Compositions comprising silica particles and methods for treatment

Abstract

The present application relates to, inter alia, methods for treating neoplasms and compositions comprising silica particles for use in the same and for treatment of skin conditions, including, without limitation, precancerous and cancerous skin lesions.

Description

[0001] AMN-014PC / 120570-5014

[0002] COMPOSITIONS COMPRISING SILICA PARTICLES AND METHODS FOR TREATMENT CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 789,534 filed April 16, 2025, and titled “COMPOSITIONS COMPRISING SILICA PARTICLES AND METHODS FOR TREATMENT,” the content of which are incorporated by reference herein in its entirety.

[0003] BACKGROUND

[0004] Cancers such as but not limited to melanoma can induce immunosuppression through various mechanisms, including the secretion of immunosuppressive cytokines and the presence of ligands that block immune cell responses, ultimately allowing the tumor to evade the immune system and promote growth and metastasis. While in some cases, tumors can be treated by resection, and / or by immunotherapy or chemotherapy, these latter options often come with high toxicity for the subject. Accordingly, other alternatives for treating neoplasms, including cancers of the skin, are desired.

[0005] DESCRIPTION OF THE FIGURES FIG. 1 shows silica fiber fragments imaged by phase contrast microscopy (PCM) and scanning electron microscopy (SEM).

[0006] FIG. 2 shows tissue (pig) treated with a silica fiber composition as part of a wound healing study. The image is a hematoxylin and eosin stain. Arrows indicate giant cell macrophages with phagocytosed silica fibers.

[0007] FIG. 3 shows treatment of a leg squamous cell carcinoma (SCC) lesion. The left panel shows the lesion prior to treatment, and the right panel shows the lesion after six days of treatment with topical silica particle cream.

[0008] DETAILED DESCRIPTION

[0009] In the various aspects and embodiments, the present disclosure provides methods for treating neoplasms, as well as compositions comprising silica particles for use in the same.

[0010] DBl / 157137097.1 1AMN-014PC / 120570-5014

[0011] Tn embodiments, the disclosure provides topical formulations of silica particles for treatment of skin conditions, including precancerous and cancerous skin lesions.

[0012] In an aspect, the present disclosure provides a method for treating a neoplasm, comprising applying a composition comprising an effective amount of silica particles to the neoplasm. In embodiments, the composition is applied to or around the neoplasm by injection or by topical application. In embodiments, the composition is applied topically, for example, to skin.

[0013] In embodiments, the silica particles are able to penetrate tissue and / or cells. In embodiments, the silica particles are of sufficient size to be taken up by phagocytosis. In various embodiments, the composition when applied to skin (e.g., topically) allows the particles to be deposited in macroscopic or microscopic breaks in skin.

[0014] In embodiments, the silica particles or fibers can be taken up by giant cell macrophages that are resident in the neoplasm (e.g., tumor). A giant cell macrophage, also known as a multinucleated giant cell (MGC), is a large, multi -nucleated cell formed by the fusion of multiple macrophages. These cells are often found in chronic inflammatory sites. Giant cell macrophages are also tumor-associated macrophages (TAMs), which are considered to play a complex and often paradoxical role in tumor development, contributing to both tumor growth and anti-tumor immunity.

[0015] In embodiments, the silica particles (e.g., silica fiber fragments) are sufficiently small to be phagocytosed by giant macrophage cells. In embodiments, the silica particles have an average size (e.g., longest dimension) of less than about 100 pm, or less than about 75 pm, or less than about 50 pm, or less than about 40 pm, or less than about 30 pm, or less than about 25 pm, or less than about 20 pm, or less than about 10 pm, or less than about 5 pm, or less than about 3 pm. In embodiments, the silica particles have an average size (e.g., longest dimension) of from about 5 pm to about 100 pm, of from about 5 pm to about 80 pm, or from about 5 pm to about 60 pm, or from about 5 pm to about 100 pm, or from about 5 pm to about 80 pm, or from about 5 pm to about 60 pm. In embodiments, the silica particles have an average diameter in the range of from about 0.5 to about 20 pm, such as from about 0.5 to about 10 pm.

[0016] DBl / 157137097.1 2AMN-014PC / 120570-5014

[0017] In embodiments, the composition, such as atopical composition, has a weakly acidic pH. For example, in embodiments, the pH of the composition is from about 4 to about 6. In embodiments, the pH of the composition is from about 5 to about 6, or from about 5 to about 5.5. In embodiments, the composition helps to bring and / or maintain the pH of the skin in a healthy range.

[0018] In embodiments, the silica particles are prepared from an electrospun silica fiber mat. In embodiments, the silica fiber mat is electrospun from a sol-gel, wherein the sol-gel is prepared with a silicon alkoxide reagent, such as tetraethyl ortho silicate (TEOS), an alcohol solvent, and an acid catalyst. The silica fiber mat is processed into a fine powder or dust (i.e. particles as described), and the powder or dust incorporated with the desired carrier. In embodiments, the silica particles are prepared by grinding of the silica fiber mat through a mesh and / or by ball mill.

[0019] In embodiments, the silica fiber composition is electrospun from a gelatinous material into a lightweight fiber mat. For example, the composition may be prepared by electrospinning a sol-gel, which can be prepared with a silicon alkoxide reagent, such as tetraethyl ortho silicate (TEOS), alcohol solvent, and an acid catalyst. In embodiments, the sol-gel for preparing the silica fiber composition is prepared by a method that includes preparing a first mixture containing an alcohol solvent, a silicon alkoxide reagent such as tetraethylorthosilicate (TEOS); preparing a second mixture containing an alcohol solvent, water, and an acid catalyst; fully titrating the second mixture into the first mixture; and processing (ripening) the combined mixture to form a gel for electrospinning. In some embodiments, the silicon alkoxide reagent is TEOS. Alternative silicon alkoxide reagents include those with the formula Si(OR)4, where R is from 1 to 6, and preferably 1, 2, or 3.

[0020] In embodiments, the sol comprises, consists essentially of, or consists of about 70% to about 90% by weight silicon alkoxide (e.g., TEOS), about 5% to about 25% by weight alcohol solvent (e.g., anhydrous ethanol), an acid catalyst (e.g., less than about 0.1% by weight when using HC1) and water. Any sol or sol-gel described herein may include the balance water (i.e., water may constitute any amount of the sol or sol-gel that is otherwise unspecified). Any sol or sol-gel described herein may optionally contain one or more reagents that may or do alter one or more properties of the sol, the sol-gel, and / or the silica

[0021] DBl / 157137097.1 3AMN-014PC / 120570-5014

[0022] fibers. Such reagents may include, but are not limited to, for example, polymers and polymeric solutions, inert reagents, alcohols, organic and / or aqueous solvents, organic salts, inorganic salts, metals, metal oxides, etc.

[0023] In embodiments, the sol contains 70% to 90% tetraethyl orthosilicate (TEOS) by weight, 8% to 25% ethanol by weight, 1% to 10% water by weight, and an acid catalyst. In some embodiments, the sol contains 75% to 85% by weight TEOS, 12% to 20% by weight ethanol, and about 2% to 5% by weight water. An exemplary sol contains about 80% by weight TEOS, about 17% by weight ethanol, and about 3% by weight water. In embodiments, the acid catalyst is HC1. For example, the sol may contain less than about 0.1% HC1 by weight. For example, the sol may contain from 0.02% to 0.08% HC1 by weight. In various embodiments, the sol does not contain an organic polymer, or other substantial reagents, such that the fiber composition will be substantially SiCh. In various embodiments, the sol does not include inorganic salts (e.g., sodium chloride, lithium chloride, potassium chloride, magnesium chloride, calcium chloride, and / or barium chloride), nor are, in various embodiments, inorganic salts mixed with other components of the sol or into the sol itself. In various embodiments, the fiber composition does not include metals or metal oxides (e.g., TiCh or ZrCh). In various embodiments, the fiber composition consists essentially of SiCh, i.e., contains only SiCh and unintentional impurities, and, in some embodiments, species and / or complexes resulting from the incomplete conversion of the sol to SiCh (e.g., water and / or chemical groups such as ethoxy groups, silanol groups, hydroxyl groups, etc.).

[0024] In some embodiments, the alcohol solvent is an anhydrous denatured ethanol, or in some embodiments, methanol, propanol, butanol or any other suitable alcohol solvent. The first mixture may be agitated, for example, using a magnetic stirrer, vibration platform or table, or other agitation means. The second mixture contains an alcohol solvent, water, and an acid catalyst. The alcohol solvent may be an anhydrous denatured alcohol, or may be methanol, propanol, butanol or any other suitably provided alcohol solvent. Water may be distilled water or deionized water. Enough acid catalyst is added to the mixture to aid in the reaction. This acid catalyst may be hydrochloric acid, or may be sulfuric acid or other suitable acid catalyst. The second mixture may be agitated, for example, magnetic stirrer,

[0025] DBl / 157137097.1 4AMN-014PC / 120570-5014

[0026] vibration platform or table, or other agitation means. Tn some embodiments, the first mixture (or sol) and the second mixture (or sol) are created without the use of direct heat (i.e., heat applied via extrinsic means such as a hot plate or other heat source).

[0027] According to various embodiments, the first mixture and the second mixture are combined by dripping or titrating the second mixture into the first mixture, preferably with agitation. The combined mixture is then further processed by allowing the sol to ripen in a controlled environment until a substantial portion of the alcohol solvent has evaporated to create a sol -gel suitable for electrospinning. For example, the controlled environment may include an enclosure with at least one vent and optionally a fan to draw gases away from the mixture, and which may involve controlled conditions in terms of humidity, temperature, and optionally barometric pressure. For example, the humidity may be controlled (e.g., via use of conventional humidifiers and / or dehumidifiers) within the range of about 30% to about 90%, such as from about 40% to about 80%, or in some embodiments, from about 50% to about 80%, or from about 50% to about 70% (e.g., about 55%, or about 60%, or about 65%). Some humidity may be helpful to slow evaporation of solvent, and thereby lengthen the window for successful electrospinning. In some embodiments, the temperature is in the range of from about 50° F to about 90° F, such as from about 60° F to about 80° F, or from about 65° F to about 75° F. In various embodiments, the sol is not exposed to heat over 150° F or heat over 100° F, so as to avoid accelerating the transition. In some embodiments, barometric pressure is optionally controlled (e.g., using a low pressure vacuum source such as a pump or a fan). By controlling the environmental conditions during ripening, the time period during which the gel may be electrospun may be lengthened; this time period may be a small window of only several minutes if the ripening process is too accelerated, such as with direct heat. When ripening the sol at a constant humidity of about 55% and temperature of about 72° F, the sol will ripen (gelatinize) in a few days, and the window for successful electrospinning may be expanded to at least several hours, and in some embodiments several days. In various embodiments, the ripening process takes at least 2 days, or at least 3 days in some embodiments. However, in various embodiments the ripening does not take more than 10 days, or more than 7 days. In some embodiments, the ripening process takes from 2 to 10 days, or from 2 to 7 days, or from 2 to 5 days, or from 2

[0028] DBl / 157137097.1 5AMN-014PC / 120570-5014

[0029] to 4 days (e.g., about 2, about 3, or about 4 days). Tn various embodiments, the sol-gel is spinnable well before it transitions into a more solidified, non-flowable mass.

[0030] The enclosure space for ripening the sol-gel may include a vent on at least one surface for exhausting gases from within the enclosure, and optionally the vent may include a fan for exhausting gases produced during the ripening process. The enclosure space may optionally include a heating source (e.g., one or more heating elements, for example resistive heating elements) for providing a nominal amount of heat within the enclosure space, to maintain a preferred temperature. In some embodiments, a source of humidity (e.g., an open container of water or other aqueous, water-based liquid) is provided within the enclosure environment to adjust the humidity to a desired range or value. The enclosure may further include one or more environmental monitors, such as a temperature reading device (e.g., a thermometer, thermocouple, or other temperature sensor) and / or a humidity reading device (e.g., a hygrometer or other humidity sensor).

[0031] In some embodiments, the sol-gel is electrospun after a ripening process of at least 2 days, or at least 36 hours, or at least 3 days, or at least 4 days, or at least 5 days at the controlled environmental conditions (but in various embodiments, not more than 10 days or not more than 7 days under the controlled environmental conditions). By slowing the ripening process, the ideal time to spin the fibers can be identified.

[0032] The weight of the sol-gel may be used as an indicator of when the sol-gel is at or near the ideal time to electrospin. Without intending to be bound by theory, it is believed that the viscosity of the sol-gel is a poor determinant for identifying the optimal time for electrospinning. For example, in various embodiments, the sol-gel is from about 10% to about 60% of the original weight of the sol (based on loss of alcohol solvent during transitioning). In some embodiments, the sol -gel is from 15 to 50% of the original weight of the sol, or in the range of about 20 to about 40% of the original weight of the sol.

[0033] In various embodiments, the sol-gel may be ripened for a shorter period of time, as long as the sol-gel remains spinnable via electrospinning. The resulting silica fiber mat or collection of fibers may in some cases be more brittle after ripening for a shorter time period, but such brittleness may not prevent the fragmenting of the fibers and dispersion into various

[0034] DBl / 157137097.1 6AMN-014PC / 120570-5014

[0035] different topical compositions. See US Patent Nos. 10,111,783 and 11,759,473, which are hereby incorporated by reference in its entirety.

[0036] Upon completion of the sol-gel process, the sol-gel is then electrospun using any known technique. The sol or sol-gel may be preserved (e.g., frozen or refrigerated) if needed (and such time generally will not apply to the time for ripening). An exemplary process for electrospinning the sol-gel is described in Choi, Sung-Seen, et al, Silica nanofibers from electrospinning / sol-gel process. Journal of Materials Science Letters 22, 2003, 891-893, which is hereby incorporated by reference in its entirety. Exemplary processes and apparatuses for electrospinning are further disclosed in U.S. Patent No. 8,088,965 and U.S. Patent No. 11,618,975, which are hereby incorporated by reference in its entirety.

[0037] In an exemplary electrospinning technique, the sol-gel is placed into one or more syringe pumps that are fluidly coupled to one or more spinnerets. The spinnerets are connected to a high-voltage (e.g., 5 kV to 50 kV) source and are external to and face toward a grounded collector drum. The drum rotates during spinning, typically along an axis of rotation approximately perpendicular to the spinning direction extending from the spinnerets to the drum. As the sol-gel is supplied to the spinnerets from the syringe pumps (or other holding tank), the high voltage between the spinnerets and the drum forms charged liquid jets that are deposited on the drum as entangled fibers. As the drum rotates and electrospinning continues, a fibrous mat of silica fibers is formed around the circumference of the drum. In various embodiments, the spinnerets and syringe pump(s) may be disposed on a movable platform that is movable parallel to the length of the drum. In this manner, the length along the drum of the resulting fiber mat may be increased without increasing the number of spinnerets. The diameter of the drum may also be increased to increase the areal size of the electrospun mat. The thickness of the mat may be largely dependent upon the amount of sol-gel used for spinning and thus the amount of electrospinning time. For example, the mat may have a thickness of greater than about 1 / 8 inch, or greater than about 1 / 4 inch, or greater than about 1 / 3 inch, or greater than about 1 / 2 inch. After completion of the electrospinning process, the resulting mat is removed from the drum. For example, the mat may be cut and peeled away from the drum in one or more pieces.

[0038] DBl / 157137097.1 7AMN-014PC / 120570-5014

[0039] The electrospun mat may then be divided into small fibrous fragments that may be incorporated into the composition. In embodiments, the resulting fibrous fragments are each intertwined collections of silica fibers, rather than unitary solid particles. In some embodiments, the electrospun mat may be fractured, cut, ground, milled, or otherwise divided into small fragments that maintain a fibrous structure. In some embodiments, the mat (or one or more portions thereof) is rubbed through one or more screens or sieves, and the mesh size of the screen determines, at least in part, the size of the resulting fibrous fragments or powder or dust produced from the electrospun mat. For example, the mat or mat portions may be rubbed through a succession of two or more screens having decreasing mesh sizes (e.g., screens having mesh numbers of 100, 200, 300, or even 400), in order to produce a powder or dust or collection of fibrous fragments (e.g., particles) having the desired sizes (as already described).

[0040] In embodiments, silica particles are created from a silica substrate (which may be electrospun silica as described) using a mechanical mill.

[0041] The silica particles are incorporated with a carrier, which in some embodiments is a topical carrier. In embodiments, the composition is in the form of a lotion, ointment, balm, paste, cream, foam, soap, shampoo, conditioner, or gel. In embodiments, the particles are distributed in a carrier system such as water or any aqueous solution containing organic or inorganic materials. The compositions may contain one or more ingredients to modify or enhance their texture, appearance, scent, performance or stability.

[0042] In embodiments, the silica particles are incorporated into the composition from about 0.5 wt% (w / w) to about 10 wt%, or from about 1 wt% to about 8 wt%, or from about 2 wt% to about 8 wt%, or from about 2 wt% to about 5 wt%, or from about 1 wt% to about 5 wt / %. For example, in embodiments, the silica particles are incorporated from about 2 wt% to about 4 wt%.

[0043] In embodiments, the topical composition comprises oily or fatty components as constituents of a hydrophobic phase, and a hydrophilic phase. In embodiments, the topical composition further comprises one or more emulsifying agents.

[0044] DBl / 157137097.1 8AMN-014PC / 120570-5014

[0045] Illustrative carriers for the compositions include: oily components, fatty components, ointment bases, hydrophilic solvents, lipophilic solvents, emollients, water, buffering agents, pH-adjusting agents, preservatives, humectants, chelating agents, antioxidants, stabilizers, emulsifying agents, detergents, suspending agents, gel-forming agents, perfumes and fragrances, skin protective agents, and antiseptics.

[0046] In embodiments, the topical composition comprises oily or fatty components, which are constituents of the hydrophobic phase, and can include one or more of: almond oil, castor oil, cacao butter, coconut oil, com oil, cottonseed oil, linseed oil, olive oil, palm oil, peanut oil, poppy seed oil, rapeseed oil, sesame oil, soybean oil, sunflower oil, teaseed oil, jojoba oil, mineral oils, silicone oils, fatty oils, liquid paraffin, beeswax, lanolin, white soft paraffin, yellow soft paraffin, petrolatum, triglycerides, cetyl alcohol, stearyl alcohol, isopropyl myristate, oleic acid, isopropyl palmitate, stearic acid, sorbitan esters of fatty acids, sorbitan esters of fatty acids and ethylene oxide (including Tween).

[0047] The topical composition may comprise an aqueous phase, which constitutes the hydrophilic phase and which may comprise water, one or more other hydrophilic solvents, and / or one or more surfactants and / or emulsifier. In various embodiments, the aqueous phase may comprise solvents such as water, polyethylene glycol, propylene glycol, glycerol, sorbitol, and alcohols such as ethanol and isopropyl alcohol.

[0048] The composition may comprise one or more emulsifiers (emulsifying agents), which can be part of the aqueous phase and / or oil phase. The term “emulsifier” means an amphiphilic molecule possessing both polar and non-polar regions which are covalently bound and capable of reducing the surface tension of water and for the interfacial tension between water and an immiscible liquid. Emulsifiers include soaps, detergents, surface active agents, and the like. The emulsifier can be cationic, anionic, non-ionic, or amphoteric. Exemplary emulsifiers include non-ionic emulsifiers such as polyol esters (e.g. ethylene glycol, diethylene glycol, glycol stearate and propylene glycol monoesters of fatty acids), and glycerol esters (e.g. glyceryl stearate, glyceryl monooleate, glycerylmonolaurate, glyceryl ricinolate, glyceryl monocaprylate).

[0049] Exemplary emulsifiers further include Sorbitan derivatives, which are esters of cyclic anhydrides of sorbitol with a fatty acid. These include sorbitan monolaurate, sorbitan DBl / 157137097.1 9AMN-014PC / 120570-5014

[0050] monooleate, sorbitan monostearate, sorbitan monopalmitate, sorbitan sesquioleate, sorbitan trioleate, sorbitan tri stearate, polyoxyethylene sorbitan esters (e.g. polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan tristearate, polyoxyethylene sorbitan monooleate). Exemplary emulsifiers also include polyoxyethylene esters, which are mixtures of mono- or di-fatty acids esters (from C12 to Cl 8) of polyoxyethylene glycol. These include stearate esters of PEG (PEG- 40, PEG-50 and PEG-55), as well as laurate, oleate, and myristate esters of PEG.

[0051] The composition can comprise polymeric thickeners including gums such as acacia, alginates, carrageenan, chitosan, collagen, tragacanth and xantham; celluloses, acrylic acids, colloidal solids such as silica, clays and microcrystalline cellulose, hydrogels such as polyvinyl alcohol and polyvinylpyrrolidone, as well as thermoreversible polymers such as poloxamers.

[0052] In embodiments, the composition comprises the excipients water, glycerin, petrolatum snow white, and one or more emollients and emulsion stabilizers. For example, in embodiments, the composition comprises petrolatum snow white from about 5 wt% to about 25 wt%, or from about 10 wt% to about 20 wt%, or about 15 wt%, about 12 wt%, or about 10 wt%. In embodiments, the composition comprises glycerin from about 3 wt% to about 15 wt%, or from about 3 wt% to about 10 wt%, or about 5 wt%, about 7.5 wt%, or about 10 wt%. In embodiments, the composition comprises water from about 40 wt% to about 70 wt%, such as about 50 wt% to about 65 wt%. (e.g., about 55 wt% or about 60 wt%).

[0053] In embodiments, at least one emollient is dicaprylyl ether or diisopropyl adipate. For example, these emollients may be included in the composition from about 0.5 wt% to about 7 wt%, or from about 0.5 wt% to about 5 wt%, or from about 1 wt% to about 4 wt%. In embodiments, at least one emollient is diisopropyl adipate, which is optionally present at from 0.5 wt% to about 2 wt% (e.g., from about 0.75 wt% to about 1.5 wt%). In embodiments, the composition comprises Glyceryl Stearate and PEG- 100 Stearate (e.g., from about 1 wt% to about 7 wt%, or from about 1 wt % to about 5 wt%). Alternatively or in addition, at least one emollient is PEG-40 castor oil, which is optionally present from about 0.5 wt% to about 5 wt% (e.g., from about 0.5 wt% to about 2 wt%).

[0054] DBl / 157137097.1 10AMN-014PC / 120570-5014

[0055] In embodiments, the composition further comprises a rheology modifier, which is optionally a carbomer. One or more carbomers (collectively) may be included in the composition from about 0.2 wt% to about 5 wt%, or from about 0.2 wt% to about 2 wt% (or about 1 wt% to about 2 wt%).

[0056] In embodiments, the composition further comprises cetyl alcohol, for example, from about 0.5 wt% to about 5 wt%, or from about 1 wt% to about 4 wt% (e.g., about 2 wt%).

[0057] In embodiments, the composition further comprises a mixture of dimethicone and dimethiconol (e.g., at about 0.1 wt% to about 5 wt%, or from about 0.1 wt% to about 3 wt%).

[0058] In embodiments, the composition further comprises a mixture of phenoxyethanol and ethylhexylglycerin (e.g., from about 0.2 wt% to about 2 wt%, such as about 0.5 wt% to about 2 wt%).

[0059] In embodiments, the composition further comprises polypropylene glycol, such as from about 0.5 wt% to about 15 wt%, such as from about 1 wt% to about 10 wt%.

[0060] In embodiments, the composition further comprises tetrasodium ED TA. In embodiments, the composition further comprises one or more antioxidants selected from vitamin E or salt thereof, butylated hydroxytoluene, and citric acid.

[0061] In embodiments, the composition has a pH of from about 5 to about 6, and optionally from about 5.25 to about 5.75.

[0062] In embodiments, the composition has the composition of components of approximately those value shown in Table 1 or 2.

[0063] In embodiments, the composition is an injectable composition, using any of the carriers known in the art, including but not limited to carriers comprising water (e.g., buffered solutions), saline, and / or glycerol.

[0064] In embodiments, the subject for treatment is a mammal, and optionally a veterinary subject. In embodiments, the subject is selected from a dog, cat, or horse. In embodiments, the subject is a human subject.

[0065] DBl / 157137097.1 11AMN-014PC / 120570-5014

[0066] In embodiments, the subject has a neoplasm, and the carrier applied to the neoplasm or its vicinity by either injection or topical / local application. A neoplasm is a type of abnormal and excessive growth of tissue. In various embodiments, the neoplasm is benign (non-cancerous) or malignant (cancerous).

[0067] As used herein, the terms “cancer” and “tumor” refer to an uncontrolled growth of cells that may interfere with the normal functioning of the bodily organs and systems, including both primary and metastatic cancers or tumors. Primary cancers or tumors that migrate from their original location and seed vital organs can eventually lead to the death of the subject through the functional deterioration of the affected organs. A metastasis is a cancer cell or group of cancer cells, distinct from the primary tumor location, resulting from the dissemination of cancer cells from the primary tumor to other parts of the body.

[0068] The composition can be administered topically or locally (e.g., by intratumoral injection) to malignant tissues. In some embodiments, the composition is administered topically to enhance or create synergistic effects in combination with another therapy applied topically or systemically.

[0069] As used herein, the term “treating” refers to providing therapy to a subject to slow or stop growth, progression or metastasis of a neoplasm (e.g., a tumor), or to reduce or shrink established growths or tumors, as well as in some embodiments, to prevent the onset, metastasis or re-occurrence of cancer. Alternatively or in addition, the composition can be employed to prevent or ameliorate side effects of other therapies.

[0070] Illustrative cancers or precancerous conditions that may be treated in accordance with this disclosure include, but are not limited to, actinic keratosis, squamous cell carcinoma (Bowen disease), squamous and basal cell carcinoma, melanoma, bladder cancer, bone cancer, brain cancer, breast cancer, cervical cancer, colon or rectum cancer, endometrial cancer, esophageal cancer, cancer of the head and neck, glioblastoma, neuroblastoma, liver cancer (e.g., hepatic carcinoma), intra-epithelial neoplasm, kidney cancer, lung cancer (e.g., small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, and squamous carcinoma of the lung), mesothelioma, myeloma, oral cavity cancer (lip, tongue, mouth, and pharynx), ovarian cancer, pancreatic cancer, prostate cancer, testicular cancer, thyroid cancer, uterine cancer, lymphoma including Hodgkin's and non-Hodgkin's DBl / 157137097.1 12AMN-014PC / 120570-5014

[0071] lymphoma, Cutaneous T-Cell Lymphoma, B-cell lymphoma, as well as other carcinomas and sarcomas.

[0072] In various embodiments, the cancer is accessible for local or topical treatment with the compositions, without systemic administration or invasive administration techniques. For example, in some embodiments the cancer is skin cancer (e.g., melanoma), breast cancer, testicular cancer, cervical cancer, uterine cancer, lymphoma, or lip or oral cancer. In various embodiments, the cancer is stage I or II. In other embodiments, the cancer is stage III or IV. In some embodiments, the cancer is non-metastatic skin cancer (e.g., melanoma, BCC, or SCC).

[0073] In some embodiments, the condition is a proliferative condition involving the skin. In embodiments, the neoplasia involves the skin, and is optionally selected from melanoma, squamous cell carcinoma, basal cell carcinoma, or cutaneous T-cell Lymphoma, optionally wherein the neoplasm is stage I or II cancer.

[0074] Squamous-cell carcinoma (SCC) is a cancer of the squamous cell, which is a main part of the epidermis of the skin. SCC is one of the major forms of skin cancer. However, squamous cells also occur in the lining of the digestive tract, lungs, and other areas of the body, and SCC occurs as a form of cancer in diverse tissues, including the lips, mouth, esophagus, urinary bladder, prostate, lung, vagina, and cervix, among others. SCC is a histologically distinct form of cancer arising from the uncontrolled multiplication of cells of epithelium, or cells showing particular cytological or tissue architectural characteristics of squamous-cell differentiation, such as the presence of keratin, tonofilament bundles, or desmosomes, structures involved in cell-to-cell adhesion. SCC of the skin begins as a small nodule and as it enlarges the center becomes necrotic and sloughs and the nodule turns into an ulcer. The lesion caused by SCC is often asymptomatic. The clinical appearance is highly variable. The tumor can lie below the level of the surrounding skin, and eventually ulcerates and invades the underlying tissue. The tumor commonly presents on sun-exposed areas. SCC is generally treated by surgical excision, Mohs surgery or electrodessication and curettage. Conventional nonsurgical options for the treatment of cutaneous SCC include topical chemotherapy, topical immune response modifiers, photodynamic therapy (PDT), radiotherapy, and systemic chemotherapy. The use of topical therapy, such as Imiquimod

[0075] DBl / 157137097.1 13AMN-014PC / 120570-5014

[0076] cream and PDT is generally limited to premalignant and in situ lesions. Radiation therapy is a primary treatment option for patients in whom surgery is not feasible and is an adjuvant therapy for those with metastatic or high-risk cutaneous SCC.

[0077] Basal-cell carcinoma (BCC) is another form of skin cancer. It rarely metastasizes or kills. However, BCC can cause significant destruction and disfigurement by invading surrounding tissues. Treatments include surgery, radiation, photodynamic therapy (PDT), as well as topical chemotherapy.

[0078] Cutaneous-T-Cell Lymphoma (CTLC) is a non-Hodgkin's lymphoma that may present with an intractable itch, and red and scaly skin.

[0079] Melanoma is a kind of skin cancer that starts in the melanocytes. Melanocytes are cells that make the pigment that gives skin its color (melanin).

[0080] In embodiments, the neoplasm is a precancerous or non-malignant lesion. In some embodiments, the method prevents (or slows progression of) pre-cancerous lesions from developing into cancers. Exemplary precancerous lesions include Actinic Keratosis.

[0081] The disclosure provides for methods of treating cancer subjects with the compositions, optionally with one or more additional therapies, such as cancer immunotherapy (e.g., immune checkpoint inhibitor therapy), tumor resection, radiation therapy, and / or chemotherapy.

[0082] In embodiments, the composition is administered to the subject before, during, or after treatment with immunotherapy, such as immune checkpoint inhibitor therapy. The composition, in combination with immune checkpoint inhibitor therapy, may further slow the growth and / or progression of the tumor. In some embodiments, the combination may prevent or ameliorate side effects of the immunotherapy, such as, but not limited to, immune- related adverse events.

[0083] As used herein, an immune checkpoint inhibitor is any agent that disrupts, blocks, reduces, and / or inhibits the transmission of an immune inhibitory signal such as an immune co-inhibitory signal. In various embodiments, the immune checkpoint inhibitor is an agent that directly or indirectly, partially or completely, inhibits the activity of one or more

[0084] DBl / 157137097.1 14AMN-014PC / 120570-5014

[0085] molecules involved in the inhibitory (e.g. , co-inhibitory) signaling pathway. Such inhibitory molecules include ligands and receptors, such as, without limitation, CTLA-4, PDL1, PDL2, PD1, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, and various B-7 family ligands. For example, the immune checkpoint inhibitor can inhibit the inhibitory signaling pathways mediated by one or more of CTLA-4, PD-1 or PDL1, LAG3, TIM3, or KIR. In some embodiments, the immune checkpoint inhibitor is a biologic therapeutic or a small molecule. In some embodiments, the immune checkpoint inhibitor is a biologic therapeutic and may comprise an antibody (e.g., a monoclonal antibody) or an antigenbinding portion thereof, or other ligand-binding molecule, and may be a mimic of the natural cellular receptor or ligand. For example, the immune checkpoint inhibitor may comprise an antibody or antigen-binding portion thereof that blocks the activity of CTLA-4 or PD-1. Exemplary anti-CTLA4 antibodies include ipilimumab and tremelimumab. Exemplary anti- PD-1 antibodies include pembrolizumab, nivolumab, and pidilizumab. Exemplary anti-PD- L1 molecules that may be used in accordance with embodiments of the present disclosure include, but are not limited to, MDX-1105 (Medarex), MEDI4736 (Medimmune) MPDL3280A(Genentech), and BMS- 936559 (Bristol-Myers Squibb).

[0086] In some embodiments, methods of the invention provide for the administration of a composition to a patient undergoing treatment with an immune stimulating molecule. As used herein, the immune stimulating molecule is any agent that activates or enhances the transmission of an immune stimulatory signal such as an immune co-stimulatory signal. In various embodiments, the immune stimulating molecule comprises an agent that directly or indirectly, partially or completely, activates or enhances the activity of one or more molecules involved in the stimulatory (e.g., co-stimulatory) signaling pathway. Such stimulatory molecules include ligands and receptors, such as, without limitation, CD27, CD28, CD30, CD30 ligand, CD40, CD40 ligand, CD70, CD122, 4-1BB / CD137, CD137 ligand, 0X40, 0X40 ligand, GITR, GITR ligand, HVEM, LIGHT / CD258, CD80 / B7-1, CD86 / B7-2, TL1 A, ICOS, and ICOS ligand. For example, the immune stimulatory molecule activates or enhances the stimulatory signaling pathway mediated by one or more of ICOS, GITR, 0X40, CD137, CD122, or CD27. In some embodiments, the stimulatory molecule is a biologic therapeutic or a small molecule. In some embodiments, the stimulatory molecule is a biologic therapeutic and may comprise an agonistic antibody or an antigen-binding DBl / 157137097.1 15AMN-014PC / 120570-5014

[0087] portion thereof. For example, the immune stimulatory molecule may comprise an agonist antibody that stimulates the activity of CD40, 4- IBB, 0X40, GITR, CD80 / B7-1, or CD86 / B7-2. In another example, the stimulatory molecule may comprise a ligand (e.g. , a soluble ligand) for any of the co-stimulatory receptors described herein such as a CD30 ligand, a CD40 ligand, an 0X40 ligand, CD70, CD80 / B7-1, CD86 / B7-2, or LIGHT, or fragments or derivatives thereof.

[0088] In embodiments, autologous or donor T cells can be engineered to express a heterologous or engineered T cell receptor. In some embodiments, the engineered T cells express a chimeric antigen receptor (CAR), which may recognize CD 19 in some embodiments. The engineered T cells may be administered to the patient by adoptive transfer. CAR-T technology is generally described in US 7,446,179 and 6,410,319, which are hereby incorporated by reference in their entireties.

[0089] In embodiments, the composition is administered to a subject after cancer resection (e.g., surgery), radiation therapy, chemotherapy, or a biologic therapy. In accordance with embodiments of the invention, the composition slows growth or progression of the tumor or cancer.

[0090] Surgery or resection involves the bulk removal of diseased tissues. While surgery is effective in removing localized tumors, it is not used, for example, in the treatment disseminated neoplastic conditions. Radiation therapy involves the exposure of living tissues to ionizing radiation causing death or damage to the exposed cells. However, both cancer cells and non-cancerous tissues are damaged by radiation. Chemotherapy involves the use of one or more compounds that inhibit cancer cell growth and is associated with significant toxicity to various organs. Chemotherapy and radiation therapy are recognized to have both acute toxicity and delayed toxicity. Acute toxicity is manifested in side effects such as nausea and vomiting, fever, chills, abdominal pain, hyperglycemia, seizures, diarrhea, hypotension, ventricular arrhythmia, anaphylaxis, dermatitis, and localized phlebitis. Delayed toxicity can appear as bone marrow depression and concomitant immuno-suppression, renal damage, thrombosis, alopecia (hair loss), cataracts, liver damage, sterility, hemorrhagic cystitis, pulmonary edema, conjunctivitis, impotence, stomatitis, dermatitis, neurological defects,

[0091] DBl / 157137097.1 16AMN-014PC / 120570-5014

[0092] hypokalemia and hypocalcemia, and the like. Cutaneous reactions, hyperpigmentation and ocular toxicity have also been reported with virtually all non-hormonal anti-cancer drugs.

[0093] In accordance with embodiments of the invention, the composition can be topically applied to manage and / or ameliorate acute and / or delayed toxicity, which may include one or more of dermatitis, skin lesions or sores, and mucosal lesions or sores.

[0094] In some embodiments, the composition is administered to a patient before, during, or after, surgery or tumor resection. For example, the composition may be administered to the site of tumor resection, or may be administered before, during, or after tumor resection for a period of time to reduce the likelihood of recurrence, progression, or metastasis of remaining cancer cells or tissue. For example, the composition can be administered to the site of skin cancer (e.g., melanoma) resection.

[0095] In some embodiments, the composition is administered to a patient before, during, or after radiation therapy. Exemplary radiation therapy may include external beam therapy such as conventional external beam radiation therapy, steriotactic radiation including stereotactic radiosurgery and stereotactic body radiation therapy, 3 -dimensional conformal radiation therapy, intensity-modulated radiation therapy, volumetric modulated arc therapy, particle therapy, Auger therapy, brachytherapy, intraoperative radiotherapy, and radioisotope therapy. For example, the composition may be administered to skin and / or mucosal surfaces to prevent and / or reduce (or reduce the severity of) lesions forming as a result of acute or delayed toxicity.

[0096] In some embodiments, the composition is administered to a patient before, during, or after treatment with one or more of kinase inhibitors, angiogenesis inhibitors, apoptosis inducers, topoisomerase (I or II) inhibitors, protease inhibitors, microtubule inhibitors, mitotic inhibitors, antimetabolites, signal transduction inhibitors, estrogen receptor inhibitors, EGFR inhibitors, Her2 inhibitors, aromatase inhibitors, monoclonal antibodies against tumor targets, and antitumor vaccination.

[0097] In various embodiments, administration of the composition provides for preventing, delaying, or reducing various skin conditions or symptoms associated with chemotherapy and / or radiation therapy. These include skin rashes, dry and itchy skin, sensitivity to light,

[0098] DBl / 157137097.1 17AMN-014PC / 120570-5014

[0099] burning and painful skin, hardening of skin (scleroderma), skin lesions, skin ulcers or sores, necrotic wounds, and malignant wounds. In embodiments, the composition is administered to prevent or treat skin or mucosal lesions or sores associated with the cancer therapy.

[0100] In some embodiments, the composition is administered topically. In some embodiments, the cancer involves the skin or is proximal to the skin (such as melanoma, basal cell carcinoma, squamous cell carcinoma, other cutaneous cancer, breast cancer, testicular cancer, lymphoma, or lip cancer). In some embodiments, the cancer therapy results in side effects that manifest in the skin, including, for example, lesions, sores, rash, blisters, hives, and itch. Administration of the topical composition reduces these symptoms and / or accelerates healing.

[0101] In embodiments, the composition is administered at least about daily, and optionally from 1 to about 10 times per day. In embodiments, the composition is administered for at least two weeks, or at least about one month, or at least about five months, or at least about six months, or at least about nine months, or at least about twelve months.

[0102] In an aspect, the disclosure provides a topical cream formulation as already described, for example, comprising silica particles and comprising excipients water, glycerin, petrolatum snow white, and one or more emollients and emulsion stabilizers. In embodiments, the silica particles are incorporated into the composition from about 0.5 wt% to about 10 wt%, or from about 1 wt% to about 5 wt / %. For example, in embodiments, the silica particles are incorporated from about 2 wt% to about 4 wt%. In embodiments, the composition has the composition of components of approximately those value shown in Table 1 or 2.

[0103] In other aspects, the disclosure provides a method for treating a skin condition, comprising administering the topical cream formulation described herein. In some embodiments reduces local production of pain and / or inflammatory mediators.

[0104] The composition may further comprise one or more pharmaceutical or antimicrobial agents suitable for topical application. Exemplary pharmaceutical agents include anti- fibrotic and anti-scarring agents.

[0105] DBl / 157137097.1 18AMN-014PC / 120570-5014

[0106] In some embodiments, the composition comprises an antibiotic or antiseptic. Antibiotics suitable for use in the present invention include, but are not limited to, cephalosporin antibiotics, tetracycline antibiotics, beta-lactams, carbapenem antibiotics, polymyxin B (neosporin), neomycin, and bacitracin. Antiseptics include, without limitation, phenol, meta-cresol, methylparaben, and sodium benzoate. In some embodiments, the composition further comprises one or more anti-inflammatory agents such as steroidal antiinflammatory agents or non-steroidal anti-inflammatory agents (NSAIDs). Steroids, particularly the adrenal corticosteroids and their synthetic analogues, are well known in the art. Examples of corticosteroids include, without limitation, hydroxyltriamcinolone, alphamethyl dexamethasone, beta-methyl betamethasone, beclomethasone dipropionate, clobetasol valerate, desonide, desoxymethasone, dexamethasone, diflorasone diacetate, diflucortolone valerate, fluadrenolone, fluclorolone acetonide, flumethasone pivalate, fluosinolone acetonide, fluocinonide, flucortine butylester, fluocortolone, fluprednidene (fluprednylidene) acetate, flurandr enol one, halcinonide, triamcinolone acetonide, cortisone, cortodoxone, flucetonide, fludrocortisone, difluorosone diacetate, fluradrenolone acetonide, medrysone, amcinafel, amcinafide, betamethasone, chloroprednisone, clocortelone, clescinolone, dichlorisone, difluprednate, flucloronide, flunisolide, fluoromethalone, fluperolone, fluprednisolone, hydrocortisone, paramethasone, prednisolone, methylprednisolone, prednisone, and budesonide. NSAIDS that may be used in the composition, include salicylic acid, acetyl salicylic acid, methyl salicylate, glycol salicylate, salicylmides, benzyl-2, 5- diacetoxybenzoic acid, ibuprofen, fulindac, naproxen, ketoprofen, etofenamate, phenylbutazone, and indomethacin. In some embodiments, the composition comprises at least one active agent for reducing pain, including but not limited to cortisone, hydrocortisone, acetaminophen, or a cannabinoid.

[0107] In accordance with embodiments of the disclosure, the silica fiber composition, when applied to wounded tissue, acts as a non-biodegradable scaffold that supports tissue healing, regeneration, and / or integrity. The composition may act as a collagen biomimetic at the site of damaged tissue, providing an environment conducive for regeneration and growth of dermal cells and / or natural deposition of collagen.

[0108] DBl / 157137097.1 19AMN-014PC / 120570-5014

[0109] Without wishing to be bound by theory, the composition and methods described herein limit pain and inflammation at the site of damaged tissue. Further, uncontrolled tissue degradation processes can destroy newly deposited collagen. The composition of the disclosure provides a scaffold that is not destroyed by proteases released at the site of tissue injury, but provides an optimal environment for population and growth of dermal cells. The fibers can become an integral part of the regenerating tissue.

[0110] In various embodiments, the disclosure provides a method for treating skin tissue in a subject. The method comprises applying the topical composition described herein to skin tissue. The composition can be applied routinely or periodically. In some embodiments, the composition is applied at least about daily, and in some embodiments from 1 to about 10 times per day. In various embodiments, the method improves healing of the skin tissue and / or prevents or reduces tissue scarring, looseness of skin, signs of aging, pain, and / or irritation.

[0111] Application of the composition can provide for improved or accelerated healing of damaged skin. For example, when the topical composition is applied to skin that has cracks, small scrapes, blemishes, etc., the scaffolding is left behind in the small “wound” for cells to grow into. This speeds up the healing process and helps to reduce scarring. In some embodiments, the composition is applied to the cracked skin (e.g., on the face, mouth or lips, neck, hands, arms, shoulders, legs, scalp, fingers, etc.) to improve tolerance of the skin to the environment, such as sun, wind, and cold, thereby reducing the impact of age and environment on the appearance, feel, and / or function of the skin.

[0112] In embodiments, the composition is applied to an insect or spider bite or sting, including bee sting, wasp sting, mosquito bite, spider bite, flea bite, fly or ant bites, bits from bed bugs, or others. In some embodiments, the composition is applied to skin that has been contacted with or is manifesting a reaction to poison ivy or poison oak. In other embodiments, the composition is applied to a skin allergic reaction or hives. The composition in these embodiments may include additional agents to reduce itch or swelling (e.g., corticosteroid or antihistamine), pain (e.g., acetaminophen or NSAID), or allergic responses (e.g., antihistamine). Exemplary antihistamines include brompheniramine, carbinoxamine maleate, chlorpheniramine, clemastine, diphenhydramine, hydroxyzine

[0113] DBl / 157137097.1 20AMN-014PC / 120570-5014

[0114] triprolidine, cetirizine, desloratadine, fexofenadine, levocetirizine, loratadine, and oloptadine.

[0115] In some embodiments, the composition is applied to skin showing signs of microbial infection, including HPV (e.g., wart), herpes simplex virus (e.g., cold sore), varicella-zoster virus (e.g., chicken pox or shingles), fungal infection (e.g., candidiasis or tinea versicolor), or staphylococcus infection or over colonization. In some embodiments, the composition comprises one or more antibiotics (e.g., antibacterial or anti-fungal agent), antiviral agent, or antiseptic.

[0116] In some embodiments, the subject is a mammal, including veterinary subjects and human subjects (e.g., as described).

[0117] In some embodiments, the composition is applied to a skin lesion, superficial wound or infection (e.g., acne), bum, cut, scrape, rash (e.g., diaper rash), blister (including ruptured blister), or hives. In some embodiments, the composition is applied to cracked or scraped skin. In some embodiments, the composition is applied to aging skin or dry skin, including eczema, atopic dermatitis, or pruritus. In some embodiments, the topical composition normalizes the tissue microenvironment, and may reduce pain and inflammation at the site, and / or provide a micro scaffold for dermal cells to multiply and grow into, and in some embodiments induce collagen deposition. In some embodiments, the subject has a first, second, or third degree bum, or a combination thereof. In some embodiments, the composition is applied to a sun bum, and reduces pain or discomfort. In some embodiments, the composition is applied to a post-surgery wound, including skin graft, skin comprising sutures, or cosmetic surgery wound.

[0118] For treatment of severe wounds and bums, it may first be necessary to apply portions of fiber mats directly to the wound for several days (see US 10,111,783, which is hereby incorporated by reference in its entirety). Once new skin is substantially formed over the wound or burn area, the subject transitions to application of the topical cream described herein. The topical cream is general applied one or more time daily, and can be used continuously until the skin barrier has normalized.

[0119] DBl / 157137097.1 21AMN-014PC / 120570-5014

[0120] In some embodiments, because the fiber material substantially reduces pain from the site of tissue damage, the patient may be able to forgo therapy with a pain medication such as an opioid.

[0121] In some embodiments, the subject has a genetic disease that impacts skin barrier function, such as but not limited to epidermolysis bullosa or ichthyosis.

[0122] Epidermolysis bullosa (EB) is a group of mainly inherited connective tissue diseases that cause blisters in the skin and mucosal membranes. It is a result of a defect in anchoring between the epidermis and dermis, resulting in friction and skin fragility. EB often involves formation of blisters following trivial trauma.

[0123] In some embodiments, the subject has epidermolysis bullosa simplex, which results in blisters at the site of rubbing, and typically affects the hands and feet. In some embodiments, the subject has junctional epidermolysis bullosa, which affects laminin and collagen. Junctional epidermolysis bullosa also presents with blisters at the site of friction, especially on the hands and feet. Dystrophic epidermolysis bullosa is an inherited variant affecting the skin and other organs, and involves skin that is very fragile. Dystrophic epidermolysis bullosa is caused by genetic defects (or mutations) within the gene encoding the protein type VII collagen (collagen VII). The human skin consists of two layers: an outermost layer called the epidermis and a layer underneath called the dermis. In individuals with healthy skin, there are protein anchors between these two layers that prevent them from moving independently from one another (shearing). In people with EB, the two skin layers lack the protein anchors that hold them together, resulting in extremely fragile skin. Even minor mechanical friction (like rubbing or pressure) or trauma will separate the layers of the skin and form blisters and painful sores. Sufferers of EB have compared the sores with third- degree bums.

[0124] In some embodiments, the subject has ichthyosis. Ichthyosis is a family of genetic skin disorders characterized by dry, thickened, scaly skin. The more than 20 types of ichthyosis range in severity of symptoms, outward appearance, and underlying genetic cause. The severity of symptoms can vary, from the mildest, most common, types such as ichthyosis vulgaris, which may be mistaken for normal dry skin, up to life-threatening conditions such as harlequin-type ichthyosis. In various embodiments, the topical DBl / 157137097.1 22AMN-014PC / 120570-5014

[0125] composition is applied to a subject having any of the types of ichthyosis, including harlequin ichthyosis.

[0126] In some embodiments, the composition is applied to diseased skin, which can be a manifestation of a proliferative disorder (e.g., carcinoma, pre-carcinoma, or melanoma lesion, or other cancer lesion, or psoriasis), or in some embodiments an autoimmune or inflammatory disorder. For example, in some embodiments, the composition is applied for treatment of rosacea or acne. Autoimmune manifestations include cutaneous manifestation of lupus and dermatitis herpetiformis, or dermatomyositis. In some embodiments, the composition is applied to skin affected by shingles, providing, for example, relief from associated pain and reduction in associated rash. In some embodiments, including but not limited to subjects experiencing shingles, psoriasis, or eczema, the composition can be applied topically to affected areas of the skin.

[0127] In some embodiments, the composition is administered to prevent or reduce (or reduce the severity of) skin or mucosal lesions or sores associated with the drug administration, such as cancer therapy.

[0128] In some embodiments, the composition is applied to the affected area at least about daily for at least about 1 week, or at least about 2 weeks. In some embodiments, the composition is applied between once and ten times per day, or in some embodiments, from once to about four times per day, or from one to three times daily. In some embodiments, the regimen is continued for at least one week, or at least two weeks, or at least one month, or at least two months, or at least four months, or at least six months, or more. In some embodiments, the regimen is continued for six months or more. For subjects having a genetic disease of the skin, the regimen may be continuous.

[0129] As used herein, the term “about” or “approximately” means ±10% of a reference value, unless the context clearly requires otherwise.

[0130] EXAMPLES

[0131] Example 1: Preparation of Electrospun Silica Fiber

[0132] Silica fibers were prepared using an electrospinning process, in which a sol-gel was spun onto a collector drum to form a non-woven mat of fibers. The sol-gel was made in two DBl / 157137097.1 23AMN-014PC / 120570-5014

[0133] parts. First, TEOS was mixed with ethanol, and then a second mixture containing HC1, water, and ethanol was titrated into the mixture. The sol-gel was then allowed to ripen for a few days under controlled conditions before spinning.

[0134] In one example, the first sol is made by weighing out 384 grams of TEOS 98% and 41.8 grams of anhydrous denatured ethanol, and pouring together. The first sol is allowed to let stand in a beaker, and a magnetic stirrer is used to create a homogenous solution. The second sol is made by weighing 41.8 grams of anhydrous denatured ethanol, 16.4 grams of distilled water, and 0.34 grams of hydrochloric acid, which is then poured together and mixed for 8 seconds with a magnetic stirrer until a homogenous second sol is formed. The second sol is then poured into the titration device, which is placed above a beaker containing the first sol. The titration device then drips about 5 drops per second until a third sol is formed via the mixing of the first sol and the second sol. During the dripping process, the first sol is continuously mixed with a magnetic stirrer while the second sol is dripped into the first sol. The combined third sol is then placed into an enclosure box. A low pressure vacuum is provided by a fan on medium speed to remove fumes. The air temperature within the box can be about 72° F with about 60% humidity. The third sol is allowed to sit and process for about three days. The mixtures are agitated daily to reduce the build-up of crystalline structures. The third sol begins to transition to sol-gel with evaporation of the alcohol solvent. Upon proper gelatinization, the sol-gel was loaded into electrospinning machine or was frozen to preserve for electrospinning. For example, proper gelatinization may occur when the total mass of the sol-gel was between about 70 grams and about 140 grams. This example may be scaled appropriately and the ranges may vary, yet still produce desirable structures. To further identify the ideal time to electropsin, portions of the gel may be dripped into the electric field of the spinning apparatus to evaluate the spinning properties of the solgel.

[0135] The electrospun amorphous silica fiber material was mechanically milled using an SR300 Rotor Beater Mill, using 0.2 mm followed by 0.08 mm milling screens. Fiber fragments have an average diameter in the range of 0.5-10 pm. The majority of fibers will be between 1 and 4 pm in diameter. FIG. 1 shows silica fiber fragments imaged by phase contrast microscopy (PCM) and scanning electron microscopy (SEM).

[0136] DBl / 157137097.1 24AMN-014PC / 120570-5014

[0137] Example 2: Topical Compositions of Silica Fiber

[0138] Initial compositions were prepared incorporating silica fibers into petroleum jelly, bacitracin ointment, as well as basic facial creams, hand creams, and acne creams. These initial formulations with simple carriers had a propensity to sediment and / or aggregate. Further, initial test formulations had a propensity to phase separate and / or lose viscosity over time. More advanced formulations were designed to address these short comings. An advanced formulation is shown below in Table 1.

[0139] Table 1: Initial Advanced Formulation

[0140] Ingredient Description CAS No. % (w / w) Water 7732-18-5 61.41% Glycerin (99.7% USP) 56-81-5 10.00% Petrolatum Snow White Mixture of mineral oils and petroleum 8009-03-08 10.00% USP wax

[0141] CETIOL OE Dicaprylyl ether (emollient) 629-82-3 4.00% LIPOMULSE 165 Glycery l Stearate and PEG- 100 Stearate 31566-31-1 / 4.00%

[0142] 9004-99-3

[0143] Silica Fiber Electrospun silica fiber ground to 11099-06-2 3.30% particles

[0144] LANETTE 16 Cetyl alcohol 36653-82-4 2.00% XIAMETER PMX 200 Dimethicone 9006-65-9 2.00% EUXYL PE 9010 Phenoxyethanol / Ethylhexylglycerin 122-99-6 / 1.00%

[0145] 70445-33-9 Propylene glycol USP 57-55-6 0.99% FLORASUN 90 Sunflower Seed Oil 8001-21-6 0.50% Sodium hydroxide 1310-73-2 0.25% CARBOPOL ULTREZ- Carbomer (Crosslinked polyacrylic 195739-91-4 0.20%

[0146]

[0147] 10 acid)

[0148] DBl / 157137097.1 25AMN-014PC / 120570-5014

[0149] CARBOPOL ULTREZ- Carbomer (Crosslinked 0.15% 20 hydrophobically-modified polyacrylic

[0150] acid)

[0151] DISSOLVINE 220 Ethylenediaminetetraacetic acid 13235-36-4 0.10% tetrasodium salt, tetrahydrate

[0152]

[0153] Vitamin E acetate 7695-91-2 0.10% Further enhancements were developed to improve viscosity, spreadability, lubricant properties, emulsion properties (including emulsion stability), and feel (particularly to reduce oily feel).

[0154] Accordingly, the formulation was further developed, ultimately arriving at the formulation defined in Table 2.

[0155] Table 2: Re-Formulation

[0156] Ingredient Description CAS No. % (w / w) Water 7732-18-5 55.30 Glycerin (99.7% USP) 56-81-5 5.00% Petrolatum Snow White Mixture of mineral oils and petroleum 8009-03-08 15.70% USP wax

[0157] Diisopropyl adipate 6938-94-9 1.10% LIPOMULSE 165 Glyceryl Stearate and PEG- 100 Stearate 31566-31-1 / 3.00%

[0158] 9004-99-3

[0159] Silica Fiber Electrospun silica fiber ground to 11099-06-2 3.30% particles

[0160] LANETTE 16 Cetyl alcohol 36653-82-4 1.50% XIAMETER PMX 200 Dimethicone 9006-65-9 0.25% EUXYL PE 9010 Phenoxyethanol / Ethylhexylglycerin 122-99-6 / 0.50%

[0161] 70445-33-9

[0162]

[0163] Propylene glycol USP 57-55-6 10.00%

[0164] DBl / 157137097.1 26AMN-014PC / 120570-5014

[0165] PEG-40 Castor Oil 61788-85-0 1.00% Sodium hydroxide 1310-73-2 2.00% CARBOPOL 974P NF Carbomer (carboxypolymethylene) 9003-01-04 1.00% DISSOLVINE 220 Ethylenediaminetetraacetic acid 13235-36-4 0.20% tetrasodium salt, tetrahydrate

[0166] Butylated hydroxytolucnc 128-37-0 0.10%

[0167]

[0168] Citric Acid 77-92-9 0.05%

[0169] The modifications in Table 2 include an increase in the percentage of petrolatum snow white while the percentage of water is decreased. This change thickens the formulation and increases the viscosity. Cetiol OE was replaced with diisopropyl adipate. Diisopropyl adipate is an emollient that lubricates skin and softens synthetic compounds, while maintaining a non-oily feel. The percentage of diisopropyl adipate also allows for change from florasun 90 to PEG-40 castor oil. Castor oil has strong emollient properties, and may have antibacterial benefits. Further, Ultrex-10 and Ultrex-20 were replaced by Carbopol 974 NF, which is a rheology modifying thickener that allowed for better suspension of active agent in the cream while stabilizing emulsions. Vitamin E acetate was replaced by Butylated Hydroxy Toluene, which has stronger antioxidant properties than vitamin E.

[0170] These changes result in a cream with a better feel, improved spreadability, optimal thickness and rheological properties, improved emulsion, improved antioxidants, and additional antibacterial proprieties.

[0171] Example 3: Treatment of neoplasia

[0172] FIG. 2 shows tissue (pig) treated with a silica fiber composition as part of a wound healing study. The image is a hematoxylin and eosin stain. FIG. 1 shows giant cell macrophages with phagocytosed silica fibers. It was observed that multi-nucleated macrophages would appear early after application of the silica fibers and disappear after a few days. Multi -nucleated macrophages are found around cancerous tumors and other areas of chronic inflammation or infection. Without wishing to be bound by theory, it is believed

[0173] DBl / 157137097.1 27AMN-014PC / 120570-5014

[0174] that the silica particles activate multi-nucleated macrophages, including within a tumor microenvironment, as well as in the context of chronic or acute inflammation.

[0175] Topical cream comprising the silica fiber fragments demonstrated the ability to normalize basal cell carcinoma and squamous cell carcinoma. FIG. 3 shows treatment of a squamous cell carcinoma of the leg before treatment, and after six days of treatment. Similar effects were observed, for example, when treating shingles rash.

[0176] DBl / 157137097.1 28

Claims

1. AMN-014PC / 120570-5014CLAIMS1. A method for treating a neoplasm, comprising, applying a composition comprising an effective amount of silica particles to the neoplasm.

2. The method of claim 1, wherein the composition is applied to or around the neoplasm by injection or topical application.

3. The method of claim 1, wherein the composition is applied topically.

4. The method of any one of claims 1 to 3, wherein the silica particles have an average size of a longest dimension of less than about 100 pm, or less than about 75 pm, or less than about 50 pm, or less than about 40 pm, or less than about 30 pm, or less than about 25 pm, or less than about 20 pm, or less than about 10 pm.

5. The method of claim 4, wherein the silica particles have an average diameter in the range of about 0.5 to about 10 pm.

6. The method of any one of claims 1 to 5, wherein the composition has a weakly acidic pH.

7. The method of any one of claims 1 to 6, wherein the silica particles are prepared from an electrospun silica fiber mat.

8. The method of claim 7, wherein the silica fiber mat is electrospun from a sol-gel, wherein the sol-gel is prepared with a silicon alkoxide reagent, such as tetraethyl ortho silicate (TEOS), an alcohol solvent, and an acid catalyst.

9. The method of any one of claims 1 to 8, wherein the silica particles are prepared by grinding a silica substrate through a mesh and / or mechanical mill.

10. The method of any one of claims 1 to 9, wherein the composition comprises a carrier, which is optionally a topical carrier.

11. The method of claim 10, wherein the composition comprises a topical carrier, which is optionally in the form of a lotion, ointment, balm, paste, cream, foam, soap, shampoo, or gel.DBl / 157137097.1 29AMN-014PC / 120570-501412. The method of claim 11, wherein the silica particles are incorporated into the composition at from about 0.5 wt% to about 10 wt%, or from about 1 wt% to about 5 wt / %.

13. The method of claim 12, wherein the silica particles are incorporated from about 2 wt% to about 4 wt%.

14. The method of any one of claims 10 to 13, wherein the topical composition comprises oily or fatty components as constituents of the hydrophobic phase, and a hydrophilic phase.

15. The method of claim 14, wherein the topical composition comprises one or more emulsifying agents.

16. The method of claim 14 or 15, wherein the composition comprises excipients water, glycerin, petrolatum snow white, and one or more emollients and emulsion stabilizers.

17. The method of any one of claims 14 to 16, wherein at least one emollient is dicaprylyl ether or diisopropyl adipate.

18. The method of claim 17, wherein at least one emollient is diisopropyl adipate.

19. The method of any one of claims 14 to 18, wherein the composition comprises Glyceryl Stearate and PEG- 100 Stearate.

20. The method of claim 19, wherein at least one emollient is PEG-40 castor oil.

21. The method of any one of claims 14 to 20, wherein the composition further comprises a rheology modifier, which is optionally a carbomer.

22. The method of any one of claims 14 to 21, wherein the composition further comprises cetyl alcohol.

23. The method of any one of claims 14 to 22, wherein the composition further comprises a mixture of dimethicone and dimethiconol.

24. The method of any one of claims 14 to 23, wherein the composition further comprises a mixture of phenoxyethanol and ethylhexylglycerin.

25. The method of any one of claims 14 to 24, wherein the composition further comprises polypropylene glycol.DBl / 157137097.1 30AMN-014PC / 120570-501426. The method of any one of claims 14 to 25, wherein the composition further comprises tetrasodium EDTA.

27. The method of any one of claims 14 to 26, wherein the composition further comprises one or more antioxidants selected from vitamin E or salt thereof, butylated hydroxytoluene, and citric acid.

28. The method of any one of claims 14 to 27, wherein the composition has a pH of from about 5 to about 6, and optionally from about 5.25 to about 5.75.

29. The method of any one of claims 1 to 28, wherein the subject is a mammal, and optionally a veterinary subject, optionally selected from a dog, cat, or horse; or is a human subject.

30. The method of any one of claims 1 to 29, wherein the neoplasia involves the skin, and is optionally selected from squamous cell carcinoma, basal cell carcinoma, or cutaneous T-cell Lymphoma, optionally wherein the neoplasm is stage I or II cancer.

31. The method of any one of claims 1 to 29, wherein the neoplasm is a precancerous lesion.

32. The method of any one of claims 1 to 30, wherein the subject further receives cancer immunotherapy which is optionally immune checkpoint inhibitor therapy, tumor resection, radiation therapy, and / or chemotherapy.

33. The method of claim 32, wherein the composition is administered to the subject before, during, or after treatment with immunotherapy, such as immune checkpoint inhibitor therapy.

34. The method of claim 32, wherein the composition to a subject after cancer resection, radiation therapy, chemotherapy, or a biologic therapy.

35. The method of claim 33 or 34, wherein the composition is administered to prevent or treat skin or mucosal lesions or sores associated with the cancer therapy.

36. The method of any one of claims 1 to 35, wherein the composition is administered at least about daily, and optionally from 1 to about 10 times per day.DBl / 157137097.1 31AMN-014PC / 120570-501437. The method of claim 36, wherein the composition is administered for at least two weeks, or at least about one month, or at least about five months, or at least about six months, or at least about nine months, or at least about twelve months.

38. A topical cream formulation comprising silica particles and comprising excipients water, glycerin, petrolatum snow white, and one or more emollients and emulsion stabilizers.

39. The topical cream of claim 38, wherein the silica particles are incorporated into the composition at from about 0.5 wt% to about 10 wt%, or from about 1 wt% to about 5 wt / %.

40. The topical cream of claim 39, wherein the silica particles are incorporated from about 2 wt% to about 4 wt%.

41. The topical cream formulation of any one of claims 38 to 40, wherein at least one emollient is dicaprylyl ether or diisopropyl adipate.

42. The topical cream formulation of claim 41, wherein at least one emollient is diisopropyl adipate.

43. The topical cream formulation of any one of claims 38 to 42, wherein the formulation comprises Glyceryl Stearate and PEG- 100 Stearate.

44. The topical cream formulation of any one of claims 38 to 43, wherein at least one emollient is PEG-40 castor oil.

45. The topical cream formulation of any one of claims 38 to 44, further comprising a rheology modifier, which is optionally a carbomer.

46. The topical cream formulation of any one of claims 38 to 45, wherein the formulation further comprises cetyl alcohol.

47. The topical cream formulation of any one of claims 38 to 46, wherein the formulation further comprises a mixture of dimethicone and dimethiconol.

48. The topical cream formulation of any one of claims 38 to 47, wherein the formulation further comprises a mixture of phenoxyethanol and ethylhexylglycerin.

49. The topical cream formulation of any one of claims 38 to 48, wherein the formulation further comprises polypropylene glycol.DBl / 157137097.1 32AMN-014PC / 120570-501450. The topical cream formulation of any one of claims 38 to 49, wherein the formulation further comprises tetrasodium EDTA.

51. The topical cream formulation of any one of claims 38 to 50, wherein the formulation further comprises one or more antioxidants selected from vitamin E or salt thereof, butylated hydroxytoluene, and citric acid.

52. The topical cream formulation of any one of claims 38 to 51 , wherein the formulation has a pH of from about 5 to about 6, and optionally from about 5.25 to about 5.75.

53. A method for treating a skin condition, comprising administering the topical cream formulation of any one of claims 38 to 52.DBl / 157137097.1 33

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