Field of the Disclosure

[001] The present disclosure relates generally to the treatment of cancer, optionally mesothelioma, using a combination of a platinum-based chemotherapeutic agent, optionally oxaliplatin, and a short chain fatty acid, optionally butyric acid, propionic acid or acetic acid, or a pharmaceutically acceptable salt or ester thereof. The present disclosure also relates to the sensitization of cancer cells to a platinum-based chemotherapeutic agent, optionally oxaliplatin, by exposure to said short chain fatty acid or a pharmaceutically acceptable salt or ester thereof.

Background

[002] Mesothelioma is an aggressive cancer of the lungs and/or abdomen. The most common form of mesothelioma is malignant pleural asbestos mesothelioma, associated with exposure to asbestos fibers. Median survival of patients with mesothelioma from time of diagnosis ranges between 1 and 2 years, and mortality is increasing due to the long latency of the disease.

[003] Despite advances in our understanding of its pathogenesis and etiology, malignant mesothelioma is extremely difficult to treat and remains largely unresponsive to standard modalities of cancer therapy. A combination of cisplatin and pemetrexed has been established as a current standard of care, however efficacy is poor with only about 40% of patients showing response to this therapy and an overall median survival of 12 months. Various different chemotherapeutic agents have been used, either as monotherapy or as part of polytherapy, as a second line of treatment for malignant mesothelioma, but largely without successful validation. Finding effective treatments for cancers such as mesothelioma is also made challenging due to the development of resistance to various therapeutic strategies.

[004] New, more effective therapeutic approaches to the treatment of cancers such as mesothelioma are urgently required.

Summary of the Disclosure

[005] According to one aspect, the present disclosure provides a method for treating cancer comprising administering to a subject in need thereof an effective amount of a combination comprising a platinum-based chemotherapeutic agent and a short chain fatty acid or a pharmaceutically acceptable salt or ester thereof.

[006] In a particular embodiment, the cancer is mesothelioma. The mesothelioma may be malignant mesothelioma.

[007] In a particular embodiment, the platinum-based chemotherapeutic agent is oxaliplatin.

[008] In a particular embodiment, the short chain fatty acid or pharmaceutically acceptable salt or ester thereof is selected from butyric acid or a pharmaceutically acceptable salt or ester thereof, propionic acid or a pharmaceutically acceptable salt or ester thereof, or acetic acid or a pharmaceutically acceptable salt or ester thereof.

[009] In a particular embodiment, the short chain fatty acid or pharmaceutically acceptable salt or ester thereof is butyric acid or a pharmaceutically acceptable salt or ester thereof. In a particular embodiment, the butyric acid salt comprises sodium butyrate.

[0010] Another aspect of the present disclosure provides a method for increasing the sensitivity of a cancer cell to a platinum-based chemotherapeutic agent, comprising exposing the cancer cell to an effective amount of a short chain fatty acid or a pharmaceutically acceptable salt or ester thereof.

[0011] In a particular embodiment, the cancer cell is a mesothelioma cell.

[0012] In a particular embodiment, the platinum-based chemotherapeutic agent is oxaliplatin.

[0013] In a particular embodiment, the short chain fatty acid or pharmaceutically acceptable salt or ester thereof is selected from butyric acid or a pharmaceutically acceptable salt or ester thereof, propionic acid or a pharmaceutically acceptable salt or ester thereof, or acetic acid or a pharmaceutically acceptable salt or ester thereof.

[0014] In a particular embodiment, the short chain fatty acid or pharmaceutically acceptable salt or ester thereof is butyric acid or a pharmaceutically acceptable salt or ester thereof. In a particular embodiment, the butyric acid salt comprises sodium butyrate. [0015] Typically, the sensitization renders the cell susceptible to a cytostatic or cytotoxic dose of the platinum-based chemotherapeutic agent that is lower than the cytostatic or cytotoxic dose required in the absence of the short chain fatty acid or salt or ester thereof.

[0016] Another aspect of the present disclosure provides the use of a combination comprising a platinum-based chemotherapeutic agent and a short chain fatty acid or a pharmaceutically acceptable salt or ester thereof in the manufacture of a medicament for the treatment of cancer, optionally mesothelioma.

[0017] Another aspect of the present disclosure provides the use of a short chain fatty acid or a pharmaceutically acceptable salt or ester thereof in the manufacture of a medicament for increasing the sensitivity of a cancer cell to a platinum-based chemotherapeutic agent.

[0018] In accordance with the above aspects one or both of the platinum-based chemotherapeutic agent and the short chain fatty acid or pharmaceutically acceptable salt or ester thereof may be formulated or encapsulated in a hydrogel. The hydrogel may comprise a polysaccharide, optionally alginate, and/or a peptide, polypeptide or protein.

[0019] In accordance with the above aspects one or both of the platinum-based chemotherapeutic agent and the short chain fatty acid or pharmaceutically acceptable salt or ester thereof may be formulated in a micellar composition. The micellar composition may comprise: the chemotherapeutic agent and/or the short chain fatty acid or salt or ester thereof contained in micelles; a polyol and/or co-solubiliser; and non-ionic surfactant. According to some embodiments, the micellar composition may further comprise an oil. The active agent(s) may be present in the oil. The micellar composition comprising one or both of the chemotherapeutic agent and/or the short chain fatty acid or salt or ester thereof may be formulated or encapsulated in a hydrogel.

[0020] Also provided herein is a micellar composition comprising: a platinum-based chemotherapeutic agent, optionally oxaliplatin, contained in micelles; a polyol and/or co solubiliser; and a non-ionic surfactant.

[0021] Also provided herein is a micellar composition comprising: a short chain fatty acid, optionally butyric acid, or a pharmaceutically acceptable salt or ester thereof contained in micelles; a polyol and/or co-solubiliser; and a non-ionic surfactant. [0022] Also provided herein is a micellar composition comprising: a platinum-based chemotherapeutic agent, optionally oxaliplatin, and short chain fatty acid, optionally butyric acid, or a pharmaceutically acceptable salt or ester thereof, contained in micelles; a polyol and/or co-solubiliser; and a non-ionic surfactant.

Brief Description of the Drawings

[0023] Embodiments of the present disclosure are described herein with reference, by way of non-limiting example only, the following figures.

[0024] Figure 1. Effects of oxaliplatin and sodium butyrate on cell viability of H2452 cells. Cont (Control) cells untreated with oxaliplatin; Oxa25, oxaliplatin treatment at 25 mg/ml; Oxa50, oxaliplatin treatment at 50 mg/ml; OxalOO, oxaliplatin treatment at 100 mg/ml; Oxa200, oxaliplatin treatment at 200 mg/ml. For Cont and each concentration of oxaliplatin, the left hand column shows cell viability in the absence of butyrate and the right hand column shows cell viability in the presence of 5 mM sodium butyrate.

[0025] Figure 2. Morphological changes in H2452 mesothelioma cells after 48 hours treatment with varying concentrations of oxaliplatin (25 mg/ml, 50 mg/ml, 100 mg/ml and 200 mg/ml) in the presence or absence of 5 mM sodium butyrate. Control represents H2452 cells untreated with either oxaliplatin or sodium butyrate. Lines indicate 100 miti.

Detailed Description

[0026] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, typical methods and materials are described.

[0027] Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.

[0028] Throughout this specification and the claims which follow, unless the context requires otherwise, the terms "consist of" and "consist essentially of", and variations such as "consists of" and "consists essentially of" or "consisting of" and "consisting essentially of" will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, to the exclusion of any other element, integer or step, or group of elements, integers or steps. It will be understood that such terms relate only to the exclusion of any further intentionally included element, integer or step, or group of elements, integers or steps, and that, for example, inconsequential or de minimis amounts of some components, such as naturally present impurities, may still be included.

[0029] The articles "a" and "an" are used herein to refer to one or to more than one (/.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0030] In the context of this specification, the term "about" is understood to refer to a range of numbers that a person of skill in the art would consider equivalent to the recited value in the context of achieving the same function or result.

[0031] The term "subject" as used herein refers to any mammal, including, but not limited to, livestock and other farm animals (such as cattle, goats, sheep, horses, pigs and chickens), performance animals (such as racehorses), companion animals (such as cats and dogs), laboratory test animals and humans. Typically the subject is a human.

[0032] As used herein the terms "treating", "treatment", "treating", "reduce", "reducing", "prevent" "preventing" and "prevention" and the like refer to any and all applications which remedy, or otherwise hinder, retard, or reverse the progression of a condition, infection or disease or at least one symptom of a condition, infection or disease, including reducing the severity of a condition, infection or disease. Thus, the terms "treat", "treating", "treatment", do not necessarily imply that a subject is treated until complete elimination of the condition or infection or recovery from a condition or disease. Similarly, the terms "prevent", "preventing", "prevention" and the like refer to any and all applications that prevent the establishment of a condition, infection or disease or otherwise delay the onset of a condition, infection or disease.

[0033] The term "optionally" is used herein to mean that the subsequently described feature may or may not be present or that the subsequently described event or circumstance may or may not occur. Hence the specification will be understood to include and encompass embodiments in which the feature is present and embodiments in which the feature is not present, and embodiments in which the event or circumstance occurs as well as embodiments in which it does not. [0034] As used herein the terms "effective amount" and "effective dose" include within their meaning a non-toxic but sufficient amount or dose of an active agent to provide the desired effect. The exact amount or dose required will vary from subject to subject depending on factors such as the species being treated, the age and general condition of the subject, the severity of the condition being treated, the particular active agent being administered and the mode of administration and so forth. Thus, it is not possible to specify an exact "effective amount" or "effective dose". However, for any given case, an appropriate "effective amount" or "effective dose" may be determined by one of ordinary skill in the art using only routine experimentation.

[0035] As used herein, the term "synergistically effective amount" as applied to the combination of platinum-based chemotherapeutic agent and a short chain fatty acid or a pharmaceutically acceptable salt or ester thereof refers to the amount of each component which, in combination, is effective in inhibiting growth, or reducing viability, of cancer cells, and which produces a response greater than either component alone.

[0036] As used herein the term "sensitivity" is used in its broadest context to refer to the ability of a cell to survive exposure to an agent designed to inhibit the growth of the cell, kill the cell or inhibit one or more cellular functions.

[0037] In the context of this specification, the term "hydrogel" is understood to refer to a water-swollen, cross-linked polymeric network. The cross-linked polymeric network may be chemical or physical (for example, but not limited to ionic interaction, hydrogen bonds and/or hydrophobic interactions) in nature.

[0038] Oncogenic signalling pathways play important roles in carcinogenesis, tumour growth and metastasis, including in malignant mesothelioma. Multiple oncogenic pathways are highly activated in mesothelioma cells due to inactivating mutations of tumour suppressive genes and over-expression of oncogenes as well as many increased growth factors. Therefore, targeted therapies against these signalling molecules could be an effective approach. Clinically, many small molecules and antibodies have been developed to inhibit signalling molecules as targeted therapies.

[0039] Butyric acid, a metabolite elaborated by gut commensal bacteria, exerts anti cancer effects through inhibition of multiple oncogenic signalling pathways. However, the impact of butyric acid on the efficacy of chemotherapeutic agents has not hitherto been investigated. [0040] The present inventors have demonstrated for the first time, as exemplified herein, that sodium butyrate increases the sensitivity of mesothelioma cells to oxaliplatin.

[0041] Accordingly, provided herein are methods for treating cancer comprising administering to a subject in need thereof an effective amount of a combination comprising a platinum-based chemotherapeutic agent and a short chain fatty acid or a pharmaceutically acceptable salt or ester thereof.

[0042] Also provided are methods for increasing the sensitivity of a cancer cell to a platinum-based chemotherapeutic agent, comprising exposing the cancer cell to an effective amount of a short chain fatty acid or a pharmaceutically acceptable salt or ester thereof.

[0043] Embodiments of the present disclosure relate to the treatment of cancer and to increasing the sensitivity of cancer cells to platinum-based chemotherapeutic agents. The cancer may be, for example, mesothelioma, such as malignant mesothelioma. The cancer may be another cancer for which platinum-based chemotherapeutic agents such as oxaliplatin are considered for treatment, such as colorectal (bowel) cancer, stomach cancer, pancreatic cancer and oesophageal cancer.

[0044] In accordance with embodiments of the present disclosure the platinum-based chemotherapeutic agent may be selected from, for example, oxaliplatin, cisplatin, and carboplatin. Other exemplary platinum-based chemotherapeutic agents include satraplatin, picoplatin, nedaplatin and triplatin. In exemplary embodiments the agent is oxaliplatin. The present disclosure also contemplates the use of combinations of two or more platinum-based chemotherapeutic agents.

In accordance with embodiments of the present disclosure the short chain fatty acid may be selected from, for example, formic acid (methanoic acid), acetic acid (ethanoic acid), propionic acid (propanoic acid), butyric acid (butanoic acid), isobutyric acid (2- methylpropanoic acid), valeric acid (pentanoic acid), isovaleric acid (3-methylbutanoic acid) or 2-methylbutyric acid. The short chain fatty acid is typically selected from butyric acid, propionic acid and acetic acid. Thus, embodiments of the disclosure contemplate the use of butyric acid or a pharmaceutically acceptable salt or ester thereof, propionic acid or a pharmaceutically acceptable salt or ester thereof, or acetic acid or a pharmaceutically acceptable salt or ester thereof. In particular embodiments, the short chain fatty acid or pharmaceutically acceptable salt or ester thereof is butyric acid or a pharmaceutically acceptable salt or ester thereof.

[0045] In accordance with embodiments of the present disclosure the short chain fatty acid is provided in pharmaceutically acceptable salt or ester form. In particular embodiments the short chain fatty acid is provided as a salt, such as butyrate, propionate or acetate. In particular embodiments the salt is, for example, a sodium, calcium, potassium or magnesium salt. In an exemplary embodiment the butyric acid salt is, for example, sodium butyrate or calcium butyrate.

[0046] Particular embodiments disclosed herein contemplate the sensitization of cancers and cancer cells to platinum-based chemotherapeutic agents such as oxaliplatin, by exposure to a short chain fatty acid or a pharmaceutically acceptable salt or ester thereof, optionally butyric acid, propionic acid or acetic acid, or a pharmaceutically acceptable salt or ester thereof. Sensitization may be achieved by administration to the cancer cells in vivo, or may comprise ex vivo administration to cancer cells or cancerous tissue, optionally isolated from a cancer patient.

[0047] The cancer cell, or the cancer or tumour from which the cell is derived may display resistance to the chemotherapeutic agent in the absence of treatment in accordance with the present disclosure. As used herein the term "resistance" is used in its broadest context to refer to the reduced effectiveness of a platinum-based chemotherapeutic agent (for example oxaliplatin) to inhibit the growth of a cancer cell, kill a cancer cell or inhibit one or more cellular functions, and to the ability of a cancer cell to survive exposure to an agent designed to inhibit the growth of the cell, kill the cell or inhibit one or more cellular functions. The resistance displayed by the cancer cell may be acquired, for example by prior exposure to the agent, or may be inherent or innate. The resistance displayed by a cancer cell may be complete in that the agent is rendered completely ineffective against the cell in the absence of treatment in accordance with the present disclosure or may be partial in that the effectiveness of the chemotherapeutic agent is reduced relative to a cancer cell that is completely susceptible to the chemotherapeutic agent in the absence of treatment in accordance with the present disclosure.

[0048] Also contemplated herein, for use in accordance with the methods of the present disclosure, is the formulation of the platinum-based chemotherapeutic agent and/or the short chain fatty acid or a pharmaceutically acceptable salt or ester thereof in a micellar composition. Where both the chemotherapeutic agent and the short chain fatty acid or salt or ester are formulated in a micellar composition, they may be formulated in the same or different micellar compositions.

[0049] Accordingly, provided herein are micellar compositions comprising : a) a platinum-based chemotherapeutic agent and/or a short chain fatty acid or a pharmaceutically acceptable salt or ester thereof, contained in micelles; b) a polyol and/or co-solubiliser; and c) a non-ionic surfactant.

[0050] In the micellar composition, the active agent(s) (i.e. the chemotherapeutic agent and/or short chain fatty acid, salt or ester) is typically incorporated in the interior of the micelle. Use of a micellar composition as disclosed herein may provide various advantages. In particular, use of a micellar composition provides protection to the active agent therein, providing chemical stability of the active agent. The micellar compositions described herein are typically clear, stable micellar microemulsions; such micellar compositions have been shown to remain stable for up to about many months (data not shown). The use of micellar compositions as described herein also provides for the delivery of nanoparticles comprising the chemotherapeutic agent and/or the short chain fatty acid, salt or ester. Such nanoparticle delivery may increase bioavailability of the active agent(s) formulated in the micellar composition.

[0051] In some embodiments the average size of particles in the micellar composition (i.e. the size of the micelles) may be up to about 300 nm. In accordance with particular embodiments of the present disclosure the average particle is from about 1 nm to about 250 nm. In accordance with particular embodiments of the disclosure the average particle size is about 5 nm, 10 nm, 15 nm, 20 nm, 25 nm, 30 nm, 40 nm, 45 nm, 50 nm, 55 nm,

60 nm, 65 nm, 70 nm, 75 nm, 80 nm, 85 nm, 90 nm, 95 nm, 100 nm, 105 nm, 110 nm, 115 nm, 120 nm, 125 nm, 130 nm, 135 nm, 140 nm, 145 nm, 150 nm, 155 nm, 160 nm, 165 nm, 170 nm, 175 nm, 180 nm, 185 nm, 190 nm, 195 nm, or 200 nm, or any range defined by the aforementioned sizes. In accordance with particular embodiments of the disclosure the average particle size is from about 1 nm to about 100 nm or, for example, from about 5 mn to about 200 nm. For example, the particle size may be about 1 nm, 2 nm, 3 nm, 4 nm, 5 nm, 6 nm, 7 nm, 8 nm, 9 nm, 10 nm, 11 nm, 12 nm, 13 nm, 14 nm, 15 nm, 16 nm, 17 nm, 18 nm, 19 nm, 20 nm, 21 nm, 22 nm, 23 nm, 24 nm, 25 nm, 26 nm, 27 nm, 28 nm, 29 nm, 30 nm, 31 nm, 32 nm, 33 nm, 34 nm, 35 nm, 36 nm, 37 nm, 38 nm, 39 nm, 40 nm, 41 nm, 42 nm, 43 nm, 44 nm, 45 nm, 46 nm, 47 nm, 48 nm, 49 nm, 50 nm, 51 nm, 52 nm, 53 nm, 54 nm, 55 nm, 56 nm, 57 nm, 58 nm, 59 nm, 60 nm,

61 nm, 62 nm, 63 nm, 64 nm, 65 nm, 66 nm, 67 nm, 68 nm, 69 nm, 70 nm, 71 nm, 72 nm, 73 nm, 74 nm, 75 nm, 76 nm, 77 nm, 78 nm, 79 nm, 80 nm, 81 nm, 82 nm, 83 nm, 84 nm, 85 nm, 86 nm, 87 nm, 88 nm, 89 nm, 90 nm, 91 nm, 92 nm, 93 nm 94 nm, 95 nm, 96 nm, 97 nm, 98 nm, 99 nm or 100 nm. Particle size may be measured, for example, using a NanoSight LM10-HSBT14 nanoparticle tracking analysis.

[0052] Exemplary micellar compositions which may be used in accordance with the present disclosure, and preparation of such micellar compositions, are disclosed in PCT publication W02016/141069, the disclosure of which is incorporated herein in its entirety.

[0053] For the purpose of the following discussion in relation to micellar compositions for use in accordance with the present disclosure platinum-based chemotherapeutic agents and short chain fatty acids or salts or esters thereof are, individually and collectively, referred to as "active agents". Thus, reference to an active agent is to be interpreted to mean a platinum-based chemotherapeutic agent, short chain fatty acid or a salt or ester thereof, or both.

[0054] Micellar compositions of the present disclosure typically comprise a non-ionic surfactant. In some embodiments the at least one non-ionic surfactant may have an Hydrophile-Lipophile Balance (HLB) value of from about 8 to about 20. In accordance with particular embodiments of the present disclosure the non-ionic surfactant may have an Hydrophile-Lipophile Balance (HLB) value of from about 10 to about 18, or more typically of from about 11 to about 17, for example from about 12 to about 16, or, in particularly preferred embodiments, from about 14 to about 16. For example, the non-ionic surfactant may have a Hydrophile-Lipophile Balance (HLB) value of 11, 12, 13, 14, 15, 16 or 17, or any subrange the limits of which are defined by the aforementioned values. The at least one non-ionic surfactant may comprise, consist essentially of, or consist of one or more non-ionic surfactants having the aforementioned HLB values.

[0055] The at least one non-ionic surfactant may include, but is not limited to, one or more of a polyethoxylated castor oil, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monoleate and tocopheryl polyethylene glycol succinate, however a person skilled in the art will appreciate that other non-ionic surfactants may also be used. The at least one non-ionic surfactant may obtained by reacting castor oil or hydrogenated castor oil with ethylene oxide. In certain embodiments the at least one nonionic surfactant comprises glycerol polyethylene glycol ricinoleate, fatty acid esters of polyethylene glycol, free polyethylene glycols and ethoxylated glycerol. In other embodiments the at least one non-ionic surfactant comprises glycerol polyethylene glycol hydroxystearate, fatty acid glycerol polyglycol esters, polyethylene glycols and glycerol ethoxylate. In one embodiment the at least one non-ionic surfactant is a polyethoxylated castor oil. The at least one non-ionic surfactant may comprise, consist essentially of, or consist of one or more of the aforementioned non-ionic surfactants. In some particular embodiments, the at least one non-ionic surfactant comprises, consists essentially of, or consists of polyethylene glycol-40 (PEG-40) hydrogenated castor oil, for example Kolliphor® RH40 (BASF, Australia).

[0056] In some embodiments, the amount of the at least one non-ionic surfactant in the micellar composition is from about 10 to about 50 % w/w, for example from about 10 to about 40 % w/w, for example from about 10 to about 30 % w/w, especially from about 15 to about 25 w/w/. Where a fabric product is dried following incorporation of the micellar composition, concentrations, weight percentages and weight ratios described herein, may refer to the micellar composition before drying, i.e. before the removal of water.

[0057] Micellar compositions of the present disclosure further typically comprise at least one polyol and/or at least one co-solubiliser. The at least one polyol may include, but is not limited to, glycerol or propylene glycol, however a person skilled in the art will appreciate that other polyols may also be used. In some preferred embodiments, the at least one polyol comprises, consists essentially of, or consists of glycerol. A co-solubiliser is an entity in which the active agent of choice is soluble, and which is also soluble in water. In some embodiments, the co-solubiliser comprises, consists essentially of, or consists of dimethyl sulfoxide (DMSO); use of DMSO is particularly advantageous as it facilitates preparation of clear, aqueous, stable micellar microemulsions which are not sticky, which can facilitate improved dispersion and coverage of the micellar composition on the fabric carrier. In embodiments wherein both a polyol and a co-solubiliser, such as DMSO, are used, references to weight percentages, weight ratios and concentrations herein may refer to the combined weight/concentration of polyol and co-solubiliser.

[0058] In some embodiments, the amount of the at least one polyol and/or cosolubiliser in the micellar composition is from about 2 to about 20 % w/w, for example from about 2 to about 15 % w/w, for example from about 2 to about 10 % w/w, especially from about 5 to about 10 w/w. In some embodiments, the amount of the at least one polyol and/or co-solubiliser in the micellar composition is from about 6 to about 10 % w/w, for example from about 8 to about 9% w/w. In particularly preferred embodiments, the amount of the at least one polyol and/or co-solubiliser in the micellar composition is from about 5 to about 10 % w/w.

[0059] In some embodiments the weight ratio of the at least one non-ionic surfactant to the at least one polyol and/or co-solubiliser present in the micellar compositions may be from about 5: 1 to about 1.5:1 by weight, for example from about 4: 1 to about 1.5:1, for example from about 3: 1 to about 2: 1. In some embodiments, the ratio of the at least one non-ionic surfactant to the at least one polyol and/or co-solubiliser is, for example, from about 3: 1 to about 2.5: 1, for example from about 2.6: 1 to about 3: 1, for example about 2.8: 1 by weight. In some embodiments, the ratio of the at least one non-ionic surfactant to the at least one polyol and/or co-solubiliser is, for example, from about 2.5: 1 to about 2: 1, for example from about 2.3:1 to about 2: 1, for example from about 2.3: 1 to about 2.2: 1.

[0060] The micellar compositions may comprise water. In some embodiments, the micellar composition may be prepared as micelles in aqueous solution, and incorporated into the fabric product by adsorption or impregnation onto/into the fabric as an aqueous solution. In some embodiments, water remains in the fabric product. In some alternative embodiments, the fabric product is subsequently dried to remove water.

[0061] In some embodiments, the micellar compositions comprise one or more oils. As used herein the term "oil" refers to a nonpolar chemical substance that is hydrophobic and lipophilic. Those skilled in the art will appreciate that an oil may be a natural oil that it is animal, plant or petrochemical in origin; may be derived from or extracted from a natural oil via a physical or chemical process; or may be a synthetic oil. Oils such as fatty acids or fatty acid esters may be derived from or extracted from a natural oil or prepared synthetically. For example, caprylic acid is a fatty acid found in naturally in milk fat, coconut oil and palm kernel oil and can also be made synthetically.

[0062] In some particular embodiments, the active agent(s) is present in the micellar composition in one or more oils. In some embodiments, the active agent(s) is present in the micellar composition in an oil/solvent mixture. The oil or oil mixture may act as a carrier or solvent for the at least one active agent. The oil or oil mixture may increase the stability of the micellar composition. The oil may be a natural oil in that it is animal, plant or petrochemical in origin; may be derived from or extracted from a natural oil via a physical or chemical process; or may be synthetic oil. Examples of suitable oils include, but are not limited to lemon oil, sunflower oil, soybean oil, canola oil, olive oil, corn oil, peanut oil, groundnut oil, rice bran oil, coconut oil, cottonseed oil, flax seed oil, palm oil, palm kernel oil, safflower oil, soybean oil, sesame oil, amaranth oil, linseed oil, argan oil, grapeseed oil, cranberry seed oil. hazelnut oil. hemp oil, jojoba oil, macadamia oil, mustard oil, neem oil, orange oil, rapeseed oil, avocado oil, almond oil, sweet almond oil, cashew oil, castor oil, vegetable oil, walnut oil, wheatgerm oil, kukui nut oil, tamuna oil, aloe vera oil, apricot kernel oil, borage oil (from, for example Borago officionalis ), camellia oil (from, for example, Camellia oleifera), cocoa butter oil , rosehip see oil, fish oils, ethyl oleate, ethyl linoleate, saturated fatty acids (such as, but not limited to, caproic acid, caprylic acid, capric acid, lauric acid, valeric acid, myristic acid, palmitic acid, stearic acid, arachidic acid), medium chain triglycerides, omega-3 fatty acids (such as, but not limited to, hexadecatrienoic acid, alpha-linolenic acid, stearidonic acid, ecosatrienoic acid, eicosapentaenoic acid, heneicosapentanoic acid, docosapentanoic acid, docosahexanoic acid, tetracosapentaenoic acid, tetracosahexanenoic acid), omega-6 fatty acids (such as, but not limited to, linoleic acid, gamma-linolenic acid, eicosadienoic acid, dihomo-gamma- linolenic acid, arachidonic acid, docosadienoic acid, adrenic acid, docosapentaenoic acid, tetracosatetraenoic acid, tetracosapentaenoic acid), and/or omega-9 fatty acids (such as, but not limited to, oleic acid, eicosenoic acid, mead acid, erucic acid, nervonic acid). In particular embodiments the oil is olive oil, medium chain triglycerides, ethyl oleate, ethyl linoleate, caproic acid, caprylic acid, capric acid, or lauric acid, or a combination thereof. The oil mixture may comprise an oil, a non-aqueous solvent (such as an organic solvent or an inorganic solvent and/or mixtures thereof) and/or water. Suitable organic solvents are known to those skilled in the art and may include, but are not limited to polar solvents (for example ethanol), non-polar solvents (for example hexane) and/or halogenated solvents (for example dichloromethane).

[0063] In some embodiments, the micellar composition does not comprise any alcohol, for example any lower alcohol, for example ethanol.

[0064] In some embodiments the amount of the active agent(s), and any oil/solvent in which the active agent is provided, in the micellar composition may be approximately 0.1% to 20% by weight. In other embodiments the amount of the active agent(s) is from 0.5% to 10% by weight. Alternatively, the amount of the active agent(s) in the micellar composition may be about 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9% or 9.5% by weight.

[0065] The ratio of the active agent(s), or, where the active agent(s) is provided in an oil or oil/solvent mixture, the oil and the active agent(s) or the oil/solvent mixture and the active agent(s), to the non-ionic surfactant may be from about 1 : 1.5 to about 1: 10 by weight, for example from about 1:2 to about 1 :10, for example from about 1 :4 to about 1: 10, for example from about 1 :6 to about 1 : 10, for example from about 1 :7 to about 1: 10, for example from about 1 :8 to about 1:10. In some embodiments, the ratio of the active agent(s) and any oil/solvent to at least one non-ionic surfactant may be from about 1: 1.5 to about 1 :8, for example from about 1:3 to 1:6, for example from about 1 :4 to 1 :5 by weight. In some embodiments, the ratio of the active agent(s) and any oil/solvent to at least one non-ionic surfactant may be about 1 :4.6 by weight, 1:4.7 by weight, 1:4.8 by weight, 1:4.9 by weight, 1:5.0 by weight, 1:5.1 by weight, 1:5.2 by weight, 1:5.3 by weight, 1:5.4 by weight, 1:5.5 by weight, 1:5.6 by weight, 1:5.7 by weight, 1:5.8 by weight, 1:5.9 by weight, 1:6.0 by weight, 1:6.1 by weight, 1:6.2 by weight, 1:6.3 by weight, or 1:6.4 by weight.

[0066] Before any subsequent drying is carried out, the micellar compositions typically contain water. The micellar composition may comprise at least about 40 % w/w water, for example from about 40% w/w to about 80% w/w water, for example at least about 50 % w/w water, for example at least about 60 % w/w water, for example from about 60 % to about 80 % w/w water, for example at least about 65 % w/w water. In particular embodiments, the micellar composition comprises at least about 60% w/w water, for example from about 60% w/w to about 80% w/w water, before any subsequent drying is carried out.

[0067] The ratio of water to the active agent(s) (and any oil or solvent in which the active agent(s) is contained), at least one non-ionic surfactant and at least one polyol and/or co-solubiliser may be from about 4:1 to about 1:1 by weight. Typically, the ratio of water to the active agent(s), at least one non-ionic surfactant and at least one polyol and/or co-solubiliser is from about 3.5:1 to about 1.5:1 by weight. For example, the ratio of water to the active agent(s), at least one non-ionic surfactant and at least one polyol and/or co-solubiliser may be about 3.5:1 by weight, 3.4:1 by weight, 3.3:1 by weight,

3.2:1 by weight, 3.1:1 by weight, 3.0:1 by weight, 2.9:1 by weight, 2.8:1 by weight,

2.7:1 by weight, 2.6:1 by weight, 2.5:1 by weight, 2.4:1 by weight, 2.3:1 by weight,

2.2:1 by weight, 2.1:1 by weight or 2:1 by weight.

[0068] In some embodiments the ratio of the active agent(s) to the at least one nonionic surfactant may be from about 1:5 to about 1:15 by weight, for example from about 1:7 to about 1:12, for example from about 1:8 to about 1:10 by weight, or, in some embodiments, from about 1:2 to about 1:10, for example from about 1:2 to about 1:8, for example from about 1:3 to about 1:6, for example from about 1:4 to about 1:5. For example, the ratio of the active agent(s) to the at least one non-ionic surfactant may be about 1:5 by weight, 1:5.5 by weight, 1:6 by weight, 1:6.5 by weight, 1:7 by weight, 1:7.5 by weight, 1:8 by weight, 1:8.5 by weight, 1:9 by weight, 1:9.5 by weight, 1:10 by weight, 1:10.5 by weight, 1:11 by weight, 1:11.5 by weight, 1:12 by weight, 1:12.5 by weight, 1:13 by weight, 1:13.5 by weight, 1:14 by weight, 1:14.5 by weight or 1:15 by weight.

[0069] In further embodiments the micellar compositions may further comprise at least one acidulant. Typically the at least one acidulant is citric acid, acetic acid or lactic acid, however a person skilled in the art will appreciate that other acidulants may also be used to modify and/or maintain the pH of the composition. In a particular embodiment the acidulant is citric acid. The acidulant may, in some embodiments, be present in the micellar composition in an amount of up to about 1% w/w, for example from about 0.5 to about 1% w/w or up to about 0.5 % w/w. An acidulant may be used to adjust the pH of the micellar composition to optimise stability of the micellar composition, and/or stability and/or activity of the particular active agent used. An acidulant may also be used to adjust the pH of the micellar composition for optimum performance for a particular preservative used.

[0070] In further embodiments the micellar compositions may further comprise at least one preservative. Typically the at least one preservative is potassium sorbate or phenoxyethanol, however a person skilled in the art will appreciate that other preservatives may also be used. The preservative may, in some embodiments, be present in the micellar composition in an amount of up to about 1% w/w, for example up to about 0.5 % w/w.

[0071] The micellar composition may be, according to some particular embodiments, suitable for transmucosally or transdermally administering the platinum-based chemotherapeutic agent and/or the short chain fatty acid or salt or ester thereof to a subject. In the present context, the term "transmucosal" refers to an active agent in a form which can be administered to a mucosa of a subject, such that the active agent is delivered across the mucosa for systemic distribution. Transmucosal delivery includes, for example, buccal and/or sublingual delivery and nasal mucosal delivery. In the present context, the term "transdermal" refers to an active agent in a form that can be administered to the skin, such that the active agent is delivered across the skin for systemic distribution.

[0072] Alternatively, or in addition, one or both of the platinum-based chemotherapeutic agent and the short chain fatty acid or pharmaceutically acceptable salt or ester thereof may be formulated or encapsulated in a hydrogel. A hydrogel may provide protection for the delivery of the active agent(s) contained therein against harsh gastric conditions when administered orally. A hydrogel may also be tailored to selectively release the active agent(s) at a targeted location, for example only at a particular pH, for example only in the intestine, rather than in the stomach. As well as offering protection to the active agent(s), this targeted delivery also maximises the effectiveness of the active agent(s) by delivering the delivery system directly to the desired location. [0073] The hydrogel may comprise, or may be based on, for example, a naturally occurring polymer. The polymer may be, for example, a polysaccharide or a peptide, polypeptide or protein. Examples of suitable polysaccharides include, but are not limited to, starch, alginate and agarose. In certain embodiments the hydrogel comprises alginate. In a certain embodiment the hydrogel comprises sodium alginate. Examples of suitable peptides, polypeptides and proteins include, but are not limited to, collagen or gelatin, as well as synthetic peptides such as AWRK6, dairy-derived ghrelinergic hydrolysate and other bioactive peptides.

[0074] Optionally, a micellar composition as described herein may be encapsulated within a hydrogel. In such embodiments, advantageously the particle size of the micellar composition is larger than the pore size of the hydrogel such that the micelles are retained within the hydrogel until conditions (such as pH) dictate the release of the micelle from the hydrogel. The hydrogel encapsulating the micelles may be present in the form of beads.

[0075] The hydrogel may be pH sensitive and/or adapted for delivery and release of the active agent to a desired location within the gastrointestinal tract. For example, in some embodiments the hydrogel is adapted for delivery and release of the active agent(s) at a pH of from about 4.0 to about 8.0, optionally from about pH 6.0 to about 7.5. Shifts in pH can cause a change in the charge on the polymer chain structure of the hydrogel leading to swelling and drug release. Those skilled in the art will appreciate that a range of other stimuli may be employed as an alternative to, or in addition to, pH to facilitate release of the active agent(s) from the hydrogel at the desired location within the gastrointestinal tract. For example, other chemical stimuli such as ionic strength, redox potential can cause hydrogel swelling and drug release, physical stimuli such as temperature changes, pressure changes, light sensitivity can affect polymer-polymer and polymer-water interaction responsible for swelling and drug release, and biological stimuli such as enzymes can degrade hydrogels and release drug.

[0076] In accordance with the methods of the present disclosure, for administration to subjects the platinum-based chemotherapeutic agent and the short chain fatty acid or pharmaceutically acceptable salt or ester thereof may be formulated into separate compositions or may be co-formulated into a single composition. If formulated in different compositions the compositions may be co-administered. By "co-administered" is meant simultaneous administration in the same formulation or in two different formulations via the same or different routes or sequential administration by the same or different routes. By "sequential" administration is meant a time difference of from seconds, minutes, hours or days between the administration of the two compositions. The compositions may be administered in any order.

[0077] Compositions may be administered to subjects in need thereof via any convenient or suitable route such as by topical (including dermal, transdermal, subcutaneous, etc), parenteral (including, for example, intraarterial, intravenous, intramuscular, subcutaneous), oral, nasal, mucosal (including sublingual), or intracavitary routes. Thus compositions may be formulated in a variety of forms including solutions, suspensions, emulsions, and solid forms and are typically formulated so as to be suitable for the chosen route of administration, for example as capsules, tablets, caplets, elixirs for oral ingestion, in an aerosol form suitable for administration by inhalation (such as by intranasal inhalation or oral inhalation), ointment, cream, gel, jelly or lotion suitable for topical administration, or in an injectible formulation suitable for parenteral administration. The preferred route of administration will depend on a number of factors including the condition to be treated and the desired outcome.

[0078] In general, suitable compositions may be prepared according to methods known to those of ordinary skill in the art and may include a pharmaceutically acceptable diluent, adjuvant and/or excipient. The diluents, adjuvants and excipients must be "acceptable" in terms of being compatible with the other ingredients of the composition, and not deleterious to the recipient thereof.

[0079] The most advantageous route for any given circumstance can be determined by those skilled in the art. For example, in circumstances where it is required that appropriate concentrations of the desired agent are delivered directly to the site in the body to be treated, administration may be regional rather than systemic. Regional administration provides the capability of delivering very high local concentrations of the desired agent to the required site and thus is suitable for achieving the desired therapeutic or preventative effect whilst avoiding exposure of other organs of the body to the compound and thereby potentially reducing side effects.

[0080] For administration as an injectable solution or suspension, non-toxic parenteral acceptable diluents or carriers can include Ringer's solution, medium chain triglyceride (MCT), isotonic saline, phosphate buffered saline, ethanol and 1 ,2 propylene glycol. Some examples of suitable carriers, diluents, excipients and adjuvants for oral use include peanut oil, liquid paraffin, sodium carboxymethylcellulose, methylcellulose, sodium alginate, gum acacia, gum tragacanth, dextrose, sucrose, sorbitol, mannitol, gelatine and lecithin. In addition these oral formulations may contain suitable flavouring and colourings agents. When used in capsule form the capsules may be coated with compounds such as glyceryl monostearate or glyceryl distearate which delay disintegration.

[0081] Adjuvants typically include emollients, emulsifiers, thickening agents, preservatives, bactericides and buffering agents.

[0082] Solid forms for oral administration may contain binders acceptable in human and veterinary pharmaceutical practice, sweeteners, disintegrating agents, diluents, flavourings, coating agents, preservatives, lubricants and/or time delay agents. Suitable binders include gum acacia, gelatine, corn starch, gum tragacanth, sodium alginate, carboxymethylcellulose or polyethylene glycol. Suitable sweeteners include sucrose, lactose, glucose, aspartame or saccharine. Suitable disintegrating agents include com starch, methylcellulose, polyvinylpyrrolidone, guar gum, xanthan gum, bentonite, alginic acid or agar. Suitable diluents include lactose, sorbitol, mannitol, dextrose, kaolin, cellulose, calcium carbonate, calcium silicate or dicalcium phosphate. Suitable flavouring agents include peppermint oil, oil of wintergreen, cherry, orange or raspberry flavouring. Suitable coating agents include polymers or copolymers of acrylic acid and/or methacrylic acid and/or their esters, waxes, fatty alcohols, zein, shellac or gluten. Suitable preservatives include sodium benzoate, vitamin E, alpha-tocopherol, ascorbic acid, methyl paraben, propylparaben or sodium bisulphite. Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride or talc. Suitable time delay agents include glyceryl monostearate or glyceryl distearate.

[0083] Suspensions for oral administration may further comprise dispersing agents and/or suspending agents. Suitable suspending agents include sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, poly-vinyl- pyrrolidone, sodium alginate or acetyl alcohol. Suitable dispersing agents include lecithin, polyoxyethylene esters of fatty acids such as stearic acid, polyoxyethylene sorbitol mono- or di-oleate, -stearate or -laurate. polyoxyethylenesorbitan mono-or di-oleate, -stearate or -laurate and the like.

[0084] Liquid forms for oral administration may contain, in addition to the above agents, a liquid carrier. Suitable liquid carriers include water, oils such as olive oil, peanut oil, sesame oil, sunflower oil, safflower oil, arachis oil, coconut oil, liquid paraffin, ethylene glycol, propylene glycol, polyethylene glycol, ethanol, propanol, isopropanol, glycerol, fatty alcohols, triglycerides or mixtures thereof. [0085] Methods for preparing parenteral administrable compositions are apparent to those skilled in the art, and are described in more detail in, for example, Remington's Pharmaceutical Science, 15th ed., Mack Publishing Company, Easton, Pa., hereby incorporated by reference herein. The composition may incorporate any suitable surfactant such as an anionic, cationic or non-ionic surfactant such as sorbitan esters or polyoxyethylene derivatives thereof. Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silica ceoussilicas, and other ingredients such as lanolin, may also be included.

[0086] Methods and pharmaceutical carriers for preparation of pharmaceutical compositions are well known in the art, as set out in textbooks such as Remington's Pharmaceutical Sciences, 20 ^th Edition, Williams8i Wilkins, Pennsylvania, USA. The carrier will depend on the route of administration, and again the person skilled in the art will readily be able to determine the most suitable formulation for each particular case.

[0087] Immunotherapy can be used to supplement and/or enhance the effects of treatment with the combination therapy disclosed herein. Thus, methods of the present disclosure may further comprise the administration of a therapeutically effective amount of one or more immunotherapeutic agents. Examples of immunotherapies contemplated herein include adoptive cell transfer or the administration of one or more anti-tumour or immune checkpoint inhibitors or tumour-specific vaccines. Adoptive cell transfer typically comprises the recovery of immune cells, typically T lymphocytes from a subject and introduction of these cells into a subject having a tumour to be treated. The cells for adoptive cell transfer may be derived from the tumour-bearing subject to be treated (autologous) or may be derived from a different subject (heterologous). Suitable immune checkpoint inhibitors include antibodies such as monoclonal antibodies, small molecules, peptides, oligonucleotides, mRNA therapeutics, bispecfic/trispecific/multispecific antibodies, domain antibodies, antibody fragments thereof, and other antibody-like molecules (such as nanobodies, affibodies, T and B cells, ImmTACs, Dual-Affinity Re- Targeting (DART) (antibody-like) bispecific therapeutic proteins, Anticalin (antibody-like) therapeutic proteins, Avimer (antibody-like) protein technology), against immune checkpoint pathways. Exemplary immune checkpoint antibodies include anti-CTLA4 antibodies (such as ipilimumab and tremelimumab), anti-PD-1 antibodies (such as MDX- 1106 [also known as BMS-936558], MK3475, CT-011 and AMP-224), and antibodies against PDL1 (PD-1 ligand), LAG3 (lymphocyte activation gene 3), TIM3 (T cell membrane protein 3), B7-H3 and B7-H4 (see, for example, Pardoll, 2012). However these are provided by way of example only, and those skilled in the art will appreciate that other antibodies directed to T cells or antibodies directed to other tumour cell markers may be employed. Other exemplary immunotherapeutic agents include immunomodulating drugs (such as thalidomide and lenalidomide), adjuvants (such as interleukin-2 and interferon- a), hormones and CD4 cell stimulators.

[0088] Immunotherapeutic agents may be administered at the same time, or sequentially in any order, or at different times, as the combination therapy of the present disclosure so as to provide the desired effect. Alternatively, the components may be formulated together in a single dosage unit as a combination product.

[0089] The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

[0090] The present disclosure will now be described with reference to the following specific examples, which should not be construed as in any way limiting the scope of the disclosure.

Examples Example 1

[0091] H2452 mesothelioma cells used in the present study were originally derived from a male mesothelioma patient (Phelps et a I 1996, J Cell Biochem Suppl 24:32-91). H2452 cells were thawed at 37°C and grown in a 75cm ² flask in a 37°C incubator in RPMI- 1640 medium containing 10% calf serum, in an atmosphere of 5% C02. After cells reached 80% confluence, the cells were seeded on 96-well plates and grown overnight in the incubator in serum-free medium. After starvation for 24hrs, the cells were treated with various concentrations of oxaliplatin (25 mg/ml, 50 mg/ml, 100 mg/ml and 200 mg/ml), with and without sodium butyrate (5 mM). After incubation for two days, cell viability was examined using a resazurin assay (Chao et a I ., 2013, J Cancer Res Clin Oncol 139:315- 325). The viabilities of treated cells were compared to a control comprising H2452 cells grown in serum-free medium untreated with oxaliplatin or sodium butyrate, and expressed as a percentage.

[0092] The results obtained (from three independent experiments conducted on different dates) demonstrate that oxaliplatin decreased mesothelioma cell growth in a dose-dependent manner (see Table 1 and Figure 1). The addition of sodium butyrate at 5mM significantly reduced cell viabilities, sensitizing the mesothelioma cells to oxaliplatin treatment (Table 1 and Figure 1). Sodium butyrate also markedly increased the damage to mesothelioma cells in the presence of oxaliplatin (Figure 2).

Table 1 Cell viability (mean ± standard deviation from three independent experiments, and significance (p)-value) of FI2452 mesothelioma cells after 48h treatment with oxaliplatin (Oxa) and sodium butyrate (SB)