat, favipiravir, camostat, chitosan and/or alginate and/or PEG-PLA and/or PEG-PLGA and/or PEG-PF127 and/or PEG and/or PL A and/or PLGA and/or PF-127 wherein; Ri and R2 are independently selected from H or -C¾; R ₃ is selected from -H or -C¾; x is a natural number between 1-250; y is a natural number between 1-70; n is a natural number between 1-200 and L is a cleavable linker and D is at least one therapeutic agent selected from a group comprising chloroquine, hydroxychloroquine, mefloquine, remdesivir, nafamostat, favipiravir, camostat or any other agent known to be effective for or indicated for a disease caused by SARS-CoV and/or SARS-CoV-2 or their pharmaceutically acceptable derivatives thereof, Z is selected from N or O; A is an end group that is optionally a polymerization initiator or a fragment thereof or A may be null; B is an end group that is optionally a polymerization initiator or a fragment thereof or B may be null. The inventors have surprisingly found that the microparticles or nanoparticles prepared according to present invention is suitable for local delivery, such as through inhalation, and because of the cleavable bond on the polymer drug conjugate the drugs are released at the target site and thus much less systemic administration and toxicity is observed. DETAILED DESCRIPTION OF THE INVENTION

The term “polymer-drug conjugate” refers to a polymeric structure having a therapeutic agent covalently attached to the polymer.

Within the present invention the term “polymer-drug conjugate as shown with formula I” refers to the structure shown with formula I wherein; Ri and R2 are independently selected from H or - CH ₃ ; R ₃ is selected from -H or -CH ₃ ; x is a natural number between 1-250; y is a natural number between 1-70; n is a natural number between 1-200 and L is a cleavable linker and D is at least one therapeutic agent selected from a group comprising comprising chloroquine, hydroxychloroquine, mefloquine, remdesivir, nafamostat, favipiravir, camostat or any other agent known to be effective for or indicated for a disease caused by SARS-CoV and/or SARS- CoV-2 or their pharmaceutically acceptable derivatives thereof, Z is selected from N or O; A is an end group that is optionally a polymerization initiator or a fragment thereof or A may be null; B is an end group that is optionally a polymerization initiator or a fragment thereof or B may be null.

The terms “polymeric backbone” and “polymer backbone” can be used interchangeably and refer to a polymer chain having side chains or pendant groups. For example, a side chain may have an oligo ethylene glycol unit and a pendant group may be bearing one therapeutic agent or any other group that can be utilized to attach a therapeutic and/or diagnostic agent or a targeting group. The term “acrylate” refers to derivatives of acrylic acids. These derivatives include the parent acid (CH2CHCO2H) and esters, thus the term “acrylate based” defines functional groups having any of the abovementioned acrylate derivatives.

The term “methacrylate” refers to derivatives of methacrylic acids. These derivatives include the parent acid (CH ₂ C(CH ₃ )C0 ₂ H) and esters. Thus the term “methacrylate based” defines functional groups having any of the abovementioned methacrylate derivatives.

The term “(meth)acrylate” refers to the terms “acrylate” and “methacrylate”. Thus, the term “(meth)acrylate” can be used interchangeably with “acrylate” and “methacrylate” and comprises all features of these terms as described above. The term “(meth)acrylate” should be construed to mean “methacrylate and/or acrylate”

Throughout the text, the term “the polymer-drug conjugate of the invention” should be construed to mean “a polymer-drug conjugate according to formula I” or “a polymer-drug conjugate of formula I” or “formula I” and these terms can be used interchangeably.

The term “PEG” refers to a polyether compound having the structure of H-(0-CH ₂ -CH ₂ )n-0R ₃ , n being a natural number between 1-200 and R ₃ selected from H or -CH _3. PEG is defined as an oligomer or polymer of ethylene oxide. The terms “PEG”, “polyethylene glycol”, “polyethylene oxide”, “PEO”, “polyoxyethylene” and “POE” refer to the same structure and may be used interchangeably within this text.

As shown by formula I the polymer-drug conjugate of the invention comprises PEG side chains. The side chains provide important physicochemical properties to the polymer-drug conjugate of the invention and leads to a polymer-drug conjugate that has better physicochemical properties in comparison to the conjugates that does not have said side chains. In a preferred embodiment n is a natural number between 1-20, preferably 1-10, most preferably 1-4. N can be for example 1 or 2 or 3 or 4 or 5 or 6 or 7. The inventors have found that, polymer-drug conjugates of formula I having an n value in between 1-4 readily forms desirable microparticles or nanoparticles without the need for further steps such as spray drying etc.

As mentioned above “L” in formula I denotes a cleavable linker. The term “Cleavable linker” refers to a group that spatially separates drug or a targeting group from the carrier molecule. The terms “linker”, “L” and “cleavable linker” refer to the same entity and can be used interchangeably. In one embodiment Ri=H, R. ₂ =H, R. ₃ =H; In another embodiment Ri=H, R ₂ =H, R ₃ = -CIR _; In another embodiment Ri=H, R ₂ = -CH ₃ , R ₃ =H; In another embodiment Ri=H, R ₂ = -CH ₃ , R ₃ — CH ₃ ; In another embodiment R ₁ —CH ₃ , R ₂ = H, R ₃ =H; In another embodiment R ₁ —CH ₃ , R ₂ = H, R ₃ —CH ₃ ; In another embodiment R ₁ —CH ₃ , R2= -CH ₃ , R ₃ =H; In another embodiment R ₁ —CH ₃ ,

R ₂ = -CH ₃ , R ₃ = -CH ₃ . The term “random copolymer” refers to a copolymer wherein the monomers forming the copolymer follow in any order. The term “block copolymer” refers to a copolymer wherein all of one type of monomer is grouped together and the all of the other type of monomers are grouped together. The polymer-drug conjugates of the invention can be in the form of block copolymer or random copolymers. In a preferred embodiment the polymer-drug conjugates of the invention are in the form of random copolymer. The linkers are cleavable so that the therapeutic agent can be released, for example, under reducing conditions, oxidizing conditions or by hydrolysis of an ester, amide, hydrazide, or similar linkage that forms the covalent bond between the linker and the therapeutic agent.

Said cleavable linker can be any hydrocarbon or substituted hydrocarbon based compound which is capable of dissociating under physiological conditions. In a preferred embodiment the linker can be selected from compounds that are cleaved under the physiological conditions of the target site or with the help of the overexpressed enzymes present in the target site. In a preferred embodiment of the invention the target site is the lungs.

The linker can also be a Ci-Cio hydrocarbon or a Ci-Cio substituted or hetero substituted hydrocarbon such that it comprises a functional group that dissociates under physiological conditions, such as an, ester, imine, amide, disulfide, carbonate, carbamate,.

The term “Ci-Cio hydrocarbon” refers to a hydrocarbon chain having 1 to 10 C atoms in the backbone.

The term “Ci-Cio substituted hydrocarbon” refers to a hydrocarbon chain having 1 to 10 C atoms in the backbone wherein one or more of its hydrogen atoms replaced by atoms of groups of other elements such as alcohol, amine, carboxyl, thiol etc.

The term “Ci-Cio heterosub stituted hydrocarbon” refers to a hydrocarbon chain having 1 to 10 C atoms in the backbone wherein at least one of the C atoms is substituted with an atom other than C such as nitrogen, oxygen, phosphorus, sulfur or a halogen atom. These substituents include but not limited to lower alkoxy such as methoxy, ethoxy, butoxy; ethers;;; esters; hetroaryl; heterocyclic; hydroxyl; protected hydroxyl; acyl; acyloxy; amino; amido; imine, disulfide, carbonate, carbamate, , hydrazine.

In an embodiment of the invention, the linker is a Ci-Cio hetero substituted hydrocarbon comprising at least one disulfide functional group.. In an embodiment of the invention the linker is a Ci-Cio hetero substituted hydrocarbon comprising at least one ester functional group. In an embodiment of the invention the linker is a Ci-Cio hetero substituted hydrocarbon comprising at least one imine functional group. In an embodiment of the invention the linker is a Ci-Cio hetero substituted hydrocarbon comprising at least one amide functional group. In an embodiment of the invention the linker is a Ci-Cio hetero substituted hydrocarbon comprising at least one carbonate functional group. In an embodiment of the invention the linker is a Ci-Cio hetero substituted hydrocarbon comprising at least one carbamate functional group.

In another embodiment of the invention the linker may comprise a Ci-Cio substituted or hetero substituted hydrocarbon comprising two or more functional groups selected from the group comprising, ester, imine, amide, disulfide, carbonate, carbamate,. The term “any other agent known to be effective for a disease caused by SARS-CoV and/or SARS-CoV-2” refers to any agent that prevents or leads to alleviation of at least one of the symptoms of a disease caused by SARS-CoV and/or SARS-CoV-2.

Chloroquine, hydroxychloroquine, mefloquine, remdesivir, nafamostat, favipiravir, camostat or any other agent known to be effective for or indicated for a disease caused by SARS-CoV and/or SARS-CoV-2 or their pharmaceutically acceptable derivatives thereof can be present in an amount in between 1% to 50% by weight of the polymer-drug conjugate, preferably in an amount between 2% to 45% by weight of the drug-polymer conjugate and most preferably in an amount between 3% to 40% by weight of the drug-polymer conjugate. The therapeutic agent can be present in an amount in the range of for example; 4% to 45% or 5% to 40% or 6% to 38% or 7% to 35% or 8% to 30% by weight of the drug-polymer conjugate.

A preferred embodiment of the invention relates to a nanoparticle or microparticle comprising a polymer-drug conjugate as shown with formula I optionally in conjugation with or as a blend with chitosan and/or alginate and/or PEG-PLA and/or PEG-PLGA and/or PEG-PF127 wherein; Ri and R2 are independently selected from H or -CH ₃ ; R ₃ is selected from -H or -CH ₃ ; x is a natural number between 1-250; y is a natural number between 1-70; n is a natural number between 1-200 and L is a cleavable linker and D is at least one therapeutic agent selected from a group comprising chloroquine, hydroxychloroquine, mefloquine, remdesivir, nafamostat, favipiravir, camostat or their pharmaceutically acceptable derivatives thereof, Z is selected from N or O; A is an end group that is optionally a polymerization initiator or a fragment thereof or A may be null; B is an end group that is optionally a polymerization initiator or a fragment thereof or B may be null.

A preferred embodiment of the invention relates to a nanoparticle or microparticle comprising a polymer-drug conjugate as shown with formula I as described above wherein x:y have a ratio in between 5:1 to 1:1, preferably in between 4,5:1 to 1:1, most preferably between 4:1 to 1,5:1. The inventors have found that when the monomers forming the polymer-drug conjugate of formula I are such that x:y are in a ratio in between 5:1 to 1:1 the polymer-drug conjugate that forms is in the form of a nanoparticle or microparticle without addition of other chemicals. The term “end group” refers to functionalities or constitutional units that are at the extremity of a polymer. The end groups shown as A and B can be identical to or different from one another.

A and B can optionally be a polymerization initiator or a fragment thereof. Particularly when an initiator is used in the polymerization reaction, the initiator fragment may stay as an end group to the polymer. The initiator used herein, may be any material suitable for initiating the polymerization reaction known in the art. The term “fragment” as used herein refers to compounds that form due to breaking of one or more of the covalent bonds forming the initiator molecule.

A and/or B is optionally null.

In an embodiment of the invention A is null and B is a polymerization initiator or a fragment of a polymerization initiator. In another embodiment B is null and A is a polymerization initiator or a fragment of a polymerization initiator. In another embodiment A and B are both fragments of a polymerization initiator however they are structurally different from one another. In other words, A and B are different fragments of the same initiator. In another embodiment A and B are both fragments of a polymerization initiator and they have the same chemical structure.

The measurement of the amount of drug in the polymer conjugate of the invention is made by using conventional techniques well-known in the art, for example by calculation of the drug ratio from an 'H-NMR of the polymer-drug conjugate. In another embodiment the polymer-drug conjugate of the invention has an average molecular weight in between 3 kDa to 150 kDa, preferably between 4kDa to 120 kDa, most preferably between 5 kDa to 100 kDa.

Molecular weight of the polymer-drug conjugate of the invention is determined by using conventional techniques known in the art for example by using gel permeation chromatography (GPC).

Polymer-drug conjugate of the invention can be prepared by using conventional methods disclosed in the art.

The cleavable linker according to present invention can be obtained from commercial sources or may be prepared according to known methods provided in literature.

The polymer-drug conjugate of the invention can be prepared by any of the known polymerization methods. Any suitable initiators and/or catalysts known in the art can be used for the preparation of the polymer-drug conjugate of the present invention. Where a polymerization initiator is used, the initiator or a fragment thereof may be present in the resulting polymer-drug conjugate.

The polymer backbone of the polymer-drug conjugate of the invention can be obtained by for example bulk polymerization, solution polymerization and/or suspension polymerization techniques known in the art.

The polymerization technique used for the preparation of the polymer-drug conjugate of the present invention may propagate through free-radical polymerization or controlled/living free radical polymerization. Herein the term “controlled/living free radical polymerization” refers to atom transfer radical polymerization (ATRP), Reversible addition fragmentation chain transfer (RAFT) polymerization, iodine transfer polymerization (ITP), selenium centered radical mediated polymerization, telluride mediated polymerization (TERP), nitroxide mediated polymerization (NMP). In a preferred embodiment of the invention RAFT polymerization is used to prepare the polymer-drug conjugates of the invention.

A polymerization initiator as used herein refers to a chemical compound that reacts with a monomer to form an intermediate compound capable of linking successively with a large number of other monomers into a polymeric compound.

In an embodiment the present invention relating to nanoparticles or microparticles comprising a polymer-drug conjugate as shown with formula I may further comprise a targeting group. Said targeting agent can be as attached to the polymer-drug conjugate as shown with formula I or can be embedded into the nanoparticle of microparticle structure or in the case that the microparticle or nanoparticle comprises a coating it can be in the coating mixture or can be embedded into the coating layer. The term "targeting group" means a molecule which serves to deliver the polymer-drug conjugate of the invention to a specific site for the desired activity, i.e. it provides localization of the compound. The localization is mediated by specific recognition of molecular determinants, molecular size of the targeting agent or conjugate, ionic interactions, hydrophobic interactions, and the like. Other mechanisms of targeting an agent to a particular tissue or region are known to those of skill in the art. Targeting ligands include, for example, molecules that bind to molecules on a targeted cell surface. Exemplary targeting ligands include antibodies, antibody fragments, small organic molecules, peptides, peptoids, proteins, polypeptides, oligosaccharides, transferrin, HS- glycoprotein, coagulation factors, serum proteins, beta-glycoprotein and the like.

The terms “targeting agent”, “targeting group” or “targeting ligand” refers to the same entity and can be used interchangeably within the context of the present invention. In an embodiment, the present invention relates to nanoparticles or microparticles comprising a polymer-drug conjugate as shown with formula I wherein said nanoparticles or microparticles are coated with a compound selected from the group comprising glucose, sucrose, maltose, fructose, trehalose, lactose, dextrose, tagatose, raffmose, erythritol, maltitol, maltodextrin mannitol, sorbitol,, polydextrose, chitosan, alginate, PEG-PLA, PEG-PLGA, PEG-PF127, PEG, PLGA, PLA, PF-127.

In an embodiment, the present invention relates to nanoparticles or microparticles comprising a polymer-drug conjugate as shown with formula I wherein polymer-drug conjugate as shown with formula I is blended with a first compound and then the formed nanoparticles or microparticles are coated with a second compound. The first compound is selected from a group comprising chitosan, alginate, PEG-PLA, PEG-PLGA, PEG-PF127, PLA, PLGA, PF-127, chloroquine, hydroxychloroquine, mefloquine, remdesivir, nafamostat, favipiravir, camostat or their pharmaceutically acceptable derivatives thereof. The second compound is selected from a group comprising glucose, sucrose, maltose, fructose, trehalose, lactose, dextrose, tagatose, raffmose, erythritol, maltitol, maltodextrin mannitol, sorbitol,, polydextrose, chitosan, alginate, PEG-PLA, PEG-PLGA, PEG-PF127, PEG, PLGA, PLA, PF-127.

In an embodiment, the present invention relates to nanoparticles or microparticles comprising a polymer-drug conjugate as shown with formula I in conjugation with chitosan wherein said conjugate is coated with alginate and/or PEG-PLA and/or PEG-PLGA and/or PEG-PF127 and/or PL A and/or PLGA and/or PF127.

The nanoparticles according to the invention can have a size in the range of 1-999 nm, preferably in the range of 10-900 nm, most preferably 50-850 nm. Any sample wherein at least 90% of the particles have a size in the range of 1-999 nm is considered as a nanoparticle.

The microparticles according to the invention can have a size in the range of 1-15 pm, preferably in the range of 1-10 pm, most preferably 1-6 pm. Any sample wherein at least 90% of the particles have a size in the range of 1-5 pm is considered as a microparticle.

Chitosan is a linear polysaccharide composed of randomly distributed P-(l 4)-linked D- glucosamine (deacetylated unit) and N-acetyl-D-glucosamine (acetylated unit). Chitosan can have an average molecular weight in between 2kDa to 300kDa.

Alginate is a salt of alginic acid which is a linear copolymer with homopolymeric blocks of (1- 4)-linked b-D-mannuronate (M) and its C-5 epimer a-L-guluronate (G) residues, respectively, covalently linked together in different sequences or blocks. Alginate can preferably be in the form of sodium alginate. Alginate, preferably sodium alginate, can have an average molecular weight in between lkDa to 200kDa.

PLGA refers to a co polymer comprising the monomers of lactide and glycolide in various ratios. The ratio of lactide to glycolide is prefereably 50:50 is a preferred embodiment of the invention. The PLGA polymer can have a molecular weight in the range of 5-20 kDa, preferably 7-17 kDa. PEG-PLGA refers to a block copolymer wherein one block is polyethylene glycol and the other block is a random copolymer of polylactide-co-glycolide. Herein the blocks can be attached to one another with any conventional means known to a person skilled in the art.

PLA refers to a polymer comprising the monomer of lactide. the PLA polymer can have a molecular weight in the range of 5-20 kDa, preferably 7-17 kDa.

PEG-PLA refers to a block copolymer wherein one block is polyethylene glycol and the other block is a polylactide. Herein the blocks can be attached to one another with any conventional means known to a person skilled in the art.

PF127 also known as poloxamer 407 refers to a triblock copolymer made up of hydrophobic residue of polyoxypropylene (POP) between the two hydrophilic units of polyoxyethylene (POE) also known as polyethylene glycol (PEG). The approximate lengths of the two PEG blocks is 101 repeat units while the approximate length of the propylene glycol block is 56 repeat units.

PEG that forms a block copolymer with PLA or PLGA can be a linear or branched PEG, for example can be randomly branched or can be in star shape or can have multiple arms, such as at least two arms. PEG that forms a block copolymer with PLA or PLGA can have a molecular weight in the range of 2-50 kDa.

Another embodiment of the present invention provides a method for delivering a therapeutic agent, comprising administering to a subject an effective amount of a microparticle or nanoparticle comprising polymer-drug conjugate shown with formula I optionally in conjugation with or as a blend with chitosan and/or alginate and/or PEG-PLA and/or PEG-PLGA and/or

PEG-PF127 and/or PLA and/or PLGA and/or PF127. Another embodiment of the invention is the microparticle or nanoparticle comprising polymer- drug conjugate of the invention optionally in conjugation with or as a blend with chloroquine and/or hydroxychloroquine and/or mefloquine and/or remdesivir and/or nafamostat and/or favipiravir and/or camostat and/or chitosan and/or alginate and/or PEG-PLA and/or PEG-PLGA and/or PEG-PF127 and/or PLA and/or PLGA and/or PF127 for use in treatment of a variety of disorders that require the delivery of chloroquine, hydroxychloroquine, mefloquine, remdesivir, nafamostat, favipiravir, camostat or any other agent known to be effective for or indicated for a disease caused by SARS-CoV and/or SARS-CoV-2 or their pharmaceutically acceptable derivatives thereof. In a preferred embodiment, the invention is related to microparticle or nanoparticle comprising a polymer-drug conjugate shown with formula I optionally in conjugation with or as a blend with chloroquine and/or hydroxychloroquine and/or mefloquine and/or remdesivir and/or nafamostat and/or favipiravir and/or camostat and/or chitosan and/or alginate and/or PEG-PLA and/or PEG- PLGA and/or PEG-PF127 and/or PLA and or PLGA and/or PEG and/or PF-127 for use as a medicament for treatment of a disease caused by SARS-CoV and/or SARS-CoV-2 viruses.

As used herein, "treat" or "treating" means to inhibit, reduce, modulate, ameliorate, or block at least one symptom that characterizes a pathologic condition, in a subject threatened by, or afflicted with, the condition

Thus, according to the invention there is provided a pharmaceutical composition comprising a microparticle or nanoparticle comprising polymer-drug conjugate according to formula I optionally in conjugation with or as a blend with chloroquine and/or hydroxychloroquine and/or mefloquine and/or remdesivir and/or nafamostat and/or favipiravir and/or camostat and/or chitosan and/or alginate and/or PEG-PLA and/or PEG-PLGA and/or PEG-PF127 and/or PLA and or PLGA and/or PEG and/or PF-127 and at least one pharmaceutically acceptable diluent, excipient and/or carrier. The term “treatment” includes either therapeutic or prophylactic therapy. The composition comprising a microparticle or nanoparticle comprising the polymer-drug conjugate of the invention optionally in conjugation with or as a blend with chloroquine and/or hydroxychloroquine and/or mefloquine and/or remdesivir and/or nafamostat and/or favipiravir and/or camostat and/or chitosan and/or alginate and/or PEG-PLA and/or PEG-PLGA and/or PEG-PF127 and/or PLA and or PLGA and/or PEG and/or PF-127 may be in any suitable form depending upon the desired method of administering it to a patient. The composition comprising polymer drug conjugates of the invention can be formulated to be administered orally, e.g. in the form of liquid dispersions or aqueous or oily suspensions or they can formulated for parenteral administration, for example for subcutaneous, intravenous, intramuscular, intrastemal, intraperitoneal, intradermal, transdermal or other infusion techniques. The composition comprising the polymer drug conjugates of the invention can also be formulated for administration by inhalation in form of an aerosol, dry powder or solution for administration with an inhaler or nebulizer. The polymer-drug conjugates of the invention are preferably administered to a subject transdermally, subcutaneously, intranasally, intravenously, intramuscularly, intratumorally or via inhalation. The most suitable route for administration in any given case will depend on the particular therapeutic agent present in the polymer-drug conjugate of the present invention, the subject, and the nature and severity of the disease and the physical condition of the subject. In a most preferred embodiment of the invention a microparticle or nanoparticle comprising the polymer-drug conjugate of the invention optionally in conjugation with or as a blend with chloroquine and/or hydroxychloroquine and/or mefloquine and/or remdesivir and/or nafamostat and/or favipiravir and/or camostat and/or chitosan and/or alginate and/or PEG-PLA and/or PEG- PLGA and/or PEG-PF127 and/or PLA and or PLGA and/or PEG and/or PF-127 is formulated in form of a dry powder or aerosol or solution for for administration with an inhaler or nebulizer. This way the inventors were able to deliver the therapeutics agents of chloroquine, hydroxychloroquine, mefloquine, remdesivir, nafamostat, camostat or any other agent known to be effective for or indicated for a disease caused by SARS-CoV and/or SARS-CoV-2 or their pharmaceutically acceptable derivatives thereof directly to the target site, that is lungs and any systemic absorption of the active agents and possible side effects originating from them are prevented. Furthermore, a more effective treatment is provided.

The micro or nanoparticles comprising the polymer-drug conjugates shown with formula I may be administered in combination, e.g. simultaneously, sequentially or separately, with one or more other therapeutically active compounds selected from a group comprising chloroquine, hydroxychloroquine, mefloquine, remdesivir, nafamostat, favipiravir, camostat or any other agent known to be effective for or indicated for a disease caused by SARS-CoV and/or SARS- CoV-2, vitamins known in the arts such as vitamin A, Vitamin Bl, Vitamin B2, Vitamin B3, vitamin B5, vitamin B6, vitamin B7, vitamin B9, vitamin B12, vitamin C, vitamin D2, vitamin D3, vitamin E, vitamin K and minerals such as potassium, chlorine, sodium, calcium, phosphorus, magnesium, iron, zinc, manganese, copper, iodine, chromium, molybdenum, selenium, cobalt and antioxidants known in the art such as quercetin, coenzyme Q-10, ubiquinol, glutathione, astaxanthin, lutein, catechin, gallocatechin, anthocyanins, reservatrol, curcumin or an agent selected from the group of antivirals, antiinfectives, antimicrobials, immunomodulatory agents.

Said second therapeutic agent can be selected from the therapeutic agents listed above on the condition that it is different from the one present in the polymer-drug conjugate of the invention. Comprising in the context of the present specification is intended to meaning including.

Where technically appropriate, embodiments of the invention may be combined.

Embodiments are described herein as comprising certain features/elements. The disclosure also extends to separate embodiments consisting or consisting essentially of said features/elements.

Technical references such as patents and applications are incorporated herein by reference. Any embodiments specifically and explicitly recited herein may form the basis of a disclaimer either alone or in combination with one or more further embodiments.

The invention will now be described with reference to the following examples, which are merely illustrative and should not in any way be construed as limiting the scope of the present invention.

EXAMPLES: Example 1: Synthesis and Characterization of Copolymer P(OEGMA-HCQ-CB).

P(OEGMA) (1.22 mmol) and HCQ-MA (0.40 mmol) were dissolved in anhydrous DMF (4 mL) and the mixture was stirred for 30 min under N2. 4-cyano-4-(thiobenzoylthio)pentanoic acid (0.028 mmol) as a chain trasfer reagent and AIBN (5.6 x 10 ³ mmol) as an initiator were added to polymer the polymer solution under N2. The reaction was sealed and heated at 70 °C for 21 hours. To purify the copolymer; it was precipitated in diethyl ether (100 mL) and then it was washed with diethyl ether (3 x 25 mL). The product was dried under vacuo and obtained as a pink viscous solid. ¾ NMR (400 MHz, CDC1 ₃ ): d/ppm = 8.48 (br s, 1H), 7.92 (s, 1H), 7.83 (s, 1H), 7.36 (br s, 1H); 6.43 (br s, 1H); 4.27-4.08 (br s, 2H), 3.65 (br s, 14H); 3.55 (br s, 2H), 3.36 (s, 3H), 1.01-0.87 (m, CH2 ve CH3 polymer backbone). GPC: Mn = 20 kDa; Mw / Mn = 1.26.

It was seen that the particles obtained with this method readily forms nanoparticles as confirmed with the DLS data (Figure 1).

Example 2: Synthesis and Characterization of Copolymer P(OEGMA-HCQ-CB).

P(OEGMA) (1.22 mmol) and HCQ-MA (0.40 mmol) were dissolved in anhydrous DMF (4 mL) and the mixture was stirred for 30 min under N2. 4-cyano-4-(thiobenzoylthio)pentanoic acid (0.012 mmol) as a chain trasfer reagent and AIBN (2.51 x 10-3 mmol) as an initiator were added to polymer the polymer solution under N2. The reaction was sealed and heated at 70 oC for 21 hours. To purify the copolymer; it was precipitated in diethyl ether (100 mL) and then it was washed with diethyl ether (3 x 25 mL) The product was dried under vacuo and obtained as a yellow viscous. 1H NMR (400 MHz, CDC13): d/ppm = 8.48 (br s, 1H), 7.91 (s, 1H), 7.82 (br s, 1H); 7.35 (br s,lH); 6.43 (br s, 1H); 4.27-4.07 (br s, 2H), 3.65 (br s, 14H); 3.55 (br s, 2H), 3.36 (s, 3H), 1.01-0.87 (m, CH2 ve CH3 polymer backbone). GPC: Mn = 49 kDa; Mw / Mn = 1.52.

It was seen that the particles obtained with this method readily forms microparticles as confirmed with the DLS data (Figure 2).