Deciparticle Anti-cancer drugs

Abstract

This invention relates to compositions, and uses and methods thereof, with therapeutic deciparticles. Described herein are deciparticle (nanoparticle) compositions composed of an amphiphilic compound complexed with an auxiliary compound such as a biologically active molecule. Deciparticles of this invention are active drugs having potency for anti-tumor effects and for immunosuppression. This invention is also directed to amphiphilic compounds useful for making deciparticle complexes.

Description

Docket No. 018988-020W01DECIPARTICLE ANTI-CANCER DRUGSTECHNICAL FIELD

[0001] This invention provides compositions, uses thereof, and methods with therapeutic deciparticles. Deciparticles of this invention are active drugs having potency for antitumor effects and for immunosuppression. This invention is also directed to amphiphilic compounds useful for making deciparticle complexes.BACKGROUND

[0002] Drug delivery has been carried out by circulatory routes with actives loaded in protective particles such as liposomes, exosomes, and other nanoparticles. Nanoparticles for these purposes often range from 50-250 nanometers in size.

[0003] Drawbacks of conventional therapies with such nanoparticles include early removal of the particles from circulation by innate processes which cuts off the delivery route.

[0004] Further drawbacks of conventional therapies include slow uptake of nanoparticles by target cells.

[0005] What is needed are therapeutic compositions, uses thereof, and methods providing enhanced anti-tumor potency.

[0006] There is an urgent need for new compositions and methods for delivery of potent actives as ultra-small particles to enhance activity.BRIEF SUMMARY

[0007] This invention provides therapeutic deciparticle compositions, as well as their uses and methods for treating disease. The deciparticle (nanoparticle) compositions can provide enhanced drug potency as compared to conventional therapies.

[0008] The deciparticle compositions of this invention include active cancer drugs or antineoplastic drugs with anti-tumor potency.

[0009] This invention is also directed to amphiphilic compounds useful for making deciparticles.

[0010] Embodiments of this invention include the following:

[0011] A deciparticle composition of matter, comprising deciparticles being a complex of:one or more therapeutic agents; andDocket No. 018988-020W01an amphiphilic compound comprising a lipophilic steryl or cholesteryl moiety linked to a hydrophilic moiety.

[0012] The deciparticle composition above, wherein the deciparticles have an average size of from about 5 nm to about 35 nm, or from 5 nm to 20 nm, or from 5 nm to 18 nm.

[0013] The deciparticle composition above, wherein the deciparticles have a dispersity of size of up to about 0.1, or up to about 0.2, or up to about 0.3, or up to about 0.4, or up to about 0.5.

[0014] The deciparticle composition above, wherein the one or more therapeutic agents are sparingly or poorly water-soluble cancer drugs or antineoplastic drugs.

[0015] The deciparticle (nanoparticle) composition above, wherein the one or more therapeutic agents are mTOR kinase inhibitors.

[0016] The deciparticle composition above, wherein the one or more therapeutic agents are selected from everolimus, rapamycin, ridaforolimus, tacrolimus, temsirolimus, umirolimus, zotarolimus, dactolisib, voxtalisib, a salt or ester form of any of the foregoing, and a combination thereof.

[0017] The deciparticle composition above, wherein the amphiphilic compound comprises Formula I:L — X— Q Formula Iwhere L is a lipophilic moiety, X is a linker region, and Q is a hydrophilic moiety.

[0018] The deciparticle composition above, wherein L is a substituted or unsubstituted cholesteryl moiety, a cholesteryl analog moiety, a sterol, or a steroid.

[0019] The deciparticle composition above, wherein L has the structure Formula II:Formula IIwhere R1is a substituted or unsubstituted 2-yl-6-methylheptane having any one of the following structuresDocket No. 018988-020W01where R3is -OH, -(Cl-6)alkyl, -(C4-6)alkenyl, -O(Cl-6)alkyl, or - (Cl-6)alkyl-(C6-12)aryl.

[0020] The deciparticle composition above, wherein linker X is an organic linker comprising 1-60 atoms selected from hydrogen, carbon, oxygen, nitrogen, and sulfur atoms, or has the structure:— -C(O)— (CH2)n — NR2C(O)— (CH2)m—— -C(O)— (CH2)n — C(O)NR2— (CH2)m—— -C(O)— (CH2)n — NR2C(O)— -— -C(O)— (CH2)n — C(O)NR2— - — -C(O)NR2— (CH2)m—— -C(O)NR2— - — -(CH2)n — NR2C(O)— - — -(CH2)n — C(O)NR2— - (CH2)n — NR2C(O)— (CH2)m—(CH2)n — C(O)NR2— (CH2)m—— -C(O)NR3— (CH2)n — NR2C(O) — (CH2)m—— -C(O)NR3— (CH2)n — C(O)NR2— (CH2)m—— -C(O)NR3— (CH2)n — NR2C(O)— or— -C(O)NR3— (CH2)n — C(O)NR2—wherein n and m are each independently from 2 to 4, and R2and R3are eachDocket No. 018988-020W01independently - (Cl - 6)alkyl, -(C4-6)alkenyl, -0(Cl-6)alkyl, or - (Cl-6)alkyl-(C6-12)aryl.

[0021] The deciparticle composition above, wherein Q is a branched or unbranched, substituted or unsubstituted polyethyleneglycol.

[0022] The deciparticle composition above, wherein Q is a polyethyleneglycol-H, polyethyleneglycol-OH, polyethyleneglycol-(Cl-6)alkyl-OH, polyethyleneglycol-NH2, or polyethyleneglycol-(Cl-6)alkyl-NH2, wherein the polyethyleneglycol has average molecular weight from about 340 to about 2,500, or about 340 to about 740, or about 470 to about 650.

[0023] The deciparticle composition above, wherein Q is a polyethyleneglycol-H, polyethyleneglycol-OH, polyethyleneglycol-(Cl-6)alkyl-OH, polyethyleneglycol-NH2, or polyethyleneglycol-(Cl-6)alkyl-NH2, wherein the polyethyleneglycol has number average molecular weight MN from N=7 to N=56.

[0024] The deciparticle composition above, wherein Q is a polyethyleneglycol-H, polyethyleneglycol-OH, polyethyleneglycol-(Cl-6)alkyl-OH, polyethyleneglycol-NH2, or polyethyleneglycol-(Cl-6)alkyl-NH2, wherein the polyethyleneglycol has number average molecular weight MN from N=7 to N=16.

[0025] The deciparticle composition above, wherein the amphiphilic compound comprises 40 to 99.9 weight percent of the deciparticle composition.

[0026] The deciparticle composition above, wherein the one or more therapeutic agents in total comprise 0.1 to 60 weight percent of the deciparticle composition.

[0027] The deciparticle composition above, wherein the deciparticle composition is in a dry powder form or reconstituted from a lyophilized form.

[0028] The deciparticle composition above, comprising a pharmaceutically-acceptable carrier.

[0029] The deciparticle composition above, comprising one or more of a dispersant excipient, an anti-caking excipient, or a particle stabilizing excipient.

[0030] The deciparticle composition above, wherein the concentration below which a deciparticle composition may have zero hemolytic activity at pH 7.4 is less than 1000 ug / ml, or less than 50 ug / ml.

[0031] The deciparticle composition above, wherein the composition is stable for at least 24 hours at 5°C.Docket No. 018988-020W01

[0032] A method for making a deciparticle composition above, the method comprising:mixing the one or more therapeutic agents in an organic solvent; contacting the amphiphilic compound with the therapeutic agents in the organic solvent;mixing or vortexing the organic solvent;filtering the deciparticle composition in the organic solvent to remove particles or aggregates larger than 15 nm, or 30 nm, or 75 nm, or 100 nm;removing residual organic solvent and / or agents from the deciparticle composition.

[0033] A deciparticle composition made by the method above.

[0034] A method for treating cancer in a subject in need, the method comprising administering a deciparticle composition above.

[0035] A use of a deciparticle composition above in the preparation of a medicament for treating cancer in a subject in need.

[0036] A deciparticle composition above for use in treating cancer in a subject in need.

[0037] A deciparticle composition above for use in the treatment of the human or animal body.

[0038] An amphiphile compound, comprising Formula I:L — X — Q. Formula Iwhere L is a lipophilic moiety, X is a linker region, and Q is a hydrophilic moiety.

[0039] The amphiphile compound above, wherein L is a substituted or unsubstituted cholesteryl moiety, a cholesteryl analog moiety, a sterol, or a steroid.

[0040] The amphiphile compound above, wherein L has the structure Formula II:where R1is a substituted or unsubstituted 2-yl-6-methylheptane having any one of the following structuresDocket No. 018988-020W01where R3is -OH, (Cl-6)alkyl, (Cl-6)alkenyl, (Cl-6)cycloalkyl, or (Cl-6)alkoxy.

[0041] The amphiphile compound above, wherein linker X is an organic linker comprising 1-60 atoms selected from hydrogen, carbon, oxygen, nitrogen, and sulfur atoms, or has the structure:— -C(O)— (CH2)n — NR2C(O)— (CH2)m—— -C(O)— (CH2)n — C(O)NR2— (CH2)m—— -C(O)— (CH2)n — NR2C(O)— -— -C(O)— (CH2)n — C(O)NR2— - — -C(O)NR2— (CH2)m—— -C(O)NR2— - — -(CH2)n — NR2C(O)— - — -(CH2)n — C(O)NR2— - — -(CH2)n — NR2C(O)— (CH2)m—— -(CH2)n — C(O)NR2— (CH2)m—— -C(O)NR3— (CH2)n — NR2C(O) — (CH2)m—— -C(O)NR3— (CH2)n — C(O)NR2— (CH2)m—— -C(O)NR3— (CH2)n — NR2C(O)— or— -C(O)NR3— (CH2)n — C(O)NR2—wherein n and m are each independently from 2 to 4, and R2and R3are eachDocket No. 018988-020W01independently -(Cl-6)alkyl, -(C4-6)alkenyl, -0(Cl-6)alkyl, or - (C l-6)alkyl-(C6-12)aryl.

[0042] The amphiphile compound above, wherein Q is a branched or unbranched, substituted or unsubstituted polyethyleneglycol.

[0043] The amphiphile compound above, wherein Q is a polyethyleneglycol-H, polyethyleneglycol-OH, polyethyleneglycol-(Cl-6)alkyl-OH, polyethyleneglycol-NH2, or polyethyleneglycol-(Cl-6)alkyl-NH2, wherein the polyethyleneglycol has average molecular weight from about 300 to about 2,500, or about 350 to about 750, or about 440 to about 660.

[0044] The amphiphile compound above, wherein Q is a polyethyleneglycol-H, polyethyleneglycol-OH, polyethyleneglycol-(Cl-6)alkyl-OH, polyethyleneglycol-NH2, or polyethyleneglycol-(Cl-6)alkyl-NH2, wherein the polyethyleneglycol has number average molecular weight MN from N=7 to N=56.

[0045] The amphiphile compound above, wherein Q is a polyethyleneglycol-H, polyethyleneglycol-OH, polyethyleneglycol-(Cl-6)alkyl-OH, polyethyleneglycol-NH2, or polyethyleneglycol-(Cl-6)alkyl-NH2, wherein the polyethyleneglycol has number average molecular weight MN from N=7 to N=16.

[0046] A compound, comprising the structure:-C(O)-(CH2)n-C(O)NR2— (CH2CH2O)XR4wherein R1is a substituted or unsubstituted 2-yl-6-methylheptane, n is from 2 to 4, X is from 7 to 56, R2is -H or -(Cl-6)alkyl, and R4is -H, -(Cl-6)alkyl, -R50H, or -R6NH2, where R5and R6are each independently -(Cl-6)alkyl.

[0047] The compound above, wherein R1is 2-yl-6-methylheptane, n is 2, X is 12 to provide PEG average molecular weight about 550, R2is -H, and R4is -CH3.

[0048] The compound above, wherein R1is 2-yl-6-methylheptane, n is 2, X is 12, R2is -H, and R4is -CH3.

[0049] The compound above, wherein R1is 2-yl-6-methylheptane, n is 2, X is 12, R2is -H, and R4is -CH2CH2OH.

[0050] The compound above, wherein R1is 2-yl-6-methylheptane, n is 2, X is 23 to provide PEG average molecular weight about 1,000, R2is -H, and R4is -CH3.Docket No. 018988-020W01

[0051] The compound above, wherein R1is 2-yl-6-methylheptane, n is 2, X is 45 to provide PEG average molecular weight about 2,000, R2is -H, and R4is -CH3.

[0052] The compound above, wherein R1is 2-yl-6-methylheptane, n is 2, X is 23 to provide PEG average molecular weight about 1,000, R2is -H, and R4is -CH2CH2OH.

[0053] The compound above, wherein R1is 2-yl-6-methylheptane, n is 2, X is 9, R2is -H, and R4is -CH3 or -CH2CH2OH.

[0054] The compound above, wherein R1is 2-yl-6-methylheptane, n is 2, X is 56, R2is -H, and R4is -CH3 or -CH2CH2OH.

[0055] A compound, comprising the structure:-C(O)-(CH2)n-NR2C(O)-(CH2CH2O)xR4wherein R1is a substituted or unsubstituted 2-yl-6-methylheptane, n is from 2 to 4, X is from 7 to 56, R2is -H or -(Cl-6)alkyl, and R4is -H, -(Cl-6)alkyl, -R5OH, or -R6NH2, where R5and R6are each independently -(Cl-6)alkyl.

[0056] The compound above, wherein R1is 2-yl-6-methylheptane, n is 2, X is 12, R2is -H, and R4is -CH3.

[0057] The compound above, wherein R1is 2-yl-6-methylheptane, n is 2, X is 12, R2is -H, and R4is -CH2CH2OH.

[0058] The compound above, wherein R1is 2-yl-6-methylheptane, n is 2, X is about 12 to provide PEG average molecular weight about 550, and R4is -CH3or- CH2CH2OH.

[0059] A compound, comprising the structure:O— C(O)NH— (CH2CH2O)XR4wherein R1is a substituted or unsubstituted 2-yl-6-methylheptane, X is from 7 to 56, and R4is -H, - (Cl-6)alkyl, -R5OH, or -R6NH2, where R5and R6are each independently -(Cl-6)alkyl.

[0060] The compound above, wherein R1is 2-yl-6-methylheptane, X is 12, and R4is -CH3.

[0061] The compound above, wherein R1is 2-yl-6-methylheptane, X is 12, and R4is - CH2CH2OH.Docket No. 018988-020W01

[0062] The compound above, wherein R1is 2-yl-6-methylheptane, X is about 12 to provide PEG average molecular weight about 550, and R4is -CH3 or - CH2CH2OH.

[0063] A compound, comprising the structure:-C(O)NH— (CH2)n— (OCH2CH2)xR5wherein R1is a substituted or unsubstituted 2-yl-6-methylheptane, n is from 2 to 4, X is from 7 to 56, and R5is -OH, -O(Cl-6)alkyl, -OR6OH, or - OR7NH2, where R6and R7are each independently (Cl-6)alkyl.

[0064] The compound above, wherein R1is 2-yl-6-methylheptane, n is 2, X is 12, and R5is - OCH3.

[0065] The compound above, wherein R1is 2-yl-6-methylheptane, n is 2, X is 12, and R5is - OCH2CH2OH.

[0066] The compound above, wherein R1is 2-yl-6-methylheptane, n is 2, X is about 12 to provide PEG average molecular weight about 550, and R5is - OCH2CH2OH.

[0067] A compound, comprising the structure:O— (CH2)n- NR2C(O)-(CH2CH2O)XR4wherein R1is a substituted or unsubstituted 2-yl-6-methylheptane, n is from 2 to 4, X is from 7 to 56, R2is -H or -(Cl-6)alkyl, and R4is -H, -(Cl-6)alkyl, -R5OH, or -R6NH2, where R5and R6are each independently -(Cl-6)alkyl.

[0068] The compound above, wherein R1is 2-yl-6-methylheptane, n is 2, X is 12, R2is -H, and R4is -CH3.

[0069] The compound above, wherein R1is 2-yl-6-methylheptane, n is 2, X is 12, R2is -H, and R4is - CH2CH2OH.

[0070] The compound above, wherein R1is 2-yl-6-methylheptane, n is 2, X is about 12 to provide PEG average molecular weight about 550, R2is -H, and R4is -CH3 or - CH2CH2OH.

[0071] A compound, comprising the structure:O-(CH2)n-C(O)NR2— (CH2CH2O)XR4R1wherein R1is a substituted or unsubstituted 2-yl-6-methylheptane, n is from 2 to 4, X isDocket No. 018988-020W01from 7 to 56, R2is -H or -(Cl-6)alkyl, and R4is -H, -(Cl-6)alkyl, -R5OH, or -R6NH2, where R5and R6are each independently -(Cl-6)alkyl.

[0072] The compound above, wherein R1is 2-yl-6-methylheptane, n is 2, X is 12 or about 12 to provide PEG average molecular weight about 550, R2is -H, and R4is -CH3.

[0073] The compound above, wherein R1is 2-yl-6-methylheptane, n is 2, X is 12 or about 12 to provide PEG average molecular weight about 550, R2is -H, and R4is - CH2CH2OH.

[0074] A compound, comprising the structure:O-(CH2CH2O)XR4wherein R1is a substituted or unsubstituted 2-yl-6-methylheptane, X is from 7 to 56, and R4is -H, - (Cl-6)alkyl, -R5OH, or -R6NH2, where R5and R6are each independently -(Cl-6)alkyl.

[0075] The compound above, wherein R1is 2-yl-6-methylheptane, X is 12 or about 12 to provide PEG average molecular weight about 550, and R4is -CH3.

[0076] The compound above, wherein R1is 2-yl-6-methylheptane, X is 12 or about 12 to provide PEG average molecular weight about 550, and R4is - CH2CH2OH.

[0077] A compound, comprising the structure:O— (CH2)n— (OCH2CH2)xR5wherein R1is a substituted or unsubstituted 2-yl-6-methylheptane, n is from 2 to 4, X is from 7 to 56, R2is -H or -(Cl-6)alkyl, and R5is -OH, -O(Cl-6)alkyl, -OR6OH, or - OR7NH2, where R6and R7are each independently (Cl-6)alkyl.

[0078] The compound above, wherein R1is 2-yl-6-methylheptane, n is 2, X is 12 or about 12 to provide PEG average molecular weight about 550, R2is -H, and R5is -OCH3.

[0079] The compound above, wherein R1is 2-yl-6-methylheptane, n is 2, X is 12 or about 12 to provide PEG average molecular weight about 550, R2is -H, and R5is -OCH2CH2OH.Docket No. 018988-020W01

[0080] A compound, comprising the structure:O-C(O)-(CH2)n— NR2C(O)-(CH2)m— (OCH2CH2)xR5R1wherein R1is a substituted or unsubstituted 2-yl-6-methylheptane, n is from 2 to 4, X is from 7 to 56, R2is -H or -(Cl-6)alkyl, and R5is -OH, -O(Cl-6)alkyl, -OR6OH, or - OR7NH2, where R6and R7are each independently (Cl-6)alkyl.

[0081] The compound above, wherein R1is 2-yl-6-methylheptane, n is 2, X is 12 or about 12 to provide PEG average molecular weight about 550, R2is -H, and R5is -OCH3.

[0082] The compound above, wherein R1is 2-yl-6-methylheptane, n is 2, X is 12 or about 12 to provide PEG average molecular weight about 550, R2is -H, and R5is -OCH2CH2OH.

[0083] A compound, comprising the structure:-C(O)-(CH2)n— C(O)NR2-(CH2)m— (OCH2CH2)xR5wherein R1is a substituted or unsubstituted 2-yl-6-methylheptane, n is from 2 to 4, X is from 7 to 56, R2is -H or -(Cl-6)alkyl, and R5is -OH, -O(Cl-6)alkyl, -OR6OH, or - OR7NH2, where R6and R7are each independently (Cl-6)alkyl.

[0084] The compound above, wherein R1is 2-yl-6-methylheptane, n is 2, X is 12 or about 12 to provide PEG average molecular weight about 550, R2is -H, and R5is -OCH3.

[0085] The compound above, wherein R1is 2-yl-6-methylheptane, n is 2, X is 12 or about 12 to provide PEG average molecular weight about 550, R2is -H, and R5is -OCH2CH2OH.

[0086] A compound, comprising the structure:O-(CH2)n— NR2C(O)-(CH2)m— (OCH2CH2)xR5wherein R1is a substituted or unsubstituted 2-yl-6-methylheptane, n and m are each independently from 2 to 4, X is from 7 to 56, R2is -H or -(Cl-6)alkyl, and R5is -OH, -O(Cl-6)alkyl, -OR6OH, or - OR7NH2, where R6and R7are each independently (Cl-6)alkyl.Docket No. 018988-020W01

[0087] The compound above, wherein R1is 2-yl-6-methylheptane, n and m are 2, X is 12 or about 12 to provide PEG average molecular weight about 550, R2is -H, and R5is -OCH3.

[0088] The compound above, wherein R1is 2-yl-6-methylheptane, n and m are 2, X is 12 or about 12 to provide PEG average molecular weight about 550, R2is -H, and R5is -OCH2CH2OH.

[0089] A compound, comprising the structure:O-(CH2)n— C(O)NR2— (CH2)m— (OCH2CH2)xR5wherein R1is a substituted or unsubstituted 2-yl-6-methylheptane, n and m are each independently from 2 to 4, X is from 7 to 56, R2is -H or -(Cl-6)alkyl, and R5is -OH, -O(Cl-6)alkyl, -OR6OH, or - OR7NH2, where R6and R7are each independently (Cl-6)alkyl.

[0090] The compound above, wherein R1is 2-yl-6-methylheptane, n and m are 2, X is 12 or about 12 to provide PEG average molecular weight about 550, R2is -H, and R5is -OCH3.

[0091] The compound above, wherein R1is 2-yl-6-methylheptane, n and m are 2, X is 12 or about 12 to provide PEG average molecular weight about 550, R2is -H, and R5is -OCH2CH2OH.

[0092] A process for making deciparticles composed of a complex of one or more therapeutic agents and an amphiphile, the process comprising:dissolving an amphiphile compound and one or more therapeutic agents in ethanol to form deciparticles;solubilizing the deciparticles into lactose and water for injection (WFI); filter-sterilizing the solubilized deciparticles;filling and finishing the solubilized deciparticles in a temperature-controlled environment with ≥98% filling weight accuracy;lyophilizing and reconstituting the deciparticles to a final concentration of 4 mg / mL for intravenous administration.

[0093] The process above, wherein the amphiphile is described above.Docket No. 018988-020W01

[0094] The process above, wherein the amphiphile is Compound 111, Compound 111A, Compound 111B, Compound 111X, Compound 111F, Compound 111G, or Compound 111H.

[0095] The process above, wherein the one or more therapeutic agents is everolimus.

[0096] The process above, wherein the one or more therapeutic agents is paclitaxel, docetaxel, palbociclib, osimertinib, celecoxib, ritonavir, fenofibrate, carbamazepine, phenytoin, glyburide, glipizide, haloperidol, olanzapine, valsartan, semaglutide, vorinostat, carboplatin, a salt or ester form of any of the foregoing, or a combination thereof.

[0097] The process above, conducted under yellow light with amber vials to minimize active agent degradation.

[0098] The process above, wherein upon reconstitution the product is monodisperse deciparticles with average particle size from about 5 nm to about 35 nm, or from 5 nm to 20 nm, or from 5 nm to 18 nm.

[0099] The process above, wherein the reconstituted product retained average particle size after storage for at least one month at 5°C.

[0100] The process above, wherein the reconstituted product retained average particle size for at least 24 hours at 25°C.

[0101] The process above, wherein the solubilized deciparticles are 1-20 g scale.BRIEF DESCRIPTION OF THE DRAWINGS

[0102] FIG. 1 shows in vivo anti-tumor potency of deciparticles composed with an amphiphile and everolimus in a HT-29 colon cancer xenograft model in mice.Deciparticle potency was compared to saline control. Deciparticle potency significantly reduced tumor volume.

[0103] FIG. 2 shows in vivo anti-tumor potency of deciparticles composed with an amphiphile and everolimus in an OVCAR-3 ovarian cancer xenograft model in mice. Deciparticle potency was compared to saline control. Deciparticle potency significantly reduced tumor volume.

[0104] FIG. 3 shows in vivo anti-tumor potency of deciparticles composed with an amphiphile and everolimus in a U-87 MG glioblastoma xenograft model in mice.Deciparticle potency was compared to TAXOL comparative compound and to saline control. Deciparticle potency surprisingly exceeded that of TAXOL.Docket No. 018988-020W01

[0105] FIG. 4 shows in vivo anti-tumor potency of deciparticles composed with an amphiphile and everolimus in a MDA-MB-231 breast cancer xenograft model in mice. Deciparticle potency was compared to saline control. Deciparticle potency significantly reduced tumor volume.

[0106] FIG. 5 shows in vivo distribution of deciparticles composed with an amphiphile and everolimus in mice. Deciparticle showed rapid distribution and accumulation of drug in target organs.

[0107] FIG. 6 shows in vivo distribution of oral everolimus in mice. Oral everolimus was trapped in the stomach and GI tract.DETAILED DESCRIPTION OF THE DISCLOSURE

[0108] This invention relates to therapeutic compositions, uses and methods with deciparticle forms useful for treating cancer. Described herein are deciparticle compositions composed of an amphiphilic compound and an MTOR inhibitor drug. Included are methods for making deciparticle compositions. This invention further relates to methods for treating cancer with potent deciparticle compositions.

[0109] Deciparticle (nanoparticle) compositions can be composed of an amphiphilic compound complexed with auxiliary compounds such as biologically active molecules. For example, an auxiliary compound can be a therapeutic agent.

[0110] Deciparticles of this invention can be much smaller, sometimes about 1 / 10ththe size, of conventional “nanoparticles” used for treating cancer. The potency of deciparticles of this invention can advantageously exceed that of conventional “nanoparticle” therapies.

[0111] In further aspects, this invention provides deciparticle forms which are stable in blood and exhibit low hemolytic activity.

[0112] In some embodiments, a deciparticle composition of this invention may be used in a method for treating cancer, for immunosuppression in transplantation, or for severe rheumatoid arthritis, or for disorders involving inflammation in a subject in need.

[0113] Deciparticles of this invention can be stable and stored for extended periods.

[0114] Deciparticles of this invention create a new regime of size and molecular mass for therapeutics. Deciparticles can be prepared with discrete amphiphilic molecules of this disclosure complexed with active agents.

[0115] As used herein, the term deciparticle can refer to small particles formed from discrete amphiphilic molecules of this disclosure contacted with one or more drug molecules.Docket No. 018988-020W01

[0116] A deciparticle (nanoparticle) composition of this invention can also be lyophilized to a solid lyophile form. A solid lyophile form made from a deciparticle composition can be reconstituted to form a suspension of deciparticles.

[0117] Because the deciparticle compositions can achieve surprisingly small size particles, typically 1 / 10ththe size of conventional nanoparticles, the deciparticle compositions can provide increased mass transport of drug through blood vessel walls.

[0118] Deciparticles of this invention can be used in a pharmaceutical composition containing a pharmaceutically-acceptable carrier and / or excipients. A pharmaceutical composition can be prepared in a conventional manner.

[0119] Without wishing to be bound by theory, deciparticle size is advantageous because the particles approach the size of biological molecules and begin to behave like a molecular drug. Deciparticles can circulate in the body largely undetected by the immune system and penetrate biological barriers, entering cells and even nuclei.Cellular uptake of deciparticles can be inversely size-dependent because of ultrasmall size, where smaller particles have increased uptake. Endocytosis pathways depend on size so that clathrin-mediated pathways dominate for 5-50 nm. Key physicochemical features can be controlled by size. For example, renal filtration, where 2-4 nm PEG-silica or PEG-Au are rapidly cleared in urine.

[0120] This disclosure relates to the discovery that deciparticles provide properties not available to larger particles such as typical liposomes and micelles. Deciparticles are not lost to renal filtration. Deciparticles can have increased cellular uptake and reduced immunogenicity.

[0121] As used herein, trademark protection for the term DECIPARTICLES has been applied for in the U. S. and under the Madrid Agreement has been granted in many countries.Deciparticle compositions and properties

[0122] A deciparticle composition of matter of this invention is an ultra-small particle which is a complex of bound molecules. Deciparticles can be composed of amphiphilic molecules bound to one or more auxiliary compounds. Examples of auxiliary compounds include pharmacologically active molecules. A deciparticle composition can be a suspension of deciparticles in a carrier, solvent, or water-solventDocket No. 018988-020W01mixture. In some embodiments, an auxiliary compound may be an active agent or therapeutic agent.

[0123] Deciparticle complexes of this invention may be composed of components which are bound by many forces. For example, forces which may bind deciparticles include ionic bonds, hydrogen bonds, Van der Waals forces, London forces, hydrophobic interactions, steric interactions, dipole-dipole interactions, and adhesive interactions.

[0124] Deciparticle compositions of this invention can be composed of amphiphilic molecules and one or more sparingly or poorly water-soluble cancer drugs or antineoplastic drugs.

[0125] A deciparticle (nanoparticle) composition may be composed of one or more therapeutic agents that are sparingly or poorly water-soluble cancer drugs or antineoplastic drugs.

[0126] Examples of poorly soluble cancer or antineoplastic drugs include cytotoxic agents such as mTOR kinase inhibitors.

[0127] Examples of mTOR kinase inhibitors include everolimus (e.g. CAS 159351-69-6), rapamycin, ridaforolimus, tacrolimus, temsirolimus, umirolimus, zotarolimus, dactolisib, voxtalisib, a salt or ester form of any of the foregoing, and a combination thereof.

[0128] A deciparticle can have an average size of from 1 nm to 50 nm, or from 2 nm to 50 nm, or from 4 nm to 50 nm, or from 5 nm to 40 nm, or from 5 nm to 30 nm, or from 5 nm to 25 nm.

[0129] In some embodiments, a deciparticle may have an average size of from 5 nm to 20 nm, or from 5 nm to 15 nm.

[0130] In certain embodiments, a deciparticle may have an average size of less than 30 nm, or less than 15 nm.

[0131] In additional embodiments, a deciparticle may have an average size of about 4 to about 15 nm, or about 4 to about 12 nm, or about 8-18 nm.

[0132] In further embodiments, a deciparticle may have an average size of from about 4 nm to about 35 nm, or from 4 nm to 20 nm, or from 4 nm to 18 nm. The deciparticles may have an average size of 5 nm to 35 nm, or 5 nm to 20 nm, or 5 nm to 18 nm.Docket No. 018988-020W01

[0133] Deciparticles may have a dispersity of size of up to about 0.1, or up to about 0.2, or up to about 0.3, or up to about 0.4, or up to about 0.5.

[0134] A deciparticle composition can be composed of an amphiphilic compound which may comprise 60 to 99.9 weight percent of the deciparticle composition.

[0135] A deciparticle composition can be composed of one or more auxiliary compounds which in total comprise 0.1 to 40 weight percent of the deciparticle composition.

[0136] In some embodiments, a deciparticle composition can be composed of an amphiphilic compound which may comprise 50 to 99.9 weight percent of the deciparticle composition.

[0137] In some embodiments, a deciparticle composition can be composed of one or more auxiliary compounds which in total comprise 0.1 to 50 weight percent of the deciparticle composition.

[0138] In some embodiments, a deciparticle composition can be composed of an amphiphilic compound which may comprise 40 to 99.9 weight percent of the deciparticle composition.

[0139] In some embodiments, a deciparticle composition can be composed of one or more auxiliary compounds which in total comprise 0.1 to 60 weight percent of the deciparticle composition.

[0140] In further embodiments, a deciparticle composition can be in a dry powder form.

[0141] In additional embodiments, a deciparticle composition can include a pharmaceutically-acceptable carrier.

[0142] In certain embodiments, a deciparticle composition may include one or more of a dispersant excipient, an anti-caking excipient, or a particle stabilizing excipient.

[0143] Deciparticles of this invention can have low hemolytic toxicity. In certain embodiments, the concentration below which a deciparticle composition may have zero hemolytic activity at pH 7.4 is less than 10 ug / ml, less than 50 ug / ml, less than 100 ug / ml, or less than 200 ug / ml, or less than 300 ug / ml, or less than 1000 ug / ml, or less than 2000 ug / ml, or less than 5000 ug / ml.

[0144] A pertinent hemolysis assay can be performed as follows:Docket No. 018988-020W01

[0145] Draw 0.4 mL from 1.3 mL of new RBC from a commercial source. Wash RBC with PBS, pH 7.4, until supernatant is clear (2000 rpm for 5 min). Test compound 10 mg in 40 uL ethanol and then add 500 uL 5% lactose water, final 20mg / mL. Make serial dilutions of the test compound. Mix 50 uL of RBC with 50 uL of test solution, incubate at 37°C for 1 hr, spin down the cells at 2000 rpm for 5 min. Transfer the supernatant into assay plate for spectrum scan at 540nm.

[0146] Deciparticles of this invention can have high stability. In some embodiments, a deciparticle composition may stable for at least 24 hours at 5°C. In further embodiments, a deciparticle composition may stable for at least 2 hours at 20-25°C, or at least 24 hours at 20-25°C, or at least 7 days at 20-25°C. Upon reconstitution in water suspension, a deciparticle composition may be stable for at least 24 hours at 5°C, or at least 2 hours at 20-25°C, or at least 24 hours at 20-25°C, or at least 7 days at 20-25°C.Amphiphilic molecules for deciparticles

[0147] An amphiphilic molecule may be composed of a lipophilic moiety connected by a linker region to a hydrophilic moiety. An amphiphilic molecule of this invention may have the structure:L — X — Q Formu ilaT1where L is the lipophilic moiety, X is the linker region, and Q is the hydrophilic moiety.

[0148] In some embodiments, L may be a substituted or unsubstituted cholesteryl moiety, a substituted or unsubstituted cholesteryl analog moiety, a substituted or unsubstituted sterol, or a substituted or unsubstituted steroid.

[0149] In certain aspects, L may be a substituted cholesteryl moiety having a carboncarbon double bond at the 5-6 position, where the substituents may be, for example, at the 3-O-position, and / or at the 17-ring-position. Examples of substituents include chemical groups having 1-60 atoms comprising one or more of-NH2, -OH, -SH, -CN, -(Cl-18)alkyl, -(Cl-18)alkenyl, -(Cl-18)alkoxy, -(Cl-18)aryl, -halo, -haloalkyl, - acyl, -carbamyl, and -carbamoyl groups.

[0150] In certain embodiments, a deciparticle composition may comprise a complex of an amphiphilic compound, which comprises a lipophilic steryl or cholesteryl moiety linked to a hydrophilic moiety, with an auxiliary compound. An auxiliary compound can be a therapeutic agent.Docket No. 018988-020W01

[0151] In additional embodiments, a deciparticle composition may comprise a complex of an amphiphilic compound, which comprises a substituted cholesteryl moiety having a carboncarbon double bond at the 5-6 ring position linked to a hydrophilic moiety, with an auxiliary compound.

[0152] In additional embodiments, a deciparticle composition may comprise a complex of an amphiphilic compound, which comprises a substituted cholesteryl moiety having a carboncarbon double bond at the 5-6 ring position and linked at the 3-O-position to a hydrophilic substituent, with an auxiliary compound.

[0153] In further embodiments, a deciparticle composition may comprise a complex of an amphiphilic compound with an auxiliary compound, where the amphiphilic compound comprises a substituted cholesteryl moiety having a carbon-carbon double bond at the 5-6 ring position, a substituent at the 17-ring position, and linked at the 3-O-position to a hydrophilic substituent.

[0154] In further aspects, L may be a cholesteryl analog moiety.

[0155] In additional aspects, L may be a substituted steryl moiety or a substituted steroid moiety.

[0156] An amphiphilic compound of this invention may comprise a lipophilic steryl or cholesteryl moiety linked to a hydrophilic moiety.

[0157] In an amphiphilic compound of this invention, L may be a lipophilic moiety, X may be a linker region, and Q may be a hydrophilic moiety.

[0158] In some embodiments, an amphiphile compound of this invention may have a LogP value from 8.7 to 12.

[0159] In further embodiments, L may have the cholesteryl structure Formula IIFormula IIwhere implicit hydrogens are not shown unless needed as stereo-informative, where R1is a substituted or unsubstituted 2-yl-6-methylheptane having any one of the following structuresDocket No. 018988-020W01(27)R3where R3is -OH, (Cl-6)alkyl, (Cl-6)alkenyl, (Cl-6)cycloalkyl, or (Cl-6)alkoxy.

[0160] The structure Formula II can for convenience also be shown without stereoisomerism or ring hydrogens as followsFormula lib

[0161] As used herein, implicit hydrogens in a structure may not be shown unless needed as stereo-informative.

[0162] As described herein, the compounds, moieties and structures of this disclosure are meant to encompass all possible isomers, stereoisomers, diastereomers, enantiomers, and / or optical isomers that would be understood to exist for the specified compound or structure, including any mixture, racemic or otherwise, thereof.

[0163] Examples of steryl and cholesteryl lipophilic moieties for amphiphilic molecules of this disclosure include moieties based on sterols, phytosterols, zoosterols, mycosterols, or derivatives of any of the foregoing, and their biological intermediates and precursors, which may include, for example, cholesterol, lanosterol, stigmastanol, stigmasterol, dihydrolanosterol, zymosterol, zymostenol, desmosterol, fucosterol, P-sitosterol, campesterol, brassicasterol, hydroxycholesterols, 7-dehydrocholesterol, and derivatives thereof. The steryl and cholesteryl lipophilic moieties may be substituted or unsubstituted.

[0164] Examples of cholesteryl lipophilic moieties include substituted steroids such as gonanes, estranes, androstanes, pregnanes, cholanes, cholestanes, ergostanes, campestanes, poriferastanes, stigmastanes, gorgostanes, lanostanes, cycloartanes, and derivatives thereof. The steroid can be substituted at the 17-carbon with R1as defined herein and an oxygen atom at the 3-carbon.Docket No. 018988-020W01

[0165] In some embodiments, cholesteryl lipophilic moieties can be a cholesterol analogue. Examples of cholesterol analogues include calcitriol, calcipotriol, vitamin D2, vitamin D3, betulinol, lupeol, ursolic acid, oleanolic acid, hydrocortisones, diplopterol, 2-methyl-diplopterol, substituted cholesterol analogue CHIM, halomethylnorcholest, and Gemini cholesterol analogues. When having the four-fused- ring structure A-B-C-D, the analogue can be substituted at the 17-carbon with R1as defined herein and an oxygen at the 3-carbon.

[0166] In certain embodiments, any of the foregoing cholesterol and cholesterol analogues can be chemically-substituted. Examples of substituents include -NH2, -OH, -SH, -CN, - alkyl, -alkenyl, -alkoxy, -aryl, -halo, - haloalkyl, -acyl, -carbamyl, and- carbamoyl.

[0167] In certain embodiments, a cholesteryl lipophilic moiety of an amphiphile may have the structure:where R1is substituted or unsubstituted 2-yl-6-methylheptaneDocket No. 018988-020W01where R3is OH.

[0168] In further embodiments, cholesteryl lipophilic moieties can be an oxy-sterol or cholesterol hydroperoxide such as 7a, P-OOH-Chol, 7a, P-OH-Chol, 7a-OH-Chol, 7-K- Chol, 5a-OOH-Chol, 5a-OH-Chol.

[0169] In additional embodiments, cholesteryl lipophilic moieties can be an oxy-sterol having an oxy substituent on R1, such as 24S-OH-Chol, and 27-OH-Chol.

[0170] In further embodiments, the linker region X of an amphiphilic molecule may be an organic linker comprising 1-60 atoms selected from hydrogen, carbon, oxygen, nitrogen, and sulfur atoms, or can have one of the following structures:— -C(O)— (CH2)n — NR2C(O)— (CH2)m—— -C(O)— (CH2)n — C(O)NR2— (CH2)m—— -C(O)— (CH2)n — NR2C(O)— -— -C(O)— (CH2)n — C(O)NR2— - — -C(O)NR2— (CH2)m—— -C(O)NR2— - — -(CH2)n — NR2C(O)— - — -(CH2)n — C(O)NR2— - (CH2)n — NR2C(O)— (CH2)m—(CH2)n — C(O)NR2— (CH2)m—— -C(O)NR3— (CH2)n — NR2C(O) — (CH2)m—Docket No. 018988-020W01— -C(O)NR3— (CH2)n — C(O)NR2— (CH2)m—— -C(O)NR3— (CH2)n — NR2C(O)—or— -C(O)NR3— (CH2)n — C(O)NR2—wherein n and m are each independently from 2 to 4, and R2and R3are each independently -(Cl-6)alkyl, -(C4-6)alkenyl, -O(Cl-6)alkyl, or -(Cl-6)alkyl-(C6-12)aryl.

[0171] An amphiphilic molecule of this invention may be composed of a lipophilic moiety connected by a linker region to a hydrophilic moiety.

[0172] Examples of hydrophilic moieties of an amphiphilic molecule include polyethylene glycols.

[0173] In some embodiments, a hydrophilic moiety of this disclosure can be a polyethylene glycol having weight molecular weight from 300 up to 20,000, or from 300 up to 10,000.

[0174] In certain embodiments, a hydrophilic moiety of this disclosure can be a polyethylene glycol or mPEG having weight molecular weight from about 300 to 2,500, or 350 to 1,000, or 500 to 1,000.

[0175] The polyethylene glycol or mPEG of a deciparticle may have a range of molecular weights. The weight molecular weight of a polyethylene glycol or mPEG can be about 339, 383, 427, 471, 515, 550, 559, 603, 647, 691, or 735.

[0176] In some embodiments, a hydrophilic moiety Q may be a branched or unbranched, substituted or unsubstituted polyethyleneglycol.

[0177] In some embodiments, a hydrophilic moiety Q may be a polyethyleneglycol-H, polyethyleneglycol-OH, polyethyleneglycol-(Cl-6)alkyl-OH, polyethyleneglycol-NEE, or polyethyleneglycol-(Cl-6)alkyl-NH2, wherein the polyethyleneglycol has molecular weight from about 340 to about 2,500, or about 340 to about 740, or about 470 to about 650.

[0178] In further embodiments, a hydrophilic moiety Q may be a polyethyleneglycol-H, polyethyleneglycol-OH, polyethyleneglycol-(Cl-6)alkyl-OH, polyethyleneglycol-NH2, or polyethyleneglycol-(Cl-6)alkyl-NH2, wherein the polyethyleneglycol has number molecular weight MN from N=7 to N=56.

[0179] In additional embodiments, a hydrophilic moiety Q may be a polyethyleneglycol-H, polyethyleneglycol-OH, polyethyleneglycol-(Cl-6)alkyl-OH,Docket No. 018988-020W01polyethyleneglycol-NH2, or polyethyleneglycol-(Cl-6)alkyl-NH2, wherein the polyethyleneglycol has number molecular weight MN from N=7 to N=16.

[0180] Examples of an amphiphilic compound of this invention include-C(O)-(CH2)n-NR2C(O)-(CH2CH2O)xR4wherein R1is a substituted or unsubstituted 2-yl-6-methylheptane, n is from 2 to 4, X is from 7 to 56, R2is -H or -(Cl-6)alkyl, and R4is -H, -(Cl-6)alkyl, -R50H, or -R6NH2, where R5and R6are each independently -(Cl-6)alkyl. In some embodiments of this amphiphilic compound, R1may be 2-yl-6-methylheptane, n can be 2, X may be 12, R2can be -H, and R4may be -CH3. In further embodiments of this amphiphilic compound, R1may be 2-yl-6-methylheptane, n can be 2, X may be 12, R2can be -H, and R4may be - CH2CH2OH.

[0181] Examples of an amphiphilic compound of this invention include-C(O)-(CH2)n-C(O)NR2— (CH2CH2O)XR4wherein R1is a substituted or unsubstituted 2-yl-6-methylheptane, n is from 2 to 4, X is from 7 to 56, R2is -H or -(Cl-6)alkyl, and R4is -H, -(Cl-6)alkyl, -R5OH, or -R6NH2, where R5and R6are each independently -(Cl-6)alkyl. In some embodiments of this amphiphilic compound, R1may be 2-yl-6-methylheptane, n can be 2, X may be 12, R2can be -H, and R4may be -CH3. In further embodiments of this amphiphilic compound, R1may be 2-yl-6-methylheptane, n can be 2, X may be 12, R2can be -H, and R4may be - CH2CH2OH. In additional embodiments of this amphiphilic compound, R1may be 2-yl-6-methylheptane, n can be 2, X may be about 12 to provide PEG average molecular weight about 550, R2can be -H, and R4may be -CH3 (Compound 111). In further embodiments of this amphiphilic compound, R1may be 2-yl-6-methylheptane, n can be 2, X may be about 12 to provide methyl-PEG average molecular weight about 550, R2can be -H, and R4may be - CH2CH2OH. In additional embodiments of this amphiphilic compound, R1may be 2-yl-6-methylheptane, n can be 2, X may be about 23 to provide PEG average molecular weight about 1,000, R2can be -H, and R4may be -CH3 (Compound 111A). In further embodiments of this amphiphilic compound, R1may be 2-yl-6-methylheptane, n can be 2, X may be about 45 to provide PEG average molecularDocketNo. 018988-020W01weight about 2,000, R2can be -H, and R4may be -CH3 (Compound 11 IB). In additional embodiments of this amphiphilic compound, R1may be 2-yl-6-methylheptane, n can be 2, X may be about 23 to provide PEG average molecular weight about 1,000, R2can be -H, and R4may be - CH2CH2OH (Compound 11 IX). In additional embodiments of this amphiphilic compound, R1may be 2-yl-6-methylheptane, n can be 2, X may be about 45 to provide PEG average molecular weight about 2,000, R2can be -H, and R4may be - CH2CH2OH. In another embodiment of this amphiphilic compound, R1is 2-yl-6-methylheptane, n is 2, X is 9, R2is -H, and R4is -CH3 or -CH2CH2OH. In a further embodiment. R1is 2-yl-6-methylheptane, n is 2, X is 54, R2is -H, and R4is -CH3 or -CH2CH2OH. In a further embodiment. R1is 2-yl-6-methylheptane, n is 2, X is 56, R2is -H, and R4is -CEE or -CH2CH2OH.

[0182] In further embodiments of this amphiphilic compound, R1may be 2-yl-6-methylheptane, n can be 2, X may be about 106 to provide PEG average molecular weight about 5,000, R2can be -H, and R4may be -CH3 (Compound 111C). In further embodiments of this amphiphilic compound, R1may be 2-yl-6-methylheptane, n can be 2, X may be about 230 to provide PEG average molecular weight about 10,000, R2can be -H, and R4may be -CH3 (Compound 11 ID). In further embodiments of this amphiphilic compound, R1may be 2-yl-6-methylheptane, n can be 2, X may be about 450 to provide PEG average molecular weight about 20,000, R2can be -H, and R4may be -CH3 (Compound 11 IE).

[0183] Examples of an amphiphilic compound of this invention includeO— C(O)NH— (CH2CH2O)xR4wherein R1is a substituted or unsubstituted 2-yl-6-methylheptane, X is from 7 to 56, and R4is -H, - (Cl-6)alkyl, -R5OH, or -R6NH2, where R5and R6are each independently -(Cl-6)alkyl. In some embodiments of this amphiphilic compound, R1may be 2-yl-6-methylheptane, X can be 12, and R4may be -CH3. In further embodiments of this amphiphilic compound, R1may be 2-yl-6-methylheptane, X can be 12, and R4may be - CH2CH2OH (Compound 111G). In additional embodiments of this amphiphilic compound, R1may be 2-yl-6-methylheptane, X can be 12, and R4may be - CH2CH2NH2. In further embodiments of this amphiphilic compound, R1may be 2-yl-Docket No. 018988-020W016-methylheptane, X may be about 23 to provide PEG average molecular weight about 1,000, and R4may be - CH3 (Compound 11 IF). In additional embodiments of this amphiphilic compound, R1may be 2-yl-6-methylheptane, X may be about 23 to provide PEG average molecular weight about 1,000, and R4may be - CH2CH2NH2 (Compound 111H).

[0184] Examples of an amphiphilic compound of this invention include-C(O)NH— (CH2)n— (OCH2CH2)xR5wherein R1is a substituted or unsubstituted 2-yl-6-methylheptane, n is from 2 to 4, X is from 7 to 56, and R5is -OH, -O(Cl-6)alkyl, -OR6OH, or - OR7NH2, where R6and R7are each independently (Cl-6)alkyl. In some embodiments of this amphiphilic compound, R1may be 2-yl-6-methylheptane, n can be 2, X may be 12, and R5can be - OCH3. In further embodiments of this amphiphilic compound, R1may be 2-yl-6-methylheptane, n can be 2, X may be 12, and R5can be - OCH2CH2OH.

[0185] Examples of an amphiphilic compound of this invention includeO-(CH2)n-NR2C(O)-(CH2CH2O)xR4wherein R1is a substituted or unsubstituted 2-yl-6-methylheptane, n is from 2 to 4, X is from 7 to 56, R2is -H or -(Cl-6)alkyl, and R4is -H, -(Cl-6)alkyl, -R5OH, or -R6NH2, where R5and R6are each independently -(Cl-6)alkyl. In some embodiments of this amphiphilic compound, R1may be 2-yl-6-methylheptane, n can be 2, X may be 12, R2can be -H, and R4may be -CH3. In further embodiments of this amphiphilic compound, R1may be 2-yl-6-methylheptane, n can be 2, X may be 12, R2can be -H, and R4may be - CH2CH2OH. In some embodiments of this amphiphilic compound, R1may be 2-yl-6-methylheptane, n can be 2, X may be about 12 to provide methyl-PEG average molecular weight about 550, R2can be -H, and R4may be -CH3 (Compound 121).

[0186] Examples of an amphiphilic compound of this invention includeO-(CH2)n-C(O)NR2— (CH2CH2O)XR4wherein R1is a substituted or unsubstituted 2-yl-6-methylheptane, n is from 2 to 4, X is from 7 to 56, R2is -H or -(Cl-6)alkyl, and R4is -H, -(Cl-6)alkyl, -R5OH, or -R6NH2,Docket No. 018988-020W01where R5and R6are each independently -(Cl-6)alkyl. In some embodiments of this amphiphilic compound, R1may be 2-yl-6-methylheptane, n can be 2, X may be 12, R2can be -H, and R4may be -CH3. In further embodiments of this amphiphilic compound, R1may be 2-yl-6-methylheptane, n can be 2, X may be 12, R2can be -H, and R4may be - CH2CH2OH.

[0187] Examples of an amphiphilic compound of this invention includeO-(CH2CH2O)XR4wherein R1is a substituted or unsubstituted 2-yl-6-methylheptane, X is from 7 to 56, and R4is -H, - (Cl-6)alkyl, -R5OH, or -R6NH2, where R5and R6are each independently -(Cl-6)alkyl. In some embodiments of this amphiphilic compound, R1may be 2-yl-6-methylheptane, X can be 12, and R4may be -CH3. In further embodiments of this amphiphilic compound, R1may be 2-yl-6-methylheptane, X can be 12, and R4may be - CH2CH2OH.

[0188] Examples of an amphiphilic compound of this invention includeO— (CH2)n— (OCH2CH2)xR5wherein R1is a substituted or unsubstituted 2-yl-6-methylheptane, n is from 2 to 4, X is from 7 to 56, R2is -H or -(Cl-6)alkyl, and R5is -OH, -O(Cl-6)alkyl, -OR6OH, or - OR7NH2, where R6and R7are each independently (Cl-6)alkyl. In some embodiments of this amphiphilic compound, R1may be 2-yl-6-methylheptane, n can be 2, X may be 12, R2can be -H, and R5may be -OCH3. In further embodiments of this amphiphilic compound, R1may be 2-yl-6-methylheptane, n can be 2, X may be 12, R2can be -H, and R5may be - OCH2CH2OH.

[0189] Examples of an amphiphilic compound of this invention include-C(O)-(CH2)n— NR2C(O)-(CH2)m— (OCH2CH2)XR5wherein R1is a substituted or unsubstituted 2-yl-6-methylheptane, n is from 2 to 4, X is from 7 to 56, R2is -H or -(Cl-6)alkyl, and R5is -OH, -O(Cl-6)alkyl, -OR6OH, or - OR7NH2, where R6and R7are each independently (Cl-6)alkyl. In some embodiments of this amphiphilic compound, R1may be 2-yl-6-methylheptane, n can be 2, X may beDocket No. 018988-020W0112, R2can be -H, and R5may be -OCH3. In further embodiments of this amphiphilic compound, R1may be 2-yl-6-methylheptane, n can be 2, X may be 12, R2can be -H, and R5may be - OCH2CH2OH.

[0190] Examples of an amphiphilic compound of this invention includeO-C(O)-(CH2)n— C(O)NR2-(CH2)m— (OCH2CH2)xR5R1wherein R1is a substituted or unsubstituted 2-yl-6-methylheptane, n is from 2 to 4, X is from 7 to 56, R2is -H or -(Cl-6)alkyl, and R5is -OH, -O(Cl-6)alkyl, -OR6OH, or - OR7NH2, where R6and R7are each independently (Cl-6)alkyl. In some embodiments of this amphiphilic compound, R1may be 2-yl-6-methylheptane, n can be 2, X may be 12, R2can be -H, and R5may be -OCH3. In further embodiments of this amphiphilic compound, R1may be 2-yl-6-methylheptane, n can be 2, X may be 12, R2can be -H, and R5may be - OCH2CH2OH.

[0191] Examples of an amphiphilic compound of this invention includeO-(CH2)n— NR2C(O)-(CH2)m— (OCH2CH2)XR5R1wherein R1is a substituted or unsubstituted 2-yl-6-methylheptane, n and m are each independently from 2 to 4, X is from 7 to 56, R2is -H or -(Cl-6)alkyl, and R5is -OH, - O(Cl-6)alkyl, -OR6OH, or - OR7NH2, where R6and R7are each independently (Cl-6)alkyl. In some embodiments of this amphiphilic compound, R1may be 2-yl-6-methylheptane, n and m can be 2, X maybe 12, R2can be -H, and R5may be -OCH3. In further embodiments of this amphiphilic compound, R1may be 2-yl-6-methylheptane, n and m can be 2, X maybe 12, R2can be -H, and R5may be -OCH2CH2OH.

[0192] Examples of an amphiphilic compound of this invention includeO-(CH2)n— C(O)NR2-(CH2)m— (OCH2CH2)XR5R1wherein R1is a substituted or unsubstituted 2-yl-6-methylheptane, n and m are each independently from 2 to 4, X is from 7 to 56, R2is -H or -(Cl-6)alkyl, and R5is -OH, - O(Cl-6)alkyl, -OR6OH, or - OR7NH2, where R6and R7are each independently (Cl-6)alkyl. In some embodiments of this amphiphilic compound, R1is 2-yl-6-methylheptane, n and m are 2, X is 12, R2is -H, and R5is -OCH3. In furtherDocket No. 018988-020W01embodiments of this amphiphilic compound, R1is 2-yl-6-methylheptane, n and m are 2, X is 12, R2is -H, and R5is -OCH2CH2OH.

[0193] Amphiphilic compounds of this invention may be made by methods known in the art, or as disclosed in US 63 / 857, 112.

[0194] In some embodiments, deciparticles can be made wherein the hydrophilic moiety Q may have a dispersity of molecular weight. For example, a polyethyleneglycol portion of a molecule may have a dispersity of molecular weights around an average value. As used herein, it is understood that for a hydrophilic moiety having a dispersity of molecular weight, a discrete, single moiety of a particular average molecular weight can also be used. For example, a polyethyleneglycol-550 moiety may have a range of molecular weights around an average of 550. In certain embodiments, a polyethyleneglycol moiety can be a single polyethyleneglycol moiety having a single molecular weight close to 550. For example, an amphiphilic compound of this invention can be referred to as having about 12 PEG units to provide PEG average molecular weight about 550, for which it is understood that some molecules will have slightly more or less than 12 PEG units to provide PEG average molecular weight about 550 in a statistical dispersity.Methods for making deciparticle compositions

[0195] In some embodiments, deciparticles were formed by mixing acetone solutions of an amphiphile compound and a drug compound together to achieve a final concentration of 2 mg / mL for drug and 20 mg / mL for amphiphile, a ratio of 1: 10. The ratio can be varied over a wide range, for example, from 1:100 (0.01% drug) to 1:1.5 (40% drug). The solvent acetone can be evaporated with vacuum to produce a dry film composed of isolated deciparticles. The isolated deciparticles can be reconstituted with 60°C deionized water. The isolated deciparticles can optionally be incubated at 60°C for about 10 minutes before or after the reconstitution step. The absence of free drug molecules can be confirmed by the absence of any white solid precipitate in the film or turbidity in the reconstituted suspension.

[0196] In this method, isolated deciparticles (nanoparticles) can be prepared.

[0197] A pertinent method for making a deciparticle composition of this disclosure can include any or all of the following steps:Docket No. 018988-020W01-mixing one or more therapeutic agents in an organic solvent;-contacting an amphiphilic compound with therapeutic agents in an organic solvent;-mixing or vortexing the organic solvent;-filtering the deciparticle composition in the organic solvent to remove particles or aggregates larger than 15 nm, or 30 nm, or 75 nm, or 100 nm;-removing residual organic solvent and / or agents from the deciparticle composition.

[0198] In some embodiments, deciparticles were formed by the following steps: dissolving one or more amphiphiles in an organic solvent;contacting one or more auxiliary taxane compounds with the one or more amphiphiles in the organic solvent;adding water or buffered water containing a cryoprotective compound slowly to the water-solvent mixture, thereby obtaining a suspension of deciparticles;mixing the water-solvent mixture;filtering the water-solvent mixture, thereby obtaining a sterilized suspension of deciparticles;lyophilizing the water-solvent mixture to obtain a deciparticle composition.

[0199] In further embodiments, compositions of deciparticles may comprise:a suspension of deciparticles in a pharmaceutically-acceptable water-solvent mixture; and a cryoprotective compound added to the water-solvent mixture.

[0200] In some embodiments, deciparticles were formed by the following steps: freezing a suspension of deciparticles; and lyophilizing the frozen composition.

[0201] In some embodiments, a deciparticle drug product were formed by the following steps:preparing a suspension of the deciparticles in a pharmaceutically acceptable solvent; adding a cryoprotectant compound to the suspension of the deciparticles;freezing and lyophilizing the suspension containing the deciparticles to form a solid lyophile; and reconstituting the solid lyophile in the same or different pharmaceutically acceptable solvent to form the drug product.

[0202] In some embodiments, isolated deciparticles can be prepared.

[0203] A pertinent method for making a deciparticle composition of this disclosure can include any or all of the following steps:-mixing one or more auxiliary taxane compounds in an organic solvent;Docket No. 018988-020W01-contacting an amphiphilic compound with auxiliary taxane compounds in an organic solvent; -mixing or vortexing the organic solvent;-filtering the deciparticle composition in the organic solvent to remove impurities, particles or aggregates larger than 15 nm, or 30 nm, or 75 nm, or 100 nm, and optionally to sterilize the composition;-removing residual organic solvent from the deciparticle composition.

[0204] In certain embodiments, clinical lots can be made in a 2-7 day process. An amphiphile such as Compound 111 and one or more active agents such as everolimus or paclitaxel can be dissolved in ethanol. The ingredients can be solubilized into lactose and water for injection to form deciparticles. The process can be conducted under yellow light and utilize amber vials to minimize active agent degradation. The deciparticles product can be filter-sterilized. Fill / finish operations can be done in a temperature-controlled environment with98% filling weight accuracy. The deciparticles everolimus product can be reconstituted to a final concentration of 4 mg / mL for intravenous administration. Upon reconstitution, the product can yield monodisperse deciparticles that meet sterility and particle-size specifications. The product can remain within specifications for at least one month at 5°C storage and for at least 24 hours of in-use stability at 25°C. The process can be scaled to over 10 g, sufficient for Phase 1 clinical supply.Methods for using deciparticle compositions

[0205] In some embodiments, a deciparticle composition of this invention may be used in a method for treating cancer in a subject in need. A deciparticle composition can be administered to a subject.

[0206] In further embodiments, a deciparticle (nanoparticle) composition of this invention may be used in the preparation of a medicament for treating cancer in a subject in need.

[0207] In certain embodiments, a deciparticle composition of this invention may be for use in treating cancer in a subject in need.

[0208] In additional embodiments, a deciparticle composition of this invention may be for use in the treatment of the human or animal body.Docket No. 018988-020W01

[0209] A deciparticle composition of this invention can be administered in combination with a standard of care for a disease, or in combination with another drug used for treating the same disease.

[0210] In certain embodiments, a deciparticle composition of this invention may be for use by injection, infusion, or long-acting depot in treating cancer, for immunosuppression in transplantation, or for severe rheumatoid arthritis, or for disorders involving inflammation in a subject in need.

[0211] A deciparticle composition of this invention can be used or administered by injection, infusion, or long-acting depot.

[0212] In some embodiments, a deciparticle composition of this invention can be administered in combination with a cancer chemotherapy, and / or a cancer radiation therapy.

[0213] A deciparticle composition, suspension, or drug product of this invention may be used as an anticancer drug. The anticancer drugs can be used for treatment of any of pancreatic cancer, a melanoma, a skin cancer, a lung cancer, a breast cancer, a prostate cancer, a colorectal cancer, a kidney cancer, a stomach cancer, an ovarian cancer, a cervical cancer, a liver cancer, or a multiple myeloma, among others.

[0214] In certain embodiments, a deciparticle composition can be administered in combination with a cancer drug selected from an antimetabolite drug, an alkylating drug, and a targeted cancer drug.

[0215] A deciparticle composition may be administered in combination with a cancer drug selected from gemcitabine, temozolamide, bevacizumab, 5 -fluorouracil (antimetabolite drugs), cyclophosphamide, busulfan (alkylating drugs), a targeted monoclonal antibody cancer drug, an immune checkpoint inhibitor, and a tyrosine kinase receptor inhibitor.

[0216] In certain embodiments, a maximum solution concentration for administration of the drugs using the deciparticle composition may be about 1-50 mg / mL, or up to 500 mg / mL.

[0217] In further embodiments, a maximum tolerated dose of a deciparticle composition may be about 100-500 mg / m2

[0218] Embodiments of this invention include methods for treating or ameliorating the symptoms of cancer in a human or animal subject in need, by administering a therapeutically sufficient amount of a deciparticle composition, suspension, or drug product of this invention.Docket No. 018988-020W01

[0219] The deciparticle compositions, suspensions, and drug products of this invention can be used to treat a disease requiring the administration of a drug, which may be contained in the deciparticle compositions, suspensions, or drug products.

[0220] A pharmaceutical composition may be in unit dosage form, or in unit doses containing one or more active components.

[0221] The actives in a composition of this invention can be administered at an initial dosage of from about 0.0001 mg / m2to about 1,000 mg / m2daily, weekly, or monthly.

[0222] In some embodiments, a daily dose range may comprise about 0.01 mg / kg to about 500 mg / kg, or about 0.1 mg / kg to about 200 mg / kg, or about 1 mg / kg to about 100 mg / kg, or about 10 mg / kg to about 50 mg / kg.

[0223] Embodiments of this invention contemplate a dose administered to a patient sufficient to effect a beneficial therapeutic response.

[0224] Determination of dosage may normally be within the skill of a health care practitioner.

[0225] Embodiments of this invention also contemplate various modalities of administration including parenteral, intravenous, infusion, intradermal, subcutaneous, intramuscular, colonical, rectal, intrathecal, intra-arterial, and intraperitoneal.

[0226] A therapeutic composition of this invention can be administered in combination with other drugs, actives, or agents, as well as standard of care treatments for the same disease, each of which can be administered concurrently, simultaneously, sequentially, or separately in time.

[0227] Examples of diseases contemplated in this invention include a pancreatic cancer, a melanoma, a skin cancer, a lung cancer, a breast cancer, a prostate cancer, a colorectal cancer, a kidney cancer, a stomach cancer, an ovarian cancer, a cervical cancer, a liver cancer, a multiple myeloma, a glioma, a glioblastoma, a diffuse midline glioma (DMG), a brain or spinal cancer, or a CNS tumor.

[0228] A therapeutic composition of this invention can include pharmaceutically acceptable salt forms, esters, polymorphs or stereoisomers of ingredients, as well as a pharmaceutically acceptable solvent carrier or carrier for suspension.

[0229] Examples of a solvent or suspension carrier include sterile water for injection, saline, isotonic saline, and combinations thereof.Docket No. 018988-020W01

[0230] In some embodiments, a deciparticle composition may be thermolytically stable for at least 24 hours at 10°C or below, or at least 24 hours at 5°C, or at least 5 days, or at least 20 days.

[0231] A composition of deciparticles may contain a pharmaceutically-acceptable carrier and / or excipients. Examples of pharmaceutically acceptable excipients and components are given in Remington, The Science and Practice of Pharmacy, 21st ed., 2005; Rowe et al., Handbook of Pharmaceutical Excipients, 6th ed., 2012; Ash, Handbook of Pharmaceutical Additives, 3rd ed., 2007; Gibson, Pharmaceutical Preformulation and Formulation, 2nd ed., 2009; Remington’s Pharmaceutical Sciences, 18thEd., 1990.Additional embodiments

[0232] As used herein, the terms "treating," “treat” and “treatment’ can refer to alleviation or amelioration of one or more symptoms associated with a disease, disorder or condition. These terms may encompass reduction or stoppage of progression of the symptoms, or the disease, disorder or condition. These terms may include curative, palliative or prophylactic treatment.

[0233] As used herein, the term "alkyl" refers to a saturated, branched or unbranched, substituted or unsubstituted aliphatic group containing from 1 to 22 carbon atoms. This definition applies to the alkyl portion of other groups. As used herein, the term “C(l-5)alkyl,” for example, includes C(l)alkyl, C(2)alkyl, C(3)alkyl, C(4)alkyl, and C(5)alkyl. Likewise, the term “C(3-12)alkyl,” for example, includes C(3)alkyl, C(4)alkyl, C(5)alkyl, C(6)alkyl, C(7)alkyl, C(8)alkyl, C(9)alkyl, C(10)alkyl, C(1 l)alkyl, C(12)alkyl. The general formula for unsubstituted, branched or unbranched alkyl is CnH2n+i.

[0234] As used herein, the term "alkenyl" refers to an unsaturated, branched or unbranched, substituted or unsubstituted alkyl or cycloalkyl group having 2 to 22 carbon atoms and at least one carbon-carbon double bond.

[0235] As used herein, the term "alkynyl" refers to an unsaturated, branched or unbranched, substituted or unsubstituted alkyl or cycloalkyl group having 2 to 22 carbon atoms and at least one carbon-carbon triple bond.

[0236] As used herein, the term "substituted" refers to an atom having one or more substitutions or substituents which can be the same or different and may include a hydrogen substituent. Thus, the terms alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkanoyloxy, alkylamino, alkylaminoalkyl, aryl, heteroaryl, heterocycle, aroyl, and aralkyl as used herein referDocket No. 018988-020W01to groups which include substituted variations. Substituted variations include linear, branched, and cyclic variations, and groups having a substituent or substituents replacing one or more hydrogens attached to any carbon atom of the group. Substituents that may be attached to a carbon atom of the group include alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkanoyloxy, alkylamino, alkylaminoalkyl, aryl, heteroaryl, heterocycle, aroyl, aralkyl, acyl, hydroxyl, cyano, halo, haloalkyl, amino, aminoacyl, alkylaminoacyl, acyloxy, aryloxy, aryloxyalkyl, mercapto, nitro, carbamyl, carbamoyl, and heterocycle. For example, the term ethyl includes withoutlimitation -CH2CH3, -CHFCH3, -CF2CH3, -CHFCH2F, -CHFCHF2, -CHFCF3, -CF2CH2F, — CF2CHF2, -CF2CF3, and other variations as described above. In general, substituents may be further substituted with any atom or group of atoms.

[0237] In general, a compound may contain one or more chiral centers. Compounds containing one or more chiral centers may include those described as an "isomer," a "stereoisomer," a "diastereomer," an "enantiomer," an "optical isomer," or as a "racemic mixture." Conventions for stereochemical nomenclature, for example the stereoisomer naming rules of Cahn, Ingold and Prelog, as well as methods for the determination of stereochemistry and the separation of stereoisomers are known in the art. See, for example, Michael B. Smith, March’s Advanced Organic Chemistry, 8th edition, 2020. The compounds and structures of this disclosure are meant to encompass all possible isomers, stereoisomers, diastereomers, enantiomers, and / or optical isomers that would be understood to exist for the specified compound or structure, including any mixture, racemic or otherwise, thereof. Stereoisomers and mixtures of diastereomers can be separated into individual isomers by means known in the art.

[0238] Some compounds, peptides and / or protein compositions of this invention may have one or more chiral centers and / or geometric isomeric centers (E- and Z-isomers), and it is to be understood that the invention encompasses all such optical isomers, diastereoisomers, geometric isomers, and mixtures thereof.

[0239] This invention encompasses any and all tautomeric, solvated or unsolvated, hydrated or unhydrated forms, as well as any atom isotope forms of the compounds, peptides and / or protein compositions disclosed herein.

[0240] This invention encompasses any and all suitable salt forms of agents. See, for example, Stahl and Wermuth, Handbook of Pharmaceutical Salts (2002).

[0241] Numbered embodiments of this invention include the following:Docket No. 018988-020W01

[0242] (1) A deciparticle composition of matter, comprising deciparticles being a complex of:one or more therapeutic agents; andan amphiphilic compound comprising a lipophilic steryl or cholesteryl moiety linked to a hydrophilic moiety.

[0243] (2) The deciparticle composition of embodiment 1, wherein the deciparticles have an average size of from about 5 nm to about 35 nm, or from 5 nm to 20 nm, or from 5 nm to 18 nm.

[0244] (3) The deciparticle composition of embodiment 1 or embodiment 2, wherein the deciparticles have a dispersity of size of up to about 0.1, or up to about 0.2, or up to about 0.3, or up to about 0.4, or up to about 0.5.

[0245] (4) The deciparticle composition of any of embodiments 1-3, wherein the one or more therapeutic agents are sparingly or poorly water-soluble cancer drugs or antineoplastic drugs.

[0246] (5) The deciparticle (nanoparticle) composition of any of embodiments 1-4, wherein the one or more therapeutic agents are mTOR kinase inhibitors.

[0247] (6) The deciparticle composition of any of embodiments 1-5, wherein the one or more therapeutic agents are selected from everolimus, rapamycin, ridaforolimus, tacrolimus, temsirolimus, umirolimus, zotarolimus, dactolisib, voxtalisib, a salt or ester form of any of the foregoing, and a combination thereof.

[0248] (7) The deciparticle composition of any of embodiments 1-6, wherein the amphiphilic compound comprises Formula I:I-Q Formula Iwhere L is a lipophilic moiety, X is a linker region, and Q is a hydrophilic moiety.

[0249] (8) The deciparticle composition of any of embodiments 1-7, wherein L is a substituted or unsubstituted cholesteryl moiety, a cholesteryl analog moiety, a sterol, or a steroid.

[0250] (9) The deciparticle composition of any of embodiments 1-8, wherein L has the structure Formula II:Formula IIDocket No. 018988-020W01where R1is a substituted or unsubstituted 2-yl-6-methylheptane having any one of the following structureswhere R3is -OH, -(Cl-6)alkyl, -(C4-6)alkenyl, -O(Cl-6)alkyl, or - (Cl-6)alkyl-(C6-12)aryl.

[0251] (10) The deciparticle composition of any of embodiments 1-9, wherein linker X is an organic linker comprising 1-60 atoms selected from hydrogen, carbon, oxygen, nitrogen, and sulfur atoms, or has the structure:— -C(O)— (CH2)n — NR2C(O)— (CH2)m—— -C(O)— (CH2)n — C(O)NR2— (CH2)m—— -C(O)— (CH2)n — NR2C(O)— - — -C(O)— (CH2)n — C(O)NR2— - — -C(O)NR2— (CH2)m—— -C(O)NR2— - — -(CH2)n — NR2c(O)— - (CH2)n — C(O)NR2-—— -(CH2)n — NR2C(O)— (CH2)m—— -(CH2)n — C(O)NR2— (CH2)m—— -C(O)NR3— (CH2)n — NR2C(O) — (CH2)m—— -C(O)NR3— (CH2)n — C(O)NR2— (CH2)m—— -C(O)NR3— (CH2)n — NR2C(O)— orDocket No. 018988-020W01— -C(O)NR3— (CH2)n — C(O)NR2—wherein n and m are each independently from 2 to 4, and R2and R3are each independently - (Cl- 6)alkyl, -(C4-6)alkenyl, -O(Cl-6)alkyl, or - (Cl-6)alkyl-(C6-12)aryl.

[0252] (11) The deciparticle composition of any of embodiments 1-10, wherein Q is a branched or unbranched, substituted or unsubstituted polyethyleneglycol.

[0253] (12) The deciparticle composition of any of embodiments 1-11, wherein Q is a polyethyleneglycol -H, polyethyleneglycol-OH, polyethyleneglycol-(Cl-6)alkyl-OH, polyethyleneglycol-NH2, or polyethyleneglycol-(Cl-6)alkyl-NH2, wherein the polyethyleneglycol has average molecular weight from about 340 to about 2,500, or about 340 to about 740, or about 470 to about 650.

[0254] (13) The deciparticle composition of any of embodiments 1-12, wherein Q is a polyethyleneglycol -H, polyethyleneglycol-OH, polyethyleneglycol-(Cl-6)alkyl-OH, polyethyleneglycol-NH2, or polyethyleneglycol-(Cl-6)alkyl-NH2, wherein the polyethyleneglycol has number average molecular weight MN from N=7 to N=56.

[0255] (14) The deciparticle composition of any of embodiments 1-13, wherein Q is a polyethyleneglycol -H, polyethyleneglycol-OH, polyethyleneglycol-(Cl-6)alkyl-OH, polyethyleneglycol-NH2, or polyethyleneglycol-(Cl-6)alkyl-NH2, wherein the polyethyleneglycol has number average molecular weight MN from N=7 to N=16.

[0256] (15) The deciparticle composition of any of embodiments 1-14, wherein the amphiphilic compound comprises 40 to 99.9 weight percent of the deciparticle composition.

[0257] (16) The deciparticle composition of any of embodiments 1-15, wherein the one or more therapeutic agents in total comprise 0.1 to 60 weight percent of the deciparticle composition.

[0258] (17) The deciparticle composition of any of embodiments 1-16, wherein the deciparticle composition is in a dry powder form or reconstituted from a lyophilized form.

[0259] (18) The deciparticle composition of any of embodiments 1-17, comprising a pharmaceutically-acceptable carrier.Docket No. 018988-020W01

[0260] (19) The deciparticle composition of any of embodiments 1-18, comprising one or more of a dispersant excipient, an anti-caking excipient, or a particle stabilizing excipient.

[0261] (20) The deciparticle composition of any of embodiments 1-19, wherein the concentration below which a deciparticle composition may have zero hemolytic activity at pH 7.4 is less than 1000 ug / ml, or less than 50 ug / ml.

[0262] (21) The deciparticle composition of any of embodiments 1-20, wherein the composition is stable for at least 24 hours at 5°C.

[0263] (22) A method for making a deciparticle composition of any of embodiments 1-21, the method comprising:mixing the one or more therapeutic agents in an organic solvent; contacting the amphiphilic compound with the therapeutic agents in the organic solvent;mixing or vortexing the organic solvent;filtering the deciparticle composition in the organic solvent to remove particles or aggregates larger than 15 nm, or 30 nm, or 75 nm, or 100 nm;removing residual organic solvent and / or agents from the deciparticle composition.

[0264] (23) A deciparticle composition made by the method of embodiment 22.

[0265] (24) A method for treating cancer in a subject in need, the method comprising administering a deciparticle composition according to any of embodiments 1-23.

[0266] (25) A use of a deciparticle composition according to any of embodiments 1- 24 in the preparation of a medicament for treating cancer in a subject in need.

[0267] (26) A deciparticle composition according to any of embodiments 1-25 for use in treating cancer in a subject in need.

[0268] (27) A deciparticle composition according to any of embodiments 1-26 for use in the treatment of the human or animal body.

[0269] (28) An amphiphile compound, comprising Formula I:L — X — Q, Formula Iwhere L is a lipophilic moiety, X is a linker region, and Q is a hydrophilic moiety.Docket No. 018988-020W01

[0270] (29) The amphiphile compound of any of embodiments 1-28, wherein L is a substituted or unsubstituted cholesteryl moiety, a cholesteryl analog moiety, a sterol, or a steroid.

[0271] (30) The amphiphile compound of any of embodiments 1-29, wherein L has the structure Formula II:Formula IIwhere R1is a substituted or unsubstituted 2-yl-6-methylheptane having any one of the following structureswhere R3is -OH, (Cl-6)alkyl, (Cl-6)alkenyl, (Cl-6)cycloalkyl, or (Cl-6)alkoxy.

[0272] (31) The amphiphile compound of any of embodiments 1-30, wherein linker X is an organic linker comprising 1-60 atoms selected from hydrogen, carbon, oxygen, nitrogen, and sulfur atoms, or has the structure:— -C(O)— (CH2)n — NR2C(O)— (CH2)m—— -C(O)— (CH2)n — C(O)NR2— (CH2)m—— -C(O)— (CH2)n — NR2C(O)— -— -C(O)— (CH2)n — C(O)NR2— - — -C(O)NR2— (CH2)m—— -C(O)NR2— - — -(CH2)n — NR2C(O)— - — -(CH2)n — C(O)NR2— -Docket No. 018988-020W01— -(CH2)n - NR2C(O)— (CH2)m—— -(CH2)n - C(O)NR2— (CH2)rn—— -C(O)NR3— (CH2)n — NR2C(O) — (CH2)rn—— -C(O)NR3— (CH2)n — C(O)NR2— (CH2)m—— -C(O)NR3— (CH2)n — NR2C(O)— or— -C(O)NR3— (CH2)n — C(O)NR2—wherein n and m are each independently from 2 to 4, and R2and R3are each independently -(Cl-6)alkyl, -(C4-6)alkenyl, -O(Cl-6)alkyl, or - (C l-6)alkyl-(C6-12)aryl.

[0273] (32) The amphiphile compound of any of embodiments 1-31, wherein Q is a branched or unbranched, substituted or unsubstituted polyethyleneglycol.

[0274] (33) The amphiphile compound of any of embodiments 1-32, wherein Q is a polyethyleneglycol-H, polyethyleneglycol-OH, polyethyleneglycol-(Cl-6)alkyl-OH, polyethyleneglycol-NH2, or polyethyleneglycol-(Cl-6)alkyl-NH2, wherein the polyethyleneglycol has average molecular weight from about 300 to about 2,500, or about 350 to about 750, or about 440 to about 660.

[0275] (34) The amphiphile compound of any of embodiments 1-33, wherein Q is a polyethyleneglycol-H, polyethyleneglycol-OH, polyethyleneglycol-(Cl-6)alkyl-OH, polyethyleneglycol-NH2, or polyethyleneglycol-(Cl-6)alkyl-NH2, wherein the polyethyleneglycol has number average molecular weight MN from N=7 to N=56.

[0276] (35) The amphiphile compound of any of embodiments 1-34, wherein Q is a polyethyleneglycol-H, polyethyleneglycol-OH, polyethyleneglycol-(Cl-6)alkyl-OH, polyethyleneglycol-NH2, or polyethyleneglycol-(Cl-6)alkyl-NH2, wherein the polyethyleneglycol has number average molecular weight MN from N=7 to N=16.

[0277] (36) A compound, comprising the structure:-C(O)-(CH2)n-C(O)NR2— (CH2CH2O)XR4wherein R1is a substituted or unsubstituted 2-yl-6-methylheptane, n is from 2 to 4, X is from 7 to 56, R2is -H or -(Cl-6)alkyl, and R4is -H, -(Cl-6)alkyl, -R5OH, or -R6NH2, where R5and R6are each independently -(Cl-6)alkyl.Docket No. 018988-020W01

[0278] (37) The compound of any of embodiments 1-36, wherein R1is 2-yl-6-methylheptane, n is 2, X is 12 to provide PEG average molecular weight about 550, R2is -H, and R4is -CH3.

[0279] (38) The compound of any of embodiments 1-37, wherein R1is 2-yl-6-methylheptane, n is 2, X is 12, R2is -H, and R4is -CH3.

[0280] (39) The compound of any of embodiments 1-38, wherein R1is 2-yl-6-methylheptane, n is 2, X is 12, R2is -H, and R4is -CH2CH2OH.

[0281] (40) The compound of any of embodiments 1-39, wherein R1is 2-yl-6-methylheptane, n is 2, X is 23 to provide PEG average molecular weight about 1,000, R2is -H, and R4is -CH3.

[0282] (41) The compound of any of embodiments 1-40, wherein R1is 2-yl-6-methylheptane, n is 2, X is 45 to provide PEG average molecular weight about 2,000, R2is -H, and R4is -CH3.

[0283] (42) The compound of any of embodiments 1-41, wherein R1is 2-yl-6-methylheptane, n is 2, X is 23 to provide PEG average molecular weight about 1,000, R2is -H, and R4is -CH2CH2OH.

[0284] (43) The compound of any of embodiments 1-42, wherein R1is 2-yl-6-methylheptane, n is 2, X is 9, R2is -H, and R4is -CH3 or -CH2CH2OH.

[0285] (44) The compound of any of embodiments 1-43, wherein R1is 2-yl-6-methylheptane, n is 2, X is 56, R2is -H, and R4is -CH3 or -CH2CH2OH.

[0286] (45) A compound, comprising the structure:-C(O)-(CH2)n-NR2C(O)-(CH2CH2O)xR4wherein R1is a substituted or unsubstituted 2-yl-6-methylheptane, n is from 2 to 4, X is from 7 to 56, R2is -H or -(Cl-6)alkyl, and R4is -H, -(Cl-6)alkyl, -R5OH, or -R6NH2, where R5and R6are each independently -(Cl-6)alkyl.

[0287] (46) The compound of any of embodiments 1-45, wherein R1is 2-yl-6-methylheptane, n is 2, X is 12, R2is -H, and R4is -CH3.

[0288] (47) The compound of any of embodiments 1-46, wherein R1is 2-yl-6-methylheptane, n is 2, X is 12, R2is -H, and R4is -CH2CH2OH.Docket No. 018988-020W01

[0289] (48) The compound of any of embodiments 1-47, wherein R1is 2-yl-6-methylheptane, n is 2, X is about 12 to provide PEG average molecular weight about 550, and R4is -CH3or - CH2CH2OH.

[0290] (49) A compound, comprising the structure:O— C(O)NH— (CH2CH2O)XR4wherein R1is a substituted or unsubstituted 2-yl-6-methylheptane, X is from 7 to 56, and R4is -H, - (Cl-6)alkyl, -R5OH, or -R6NH2, where R5and R6are each independently -(Cl-6)alkyl.

[0291] (50) The compound of any of embodiments 1-49, wherein R1is 2-yl-6-methylheptane, X is 12, and R4is -CH3.

[0292] (51) The compound of any of embodiments 1-50, wherein R1is 2-yl-6-methylheptane, X is 12, and R4is - CH2CH2OH.

[0293] (52) The compound of any of embodiments 1-51, wherein R1is 2-yl-6-methylheptane, X is about 12 to provide PEG average molecular weight about 550, and R4is -CH3or - CH2CH2OH.

[0294] (53) A compound, comprising the structure:-C(O)NH— (CH2)n— (OCH2CH2)xR5wherein R1is a substituted or unsubstituted 2-yl-6-methylheptane, n is from 2 to 4, X is from 7 to 56, and R5is -OH, -O(Cl-6)alkyl, -OR6OH, or - OR7NH2, where R6and R7are each independently (Cl-6)alkyl.

[0295] (54) The compound of any of embodiments 1-53, wherein R1is 2-yl-6-methylheptane, n is 2, X is 12, and R5is - OCH3.

[0296] (55) The compound of any of embodiments 1-54, wherein R1is 2-yl-6-methylheptane, n is 2, X is 12, and R5is - OCH2CH2OH.

[0297] (56) The compound of any of embodiments 1-55, wherein R1is 2-yl-6-methylheptane, n is 2, X is about 12 to provide PEG average molecular weight about 550, and R5is - OCH2CH2OH.Docket No. 018988-020W01

[0298] (57) A compound, comprising the structure:O-(CH2)n-NR2C(O)-(CH2CH2O)xR4R1wherein R1is a substituted or unsubstituted 2-yl-6-methylheptane, n is from 2 to 4, X is from 7 to 56, R2is -H or -(Cl-6)alkyl, and R4is -H, -(Cl-6)alkyl, -R5OH, or -R6NH2, where R5and R6are each independently -(Cl-6)alkyl.

[0299] (58) The compound of any of embodiments 1-57, wherein R1is 2-yl-6-methylheptane, n is 2, X is 12, R2is -H, and R4is -CH3.

[0300] (59) The compound of any of embodiments 1-58, wherein R1is 2-yl-6-methylheptane, n is 2, X is 12, R2is -H, and R4is - CH2CH2OH.

[0301] (60) The compound of any of embodiments 1-59, wherein R1is 2-yl-6-methylheptane, n is 2, X is about 12 to provide PEG average molecular weight about 550, R2is -H, and R4is -CH3 or - CH2CH2OH.

[0302] (61) A compound, comprising the structure:O-(CH2)n-C(O)NR2— (CH2CH2O)xR4R1wherein R1is a substituted or unsubstituted 2-yl-6-methylheptane, n is from 2 to 4, X is from 7 to 56, R2is -H or -(Cl-6)alkyl, and R4is -H, -(Cl-6)alkyl, -R5OH, or -R6NH2, where R5and R6are each independently -(Cl-6)alkyl.

[0303] (62) The compound of any of embodiments 1-61, wherein R1is 2-yl-6-methylheptane, n is 2, X is 12 or about 12 to provide PEG average molecular weight about 550, R2is -H, and R4is -CH3.

[0304] (63) The compound of any of embodiments 1-62, wherein R1is 2-yl-6-methylheptane, n is 2, X is 12 or about 12 to provide PEG average molecular weight about 550, R2is -H, and R4is - CH2CH2OH.

[0305] (64) A compound, comprising the structure:O-(CH2CH2O)xR4R1wherein R1is a substituted or unsubstituted 2-yl-6-methylheptane, X is from 7 to 56, and R4is -H, - (Cl-6)alkyl, -R5OH, or -R6NH2, where R5and R6are each independently -(Cl-6)alkyl.Docket No. 018988-020W01

[0306] (65) The compound of any of embodiments 1-64, wherein R1is 2-yl-6-methylheptane, X is 12 or about 12 to provide PEG average molecular weight about 550, and R4is -CH3.

[0307] (66) The compound of any of embodiments 1-65, wherein R1is 2-yl-6-methylheptane, X is 12 or about 12 to provide PEG average molecular weight about 550, and R4is - CH2CH2OH.

[0308] (67) A compound, comprising the structure:O— (CH2)n— (OCH2CH2)XR5wherein R1is a substituted or unsubstituted 2-yl-6-methylheptane, n is from 2 to 4, X is from 7 to 56, R2is -H or -(Cl-6)alkyl, and R5is -OH, -O(Cl-6)alkyl, -OR6OH, or - OR7NH2, where R6and R7are each independently (Cl-6)alkyl.

[0309] (68) The compound of any of embodiments 1-67, wherein R1is 2-yl-6-methylheptane, n is 2, X is 12 or about 12 to provide PEG average molecular weight about 550, R2is -H, and R5is -OCH3.

[0310] (69) The compound of any of embodiments 1-68, wherein R1is 2-yl-6-methylheptane, n is 2, X is 12 or about 12 to provide PEG average molecular weight about 550, R2is -H, and R5is -OCH2CH2OH.

[0311] (70) A compound, comprising the structure:-C(O)-(CH2)n— NR2C(O)-(CH2)m— (OCH2CH2)xR5wherein R1is a substituted or unsubstituted 2-yl-6-methylheptane, n is from 2 to 4, X is from 7 to 56, R2is -H or -(Cl-6)alkyl, and R5is -OH, -O(Cl-6)alkyl, -OR6OH, or - OR7NH2, where R6and R7are each independently (Cl-6)alkyl.

[0312] (71) The compound of any of embodiments 1-70, wherein R1is 2-yl-6-methylheptane, n is 2, X is 12 or about 12 to provide PEG average molecular weight about 550, R2is -H, and R5is -OCH3.

[0313] (72) The compound of any of embodiments 1-71, wherein R1is 2-yl-6-methylheptane, n is 2, X is 12 or about 12 to provide PEG average molecular weight about 550, R2is -H, and R5is -OCH2CH2OH.Docket No. 018988-020W01

[0314] (73) A compound, comprising the structure:O-C(O)-(CH2)n— C(O)NR2-(CH2)m— (OCH2CH2)xR5R1wherein R1is a substituted or unsubstituted 2-yl-6-methylheptane, n is from 2 to 4, X is from 7 to 56, R2is -H or -(Cl-6)alkyl, and R5is -OH, -O(Cl-6)alkyl, -OR6OH, or - OR7NH2, where R6and R7are each independently (Cl-6)alkyl.

[0315] (74) The compound of any of embodiments 1-73, wherein R1is 2-yl-6-methylheptane, n is 2, X is 12 or about 12 to provide PEG average molecular weight about 550, R2is -H, and R5is -OCH3.

[0316] (75) The compound of any of embodiments 1-74, wherein R1is 2-yl-6-methylheptane, n is 2, X is 12 or about 12 to provide PEG average molecular weight about 550, R2is -H, and R5is -OCH2CH2OH.

[0317] (76) A compound, comprising the structure:O-(CH2)n— NR2C(O)-(CH2)m— (OCH2CH2)XR5wherein R1is a substituted or unsubstituted 2-yl-6-methylheptane, n and m are each independently from 2 to 4, X is from 7 to 56, R2is -H or -(Cl-6)alkyl, and R5is -OH, -O(Cl-6)alkyl, -OR6OH, or - OR7NH2, where R6and R7are each independently (Cl-6)alkyl.

[0318] (77) The compound of any of embodiments 1-76, wherein R1is 2-yl-6-methylheptane, n and m are 2, X is 12 or about 12 to provide PEG average molecular weight about 550, R2is -H, and R5is -OCH3.

[0319] (78) The compound of any of embodiments 1-77, wherein R1is 2-yl-6-methylheptane, n and m are 2, X is 12 or about 12 to provide PEG average molecular weight about 550, R2is -H, and R5is -OCH2CH2OH.

[0320] (79) A compound, comprising the structure:O-(CH2)n— C(O)NR2— (CH2)m— (OCH2CH2)XR5wherein R1is a substituted or unsubstituted 2-yl-6-methylheptane, n and m are each independently from 2 to 4, X is from 7 to 56, R2is -H or -(Cl-6)alkyl, and R5is -OH, -Docket No. 018988-020W010(Cl-6)alkyl, -OR6OH, or - OR7NH2, where R6and R7are each independently (Cl-6)alkyl.

[0321] (80) The compound of any of embodiments 1-79, wherein R1is 2-yl-6-methylheptane, n and m are 2, X is 12 or about 12 to provide PEG average molecular weight about 550, R2is -H, and R5is -OCH3.

[0322] (81) The compound of any of embodiments 1-80, wherein R1is 2-yl-6-methylheptane, n and m are 2, X is 12 or about 12 to provide PEG average molecular weight about 550, R2is -H, and R5is -OCH2CH2OH.

[0323] (82) A process for making deciparticles composed of a complex of one or more therapeutic agents and an amphiphile, the process comprising:dissolving an amphiphile compound and one or more therapeutic agents in ethanol to form deciparticles;solubilizing the deciparticles into lactose and water for injection (WFI); filter-sterilizing the solubilized deciparticles;filling and finishing the solubilized deciparticles in a temperature-controlled environment with ≥98% filling weight accuracy;lyophilizing and reconstituting the deciparticles to a final concentration of 4 mg / mL for intravenous administration.

[0324] (83) The process of any of embodiments 1-82, wherein the amphiphile is described in any one of embodiments 28-81.

[0325] (84) The process of any of embodiments 1-83, wherein the amphiphile is Compound 111, Compound 111A, Compound 111B, Compound 111X, Compound 111F, Compound 111G, or Compound 111H.

[0326] (85) The process of any of embodiments 1-84, wherein the one or more therapeutic agents is everolimus.

[0327] (86) The process of any of embodiments 1-85, wherein the one or more therapeutic agents is paclitaxel, docetaxel, palbociclib, osimertinib, celecoxib, ritonavir, fenofibrate, carbamazepine, phenytoin, glyburide, glipizide, haloperidol, olanzapine, valsartan, semaglutide, vorinostat, carboplatin, a salt or ester form of any of the foregoing, or a combination thereof.

[0328] (87) The process of any of embodiments 1-86, conducted under yellow light with amber vials to minimize active agent degradation.Docket No. 018988-020W01

[0329] (88) The process of any of embodiments 1-87, wherein upon reconstitution the product is monodisperse deciparticles with average particle size from about 5 nm to about 35 nm, or from 5 nm to 20 nm, or from 5 nm to 18 nm.

[0330] (89) The process of any of embodiments 1-88, wherein the reconstituted product retained average particle size after storage for at least one month at 5°C.

[0331] (90) The process of any of embodiments 1-89, wherein the reconstituted product retained average particle size for at least 24 hours at 25°C.

[0332] (91) The process of any of embodiments 1-90, wherein the solubilized deciparticles are 1-20 g scale.

[0333] All publications including patents, patent application publications, and nonpatent publications referred to in this description, as well as the sequence listing are each expressly incorporated herein by reference in their entirety for all purposes.

[0334] Although the foregoing disclosure has been described in detail by way of example for purposes of clarity of understanding, it will be apparent to the artisan that certain changes and modifications are comprehended by the disclosure and may be practiced without undue experimentation within the scope of the appended claims, which are presented by way of illustration not limitation. This invention includes all such additional embodiments, equivalents, and modifications. This invention includes any combinations or mixtures of the features, materials, elements, or limitations of the various illustrative components, examples, and claimed embodiments.

[0335] It is emphasized herein according to common practice the features of the drawings have arbitrary scale and are intended to cover similar features that may be arbitrarily expanded or reduced.EXAMPLES

[0336] Deciparticle (nanoparticle) characteristics were determined using a ZETASIZER 3600 (Malvern). Typically, 20 pL of a sample was diluted with 280 pL of DI water, resulting in a minimum final volume of 300 pL in a quartz cuvette. Three readings were taken for each sample. Data provided can be Z-average mean particle size, volume mean average size of particles based on volume distribution within the sample, and polydispersity index (PDI).Docket No. 018988-020W01

[0337] Example 1. Deciparticles were formed by mixing acetone solutions of amphiphile Compound 111 and everolimus at a final concentration of 2 mg / mL for everolimus and 20 mg / mL for amphiphile Compound 111, a 1: 10 ratio wt / wt. After vortexing, incubating on a 60°C heat block for 10 minutes, and evaporating the acetone with a vacuum pump, the resultant dry film was reconstituted with 60°C deionized water followed by additional incubation in a mini dry bath at 60°C for 10 minutes to suspend deciparticles. The deciparticles were stable for more than 24 hours after reconstitution.

[0338] The deciparticles were found to have Z-average mean particle size of 9.2 nm, volume mean average size of 8.2 nm.

[0339] Example 2. Deciparticles were formed by mixing acetone solutions of amphiphile Compound 111 and everolimus at a final concentration of 2 mg / mL for everolimus and 20 mg / mL for amphiphile Compound 111, a 1: 10 ratio wt / wt. After vortexing, incubating on a 60°C heat block for 10 minutes, and evaporating the acetone with a vacuum pump, the resultant dry film was reconstituted with 60°C deionized water followed by additional incubation in a mini dry bath at 60°C for 10 minutes to suspend deciparticles. The deciparticles were stable for more than 24 hours at 5 °C.

[0340] The deciparticles were found to have Z-average mean particle size of 8.4 nm.

[0341] Example 3. Deciparticles were formed by mixing acetone solutions of amphiphile Compound 121 and everolimus at a final concentration of 2 mg / mL for everolimus and 20 mg / mL for amphiphile Compound 121, a 1: 10 ratio wt / wt. After vortexing, incubating on a 60°C heat block for 10 minutes, and evaporating the acetone with a vacuum pump, the resultant dry film was reconstituted with 60°C deionized water followed by additional incubation in a mini dry bath at 60°C for 10 minutes to suspend deciparticles. The deciparticles were stable for more than 24 hours at 5 °C.

[0342] The deciparticles were found to have Z-average mean particle size of 9.29 nm.

[0343] Example 4. Deciparticles were formed by mixing acetone solutions of amphiphile Compound 111 A and everolimus at a final concentration of 2 mg / mL for everolimus and 20 mg / mL for amphiphile Compound 111 A, a l:10 ratio wt / wt. After vortexing, incubating on a 60°C heat block for 10 minutes, and evaporating the acetone with a vacuum pump, the resultant dry film was reconstituted with 60°C deionized water followed by additional incubation in a mini dry bath at 60°C for 10 minutes to suspend deciparticles. The deciparticles were stable for more than 24 hours at 5 °C.Docket No. 018988-020W01

[0344] The deciparticles were found to have Z-average mean particle size of 11.96 nm.

[0345] Example 5. Deciparticles were formed by mixing acetone solutions of amphiphile Compound 11 IB and everolimus at a final concentration of 2 mg / mL for everolimus and 20 mg / mL for amphiphile Compound 11 IB, a 1: 10 ratio wt / wt. After vortexing, incubating on a 60°C heat block for 10 minutes, and evaporating the acetone with a vacuum pump, the resultant dry film was reconstituted with 60°C deionized water followed by additional incubation in a mini dry bath at 60°C for 10 minutes to suspend deciparticles. The deciparticles were stable for more than 24 hours at 5 °C.

[0346] The deciparticles were found to have Z-average mean particle size of 13.2 nm.

[0347] Example 6. Deciparticles were formed by mixing acetone solutions of amphiphile Compound 111G and everolimus at a final concentration of 2 mg / mL for everolimus and 20 mg / mL for amphiphile Compound 111G, a l:10 ratio wt / wt. After vortexing, incubating on a 60°C heat block for 10 minutes, and evaporating the acetone with a vacuum pump, the resultant dry film was reconstituted with 60°C deionized water followed by additional incubation in a mini dry bath at 60°C for 10 minutes to suspend deciparticles. The deciparticles were stable for more than 24 hours at 5 °C.

[0348] The deciparticles were found to have Z-average mean particle size of 11.38 nm.

[0349] Example 7. Deciparticles were formed by mixing acetone solutions of amphiphile Compound 111G and everolimus at a 1:6 ratio wt / wt everolimus / Compound 111G. After vortexing, incubating on a 60°C heat block for 10 minutes, and evaporating the acetone with a vacuum pump, the resultant dry film was reconstituted with 60°C deionized water followed by additional incubation in a mini dry bath at 60°C for 10 minutes to suspend deciparticles. The deciparticles were stable.

[0350] The deciparticles were found to have Z-average mean particle size of 10.94 nm.

[0351] After 7 days, the deciparticles were reconstituted in water suspension and found to have Z-average mean particle size of 10.45 nm.

[0352] Example 8. Deciparticles were formed by mixing acetone solutions of amphiphile Compound 111 and everolimus at a 1:6 ratio wt / wt everolimus / Compound 111. After vortexing, incubating on a 60°C heat block for 10 minutes, and evaporating the acetone with a vacuum pump, the resultant dry film was reconstituted with 60°C deionized water followed by additional incubation in a mini dry bath at 60°C for 10 minutes to suspend deciparticles. The deciparticles were stable.Docket No. 018988-020W01

[0353] The deciparticles were found to have Z-average mean particle size of 5.23 nm.

[0354] Example 9. Deciparticles were formed by mixing acetone solutions of amphiphile Compound 111 and everolimus at a 1:6 ratio wt / wt everolimus / Compound 111. After vortexing, incubating on a 60°C heat block for 10 minutes, and evaporating the acetone with a vacuum pump, the resultant dry film was reconstituted with 60°C deionized water followed by additional incubation in a mini dry bath at 60°C for 10 minutes to suspend deciparticles. The deciparticles were stable.

[0355] The deciparticles were found to have Z-average mean particle size of 5.26 nm.

[0356] Example 10. Deciparticles were formed by mixing acetone solutions of amphiphile Compound 111 and rapamycin (sirolimus) at a final concentration of 2 mg / mL for sirolimus and 20 mg / mL for amphiphile Compound 111, a 1: 10 ratio wt / wt. After vortexing, incubating on a 60°C heat block for 10 minutes, and evaporating the acetone with a vacuum pump, the resultant dry film was reconstituted with 60°C deionized water followed by additional incubation in a mini dry bath at 60°C for 10 minutes to suspend deciparticles. The deciparticles were stable for more than 24 hours at 5 °C.

[0357] The deciparticles were found to have Z-average mean particle size of 4.22 nm.

[0358] Example 11. Deciparticles were formed by mixing acetone solutions of amphiphile Compound 111 and rapamycin (sirolimus) at a final concentration of 2 mg / mL for sirolimus and 20 mg / mL for amphiphile Compound 111, a 1: 10 ratio wt / wt. After vortexing, incubating on a 60°C heat block for 10 minutes, and evaporating the acetone with a vacuum pump, the resultant dry film was reconstituted with 60°C deionized water followed by additional incubation in a mini dry bath at 60°C for 10 minutes to suspend deciparticles. The deciparticles were stable for more than 24 hours at 5 °C.

[0359] The deciparticles were found to have Z-average mean particle size of 8.66 nm.

[0360] Example 12. Deciparticles were formed by mixing acetone solutions of amphiphile Compound 111B and rapamycin (sirolimus) at a final concentration of 2 mg / mL for sirolimus and 20 mg / mL for amphiphile Compound 111B, a 1: 10 ratio wt / wt. After vortexing, incubating on a 60°C heat block for 10 minutes, and evaporating the acetone with a vacuum pump, the resultant dry film was reconstituted with 60°C deionized water followed by additional incubation in a mini dry bath at 60°C for 10 minutes to suspend deciparticles. The deciparticles were stable for more than 24 hours at 5°C.

[0361] The deciparticles were found to have Z-average mean particle size of 12.12 nm.Docket No. 018988-020W01

[0362] Example 13. Deciparticles were formed by mixing acetone solutions of amphiphile Compound 111G and rapamycin (sirolimus) at a final concentration of 2 mg / mL for sirolimus and 20 mg / mL for amphiphile Compound 111G, a l:10 ratio wt / wt. After vortexing, incubating on a 60°C heat block for 10 minutes, and evaporating the acetone with a vacuum pump, the resultant dry film was reconstituted with 60°C deionized water followed by additional incubation in a mini dry bath at 60°C for 10 minutes to suspend deciparticles. The deciparticles were stable for more than 24 hours at 5 °C.

[0363] The deciparticles were found to have Z-average mean particle size of 11.56 nm.

[0364] Example 14. Deciparticles were formed by mixing acetone solutions of amphiphile Compound 111 and tacrolimus at a final concentration of 2 mg / mL for tacrolimus and 20 mg / mL for amphiphile Compound 111, a 1: 10 ratio wt / wt. After vortexing, incubating on a 60°C heat block for 10 minutes, and evaporating the acetone with a vacuum pump, the resultant dry film was reconstituted with 60°C deionized water followed by additional incubation in a mini dry bath at 60°C for 10 minutes to suspend deciparticles. The deciparticles were stable for more than 24 hours at 5 °C.

[0365] The deciparticles were found to have Z-average mean particle size of 10.04 nm.

[0366] Example 15. Deciparticles were formed by mixing acetone solutions of amphiphile Compound 111 and tacrolimus at a final concentration of 2 mg / mL for tacrolimus and 20 mg / mL for amphiphile Compound 111, a 1: 10 ratio wt / wt. After vortexing, incubating on a 60°C heat block for 10 minutes, and evaporating the acetone with a vacuum pump, the resultant dry film was reconstituted with 60°C deionized water followed by additional incubation in a mini dry bath at 60°C for 10 minutes to suspend deciparticles. The deciparticles were stable for more than 24 hours at 5 °C.

[0367] The deciparticles were found to have Z-average mean particle size of 8.68 nm.

[0368] Example 16. Deciparticles were formed by mixing acetone solutions of amphiphile Compound 121 and tacrolimus at a final concentration of 2 mg / mL for tacrolimus and 20 mg / mL for amphiphile Compound 121, a 1: 10 ratio wt / wt. After vortexing, incubating on a 60°C heat block for 10 minutes, and evaporating the acetone with a vacuum pump, the resultant dry film was reconstituted with 60°C deionized water followed by additional incubation in a mini dry bath at 60°C for 10 minutes to suspend deciparticles. The deciparticles were stable for more than 24 hours at 5 °C.

[0369] The deciparticles were found to have Z-average mean particle size of 5.02 nm.Docket No. 018988-020W01

[0370] Example 17. Deciparticles were formed by mixing acetone solutions of amphiphile Compound 111A and tacrolimus at a final concentration of 2 mg / mL for tacrolimus and 20 mg / mL for amphiphile Compound 111A, a 1:10 ratio wt / wt. After vortexing, incubating on a 60°C heat block for 10 minutes, and evaporating the acetone with a vacuum pump, the resultant dry film was reconstituted with 60°C deionized water followed by additional incubation in a mini dry bath at 60°C for 10 minutes to suspend deciparticles. The deciparticles were stable for more than 24 hours at 5 °C.

[0371] The deciparticles were found to have Z-average mean particle size of 11.76 nm.

[0372] Example 18. Deciparticles were formed by mixing acetone solutions of amphiphile Compound 111B and tacrolimus at a final concentration of 2 mg / mL for tacrolimus and 20 mg / mL for amphiphile Compound 111B, a 1: 10 ratio wt / wt. After vortexing, incubating on a 60°C heat block for 10 minutes, and evaporating the acetone with a vacuum pump, the resultant dry film was reconstituted with 60°C deionized water followed by additional incubation in a mini dry bath at 60°C for 10 minutes to suspend deciparticles. The deciparticles were stable for more than 24 hours at 5 °C.

[0373] The deciparticles were found to have Z-average mean particle size of 14.35 nm.

[0374] Example 19. Deciparticles were formed by mixing acetone solutions of amphiphile Compound 111G and tacrolimus at a final concentration of 2 mg / mL for tacrolimus and 20 mg / mL for amphiphile Compound 111G, a l:10 ratio wt / wt. After vortexing, incubating on a 60°C heat block for 10 minutes, and evaporating the acetone with a vacuum pump, the resultant dry film was reconstituted with 60°C deionized water followed by additional incubation in a mini dry bath at 60°C for 10 minutes to suspend deciparticles. The deciparticles were stable for more than 24 hours at 5 °C.

[0375] The deciparticles were found to have Z-average mean particle size of 12.07 nm.

[0376] Example 20. The in vivo anti-tumor potency of deciparticles composed from Compound 111 and everolimus was determined with an HT-29 xenograft model in mice.

[0377] Deciparticles were prepared composed from Compound 111 complexed with everolimus as described in Example 1. Deciparticles were lyophilized and reconstituted with water.

[0378] FIG. 1 shows the results of the tumor volume in the HT-29 xenograft model. These result showed that tumor growth was significantly inhibited by the Deciparticle treatment as compared with the Saline group.Docket No. 018988-020W01

[0379] Mice were housed and treated as follows: Species and strain: BALB / c Nude mice. Sex and age range: Female, 8 - 10 weeks old. Body weight range: 18 - 20 g, approximately ± 20% of the mean body weights. Housing: IVC Cage in SPF area. Animals were housed 4 mice per cage. Range of daily temperature: 20 - 26 °C. Range of daily relative humidity: 40 - 70 %. Light: 12 hours on and 12 hours off. Diet: Irradiated rodent diet was provided ad libitum. Water: Autoclaved tap water was freely available from water bottles. Bedding: Bedding was changed once a week.

[0380] HT-29 cells were maintained in McCoy's 5A medium with 10% FBS and incubated at 37°C in a humidified incubator with 5% CO2. An HT-29 xenograft model was established by injecting tumor cells at logarithmic phase (2x106cells / mouse with 50% Matrigel) into the right flank of the mice by S. C. administration under sterile conditions. When the mean tumor volume reached an appropriate size (around 150 mm3), mice were randomized to treatment groups according to the randomized grouping method. The tumor sizes and animal body weights were measured twice per week. The tumors were measured using a caliper. Tumor volumes were estimated from measurements of the two diameters of the individual tumors. Dosing was saline -IV, BIWx4 and deciparticles - 30 mg / kg, IV, BIWx4.

[0381] Example 21 The in vivo anti-tumor potency of deciparticles composed from Compound 111 and everolimus was determined with an OVCAR-3 xenograft model in mice.

[0382] Deciparticles were prepared composed from Compound 111 complexed with everolimus as described in Example 1. Deciparticles were lyophilized and reconstituted with water.

[0383] FIG. 2 shows the results of the tumor volume in the OVCAR-3 xenograft model. These result showed that tumor growth was significantly inhibited by the Deciparticle treatment as compared with the Saline group.

[0384] Mice were housed and treated as follows: Species and strain: BALB / c Nude mice. Sex and age range: Female, 8 - 10 weeks old. Body weight range: 18 - 20 g. Housing: IVC Cage in SPF area. Animals were housed 4 mice per cage. Range of daily temperature: 20 - 26 °C. Range of daily relative humidity: 30 - 70 %. Light: 12 hours on and 12 hours off. Diet: Irradiated rodent diet was provided ad libitum. Water: Autoclaved tap water was freely available from water bottles. Bedding: Autoclaved corncob. Bedding was changed once a week.

[0385] OVCAR-3 cells were maintained in medium RPMI 1640 with 0.01 mg / mL Insulin and 20% FBS and incubated at 37°C in a humidified incubator with 5% CO2. OVCAR-3Docket No. 018988-020W01xenograft model was established by injecting tumor cells at logarithmic phase (6x106cells / mouse with 50% Matrigel) into the right flank of the mice by S. C. administration under sterile conditions.

[0386] When the mean tumor volume reached an appropriate size (around 180 mm3), mice were randomized to treatment groups.

[0387] Dosing was saline - IV, BIWx4, and deciparticles - 30 mg / kg, IV, BIWx4.

[0388] Example 22. The in vivo anti-tumor potency of deciparticles composed from Compound 111 and everolimus was determined with a U-87 glioblastoma xenograft model in mice.

[0389] Deciparticles were prepared composed from Compound 111 complexed with everolimus as described in Example 1. Deciparticles were lyophilized and reconstituted with water.

[0390] FIG. 3 shows the results of the tumor volume in the U-87 xenograft model. These result showed that tumor growth was significantly inhibited by the Deciparticle treatment as compared with the Saline group and another comparative group (TAXOL).

[0391] Mice were housed and treated as follows: Species and strain: BALB / c Nude mice. Sex and age range: Female, 8 - 10 weeks old. Body weight range: 18 - 20 g. Housing: IVC Cage in SPF area. Animals were housed 4 mice per cage. Range of daily temperature: 20 - 26 °C. Range of daily relative humidity: 30 - 70 %. Light: 12 hours on and 12 hours off. Diet: Irradiated rodent diet was provided ad libitum. Water: Autoclaved tap water was freely available from water bottles. Bedding: Autoclaved corncob. Bedding was changed once a week.

[0392] U-87 MG cells were purchased from American Type Culture Collection (ATCC, Manassas). U-87 MG cells were maintained in MEM medium and 10% FBS and incubated at 37°C in a humidified incubator with 5% CO2. U-87 MG xenograft model was established by injecting tumor cells at logarithmic phase (3x106cells / mouse with 50% Matrigel) into the right flank of the mice by S. C. administration under sterile conditions. When the mean tumor volume reached an appropriate size (around 120 mm3), mice were randomized to treatment groups according to the randomized grouping method. The tumor sizes and animal body weights were measured twice per week. Dosing was saline - IV, BIWx4, TAXOL - 20 mg / kg, IV, QDx5, and Deciparticles - 30 mg / kg, IV, BIWx4.Docket No. 018988-020W01

[0393] Example 23. The in vivo anti-tumor potency of deciparticles composed from Compound 111 and everolimus was determined with a MDA-MB-231 breast xenograft model in mice.

[0394] Deciparticles were prepared composed from Compound 111 complexed with everolimus as described in Example 1. Deciparticles were lyophilized and reconstituted with water.

[0395] FIG. 4 shows the results of the tumor volume in the MDA-MB-231 breast xenograft model. These result showed that tumor growth was significantly inhibited by the Deciparticle treatment as compared with a Saline control group.

[0396] Mice were housed and treated as follows: Species and strain: BALB / c Nude mice. Sex and age range: Female, 8 - 10 weeks old. Body weight range: 18 - 20 g. Housing: IVC Cage in SPF area. Animals were housed 4 mice per cage. Range of daily temperature: 20 - 26 °C. Range of daily relative humidity: 30 - 70 %. Light: 12 hours on and 12 hours off. Diet: Irradiated rodent diet was provided ad libitum. Water: Autoclaved tap water was freely available from water bottles. Bedding: Autoclaved corncob. Bedding was changed once a week.

[0397] MDA-MB-231 cells were purchased from American Type Culture Collection (ATCC, Manassas) MDA-MB-231 cells were maintained in Leibovitz's L-15 medium with 10% FBS and incubated at 37°C in a humidified incubator without 5% CO2. MDA-MB-231 xenograft model was established by injecting tumor cells at logarithmic phase (6x106cells / mouse with 50% Matrigel) into the right flank of the mice by S. C. administration under sterile conditions. When the mean tumor volume reached an appropriate size (about 180 mm3), mice were randomized to treatment groups according to the randomized grouping method. The tumor sizes and animal body weights were measured twice per week. Dosing was saline - IV, QDx5, and Deciparticles -30 mg / kg, IV, BIWx4.

[0398] Example 24. This example shows that deciparticles composed of Compound 111 complexed with everolimus exhibited advantageously greater tissue accumulation in vivo as compared to oral everolimus.

[0399] FIG. 5 shows in vivo distribution of deciparticles composed with an amphiphile complexed with everolimus in mice. The Deciparticles showed rapid distribution and accumulation of drug in target organs. The Deciparticles showed essentially 100% bioavailability by intravenous injection.Docket No. 018988-020W01

[0400] By comparison, FIG. 6 shows in vivo distribution of oral everolimus in mice. Oral everolimus was trapped in the stomach and GI tract. Oral everolimus exhibited only 10% bioavailability.

[0401] Therefore, deciparticles of this invention can provide improved absorption and delivery in target tissues and provide therapeutic effect at significantly lower dose.

[0402] Example 25 Everolimus for injection clinical lots were made in a 7-day process. Amphiphile Compound 111 and active agent everolimus was dissolved in ethanol. The ingredients were solubilized into lactose and water for injection to form deciparticles. The process was conducted under yellow light and utilize amber vials to minimize active agent degradation. The deciparticles product was filter-sterilized. Fill / finish operations were done in a temperature-controlled environment with >98% filling weight accuracy. The deciparticles everolimus product was reconstituted to a final concentration of 4 mg / mL for intravenous administration. Upon reconstitution, the product yielded monodisperse deciparticles that met sterility and particle-size specifications. The product remained within specifications for at least one month at 5°C storage and for at least 24 hours of in-use stability at 25°C. The process was scaled to over 10 g, which was sufficient for Phase 1 clinical supply.

Claims

1. Docket No. 018988-020W01WHAT IS CLAIMED IS:

1. A deciparticle composition of matter, comprising deciparticles being a complex of:one or more therapeutic agents; andan amphiphilic compound comprising a lipophilic steryl or cholesteryl moiety linked to a hydrophilic moiety.

2. The deciparticle composition of claim 1, wherein the deciparticles have an average size of from about 5 nm to about 35 nm, or from 5 nm to 20 nm, or from 5 nm to 18 nm.

3. The deciparticle composition of claim 1, wherein the deciparticles have a dispersity of size of up to about 0.1, or up to about 0.2, or up to about 0.3, or up to about 0.4, or up to about 0.5.

4. The deciparticle composition of any of claims 1-3, wherein the one or more therapeutic agents are sparingly or poorly water-soluble cancer drugs or antineoplastic drugs.

5. The deciparticle (nanoparticle) composition of any of claims 1-3, wherein the one or more therapeutic agents are mTOR kinase inhibitors.

6. The deciparticle composition of any of claims 1-3, wherein the one or more therapeutic agents are selected from everolimus, rapamycin, ridaforolimus, tacrolimus, temsirolimus, umirolimus, zotarolimus, dactolisib, voxtalisib, a salt or ester form of any of the foregoing, and a combination thereof.

7. The deciparticle composition of any of claims 1-3, wherein the amphiphilic compound comprises Formula I:L — X— Q Formula Iwhere L is a lipophilic moiety, X is a linker region, and Q is a hydrophilic moiety.

8. The deciparticle composition of claim 7, wherein L is a substituted or unsubstituted cholesteryl moiety, a cholesteryl analog moiety, a sterol, or a steroid.

9. The deciparticle composition of claim 7, wherein L has the structure Formula II:Formula IIwhere R1is a substituted or unsubstituted 2-yl-6-methylheptane having any one of the following structuresDocket No. 018988-020W01where R3is -OH, -(Cl-6)alkyl, -(C4-6)alkenyl, -O(Cl-6)alkyl, or - (Cl-6)alkyl-(C6-12)aryl.

10. The deciparticle composition of claim 7, wherein linker X is an organic linker comprising 1-60 atoms selected from hydrogen, carbon, oxygen, nitrogen, and sulfur atoms, or has the structure:— -C(O)— (CH2)n — NR2C(O)— (CH2)m—— -C(O)— (CH2)n — C(O)NR2— (CH2)m—— -C(O)— (CH2)n — NR2C(O)— -— -C(O)— (CH2)n — C(O)NR2— - — -C(O)NR2— (CH2)m—— -C(O)NR2— - — -(CH2)n — NR2C(O)— - — -(CH2)n — C(O)NR2— - — -(CH2)n — NR2C(O)— (CH2)m—— -(CH2)n — C(O)NR2— (CH2)m—— -C(O)NR3— (CH2)n — NR2C(O) — (CH2)m—— -C(O)NR3— (CH2)n — C(O)NR2— (CH2)m—— -C(O)NR3— (CH2)n — NR2C(O)— or— -C(O)NR3— (CH2)n — C(O)NR2—Docket No. 018988-020W01wherein n and m are each independently from 2 to 4, and R2and R3are each independently - (Cl - 6)alkyl, -(C4-6)alkenyl, -O(Cl-6)alkyl, or - (Cl-6)alkyl-(C6-12)aryl.

11. The deciparticle composition of claim 7, wherein Q is a branched or unbranched, substituted or unsubstituted polyethyleneglycol.

12. The deciparticle composition of claim 7, wherein Q is a polyethyleneglycol-H, polyethyleneglycol-OH, polyethyleneglycol-(Cl-6)alkyl-OH, poly ethylenegly col -NH2, or polyethyleneglycol-(Cl-6)alkyl-NH2, wherein the polyethyleneglycol has average molecular weight from about 340 to about 2,500, or about 340 to about 740, or about 470 to about 650.

13. The deciparticle composition of claim 7, wherein Q is a polyethyleneglycol-H, polyethyleneglycol-OH, polyethyleneglycol-(Cl-6)alkyl-OH, poly ethylenegly col -NH2, or polyethyleneglycol-(Cl-6)alkyl-NH2, wherein the polyethyleneglycol has number average molecular weight MN from N=7 to N=56.

14. The deciparticle composition of claim 7, wherein Q is a polyethyleneglycol-H, polyethyleneglycol-OH, polyethyleneglycol-(Cl-6)alkyl-OH, poly ethylenegly col -NH2, or polyethyleneglycol-(Cl-6)alkyl-NH2, wherein the polyethyleneglycol has number average molecular weight MN from N=7 to N=16.

15. The deciparticle composition of claim 7, wherein the amphiphilic compound comprises 40 to 99.9 weight percent of the deciparticle composition.

16. The deciparticle composition of claim 7, wherein the one or more therapeutic agents in total comprise 0.1 to 60 weight percent of the deciparticle composition.

17. The deciparticle composition of claim 7, wherein the deciparticle composition is in a dry powder form or reconstituted from a lyophilized form.

18. The deciparticle composition of claim 7, comprising a pharmaceutically-acceptable carrier.

19. The deciparticle composition of claim 7, comprising one or more of a dispersant excipient, an anti-caking excipient, or a particle stabilizing excipient.

20. The deciparticle composition of claim 7, wherein the concentration below which a deciparticle composition may have zero hemolytic activity at pH 7.4 is less than 1000 ug / ml, or less than 50 ug / ml.Docket No. 018988-020W0121. The deciparticle composition of claim 7, wherein the composition is stable for at least 24 hours at 5 °C.

22. A method for making a deciparticle composition of claim 7, the method comprising: mixing the one or more therapeutic agents in an organic solvent;contacting the amphiphilic compound with the therapeutic agents in the organic solvent; mixing or vortexing the organic solvent;filtering the deciparticle composition in the organic solvent to remove particles or aggregates larger than 15 nm, or 30 nm, or 75 nm, or 100 nm;removing residual organic solvent and / or agents from the deciparticle composition.

23. A deciparticle composition made by the method of claim 22.

24. A method for treating cancer in a subject in need, the method comprising administering a deciparticle composition according to claim 7.

25. A use of a deciparticle composition according to claim 7 in the preparation of a medicament for treating cancer in a subject in need.

26. A deciparticle composition according to claim 7 for use in treating cancer in a subject in need.

27. A deciparticle composition according to claim 7 for use in the treatment of the human or animal body.

28. An amphiphile compound, comprising Formula I:L — X — Q Formula Iwhere L is a lipophilic moiety, X is a linker region, and Q is a hydrophilic moiety.

29. The amphiphile compound of claim 28, wherein L is a substituted or unsubstituted cholesteryl moiety, a cholesteryl analog moiety, a sterol, or a steroid.

30. The amphiphile compound of claim 28, wherein L has the structure Formula II:OFormula IIwhere R1is a substituted or unsubstituted 2-yl-6-methylheptane having any one of the following structuresDocket No. 018988-020W01where R3is -OH, (Cl-6)alkyl, (Cl-6)alkenyl, (Cl-6)cycloalkyl, or (Cl-6)alkoxy.

31. The amphiphile compound of claim 28, wherein linker X is an organic linker comprising 1-60 atoms selected from hydrogen, carbon, oxygen, nitrogen, and sulfur atoms, or has the structure:— -C(O)— (CH2)n — NR2C(O)— (CH2)m—— -C(O)— (CH2)n — C(O)NR2— (CH2)m—— -C(O)— (CH2)n — NR2C(O)— -— -C(O)— (CH2)n — C(O)NR2— - — -C(O)NR2— (CH2)m—— -C(O)NR2— - — -(CH2)n — NR2C(O)— - — -(CH2)n — C(O)NR2— - — -(CH2)n — NR2C(O)— (CH2)m—— -(CH2)n — C(O)NR2— (CH2)m—— -C(O)NR3— (CH2)n — NR2C(O) — (CH2)m—— -C(O)NR3— (CH2)n — C(O)NR2— (CH2)m—— -C(O)NR3— (CH2)n — NR2C(O)— or— -C(O)NR3— (CH2)n — C(O)NR2—Docket No. 018988-020W01wherein n and m are each independently from 2 to 4, and R2and R3are each independently -(Cl-6)alkyl, -(C4-6)alkenyl, -O(Cl-6)alkyl, or - (Cl-6)alkyl-(C6-12)aryl.

32. The amphiphile compound of claim 28, wherein Q is a branched or unbranched, substituted or unsubstituted polyethyleneglycol.

33. The amphiphile compound of claim 28, wherein Q is a polyethyleneglycol-H, polyethyleneglycol-OH, polyethyleneglycol-(Cl-6)alkyl-OH, poly ethylenegly col -NH2, or polyethyleneglycol-(Cl-6)alkyl-NH2, wherein the polyethyleneglycol has average molecular weight from about 300 to about 2,500, or about 350 to about 750, or about 440 to about 660.

34. The amphiphile compound of claim 28, wherein Q is a polyethyleneglycol-H, polyethyleneglycol-OH, polyethyleneglycol-(Cl-6)alkyl-OH, poly ethylenegly col -NH2, or polyethyleneglycol-(Cl-6)alkyl-NH2, wherein the polyethyleneglycol has number average molecular weight MN from N=7 to N=56.

35. The amphiphile compound of claim 28, wherein Q is a polyethyleneglycol-H, polyethyleneglycol-OH, polyethyleneglycol-(Cl-6)alkyl-OH, poly ethylenegly col -NH2, or polyethyleneglycol-(Cl-6)alkyl-NH2, wherein the polyethyleneglycol has number average molecular weight MN from N=7 to N=16.

36. A compound, comprising the structure:-C(O)-(CH2)n-C(O)NR2— (CH2CH2O)XR4wherein R1is a substituted or unsubstituted 2-yl-6-methylheptane, n is from 2 to 4, X is from 7 to 56, R2is -H or -(Cl-6)alkyl, and R4is -H, -(Cl-6)alkyl, -R50H, or -R6NH2, where R5and R6are each independently -(Cl-6)alkyl.

37. The compound of claim 36, wherein R1is 2-yl-6-methylheptane, n is 2, X is 12 to provide PEG average molecular weight about 550, R2is -H, and R4is -CH3.

38. The compound of claim 36, wherein R1is 2-yl-6-methylheptane, n is 2, X is 12, R2is -H, and R4is -CH3.

39. The compound of claim 36, wherein R1is 2-yl-6-methylheptane, n is 2, X is 12, R2is -H, and R4is -CH2CH2OH.Docket No. 018988-020W0140. The compound of claim 36, wherein R1is 2-yl-6-methylheptane, n is 2, X is 23 to provide PEG average molecular weight about 1,000, R2is -H, and R4is -CH3.

41. The compound of claim 36, wherein R1is 2-yl-6-methylheptane, n is 2, X is 45 to provide PEG average molecular weight about 2,000, R2is -H, and R4is -CH3.

42. The compound of claim 36, wherein R1is 2-yl-6-methylheptane, n is 2, X is 23 to provide PEG average molecular weight about 1,000, R2is -H, and R4is -CH2CH2OH.

43. The compound of claim 36, wherein R1is 2-yl-6-methylheptane, n is 2, X is 9, R2is -H, and R4is -CH3or -CH2CH2OH.

44. The compound of claim 36, wherein R1is 2-yl-6-methylheptane, n is 2, X is 56, R2is -H, and R4is -CH3 or -CH2CH2OH.

45. A compound, comprising the structure:-C(O)-(CH2)n-NR2C(O)-(CH2CH2O)xR4wherein R1is a substituted or unsubstituted 2-yl-6-methylheptane, n is from 2 to 4, X is from 7 to 56, R2is -H or -(Cl-6)alkyl, and R4is -H, -(Cl-6)alkyl, -R5OH, or -R6NH2, where R5and R6are each independently -(Cl-6)alkyl.

46. The compound of claim 45, wherein R1is 2-yl-6-methylheptane, n is 2, X is 12, R2is -H, and R4is -CH3.

47. The compound of claim 45, wherein R1is 2-yl-6-methylheptane, n is 2, X is 12, R2is -H, and R4is -CH2CH2OH.

48. The compound of claim 45, wherein R1is 2-yl-6-methylheptane, n is 2, X is about 12 to provide PEG average molecular weight about 550, and R4is -CH3or - CH2CH2OH.

49. A compound, comprising the structure:O— C(O)NH— (CH2CH2O)XR4wherein R1is a substituted or unsubstituted 2-yl-6-methylheptane, X is from 7 to 56, and R4is -H, - (Cl-6)alkyl, -R5OH, or -R6NH2, where R5and R6are each independently -(Cl-6)alkyl.

50. The compound of claim 49, wherein R1is 2-yl-6-methylheptane, X is 12, and R4is -CH3.Docket No. 018988-020W0151. The compound of claim 49, wherein R1is 2-yl-6-methylheptane, X is 12, and R4is - CH2CH2OH.

52. The compound of claim 49, wherein R1is 2-yl-6-methylheptane, X is about 12 to provide PEG average molecular weight about 550, and R4is -CH3 or - CH2CH2OH.

53. A compound, comprising the structure:-C(O)NH— (CH2)n— (OCH2CH2)xR5wherein R1is a substituted or unsubstituted 2-yl-6-methylheptane, n is from 2 to 4, X is from 7 to 56, and R5is -OH, -O(Cl-6)alkyl, -OR6OH, or - OR7NH2, where R6and R7are each independently (Cl-6)alkyl.

54. The compound of claim 53, wherein R1is 2-yl-6-methylheptane, n is 2, X is 12, and R5is - OCH3.

55. The compound of claim 53, wherein R1is 2-yl-6-methylheptane, n is 2, X is 12, and R5is - OCH2CH2OH.

56. The compound of claim 53, wherein R1is 2-yl-6-methylheptane, n is 2, X is about 12 to provide PEG average molecular weight about 550, and R5is - OCH2CH2OH.

57. A compound, comprising the structure:- (CH2)n- NR2C(O)-(CH2CH2O)XR4wherein R1is a substituted or unsubstituted 2-yl-6-methylheptane, n is from 2 to 4, X is from 7 to 56, R2is -H or -(Cl-6)alkyl, and R4is -H, -(Cl-6)alkyl, -R5OH, or -R6NH2, where R5and R6are each independently -(Cl-6)alkyl.

58. The compound of claim 57, wherein R1is 2-yl-6-methylheptane, n is 2, X is 12, R2is -H, and R4is -CH3.

59. The compound of claim 57, wherein R1is 2-yl-6-methylheptane, n is 2, X is 12, R2is -H, and R4is - CH2CH2OH.

60. The compound of claim 57, wherein R1is 2-yl-6-methylheptane, n is 2, X is about 12 to provide PEG average molecular weight about 550, R2is -H, and R4is -CH3 or - CH2CH2OH.Docket No. 018988-020W0161. A compound, comprising the structure:O-(CH2)n-C(O)NR2— (CH2CH2O)XR4R1wherein R1is a substituted or unsubstituted 2-yl-6-methylheptane, n is from 2 to 4, X is from 7 to 56, R2is -H or -(Cl-6)alkyl, and R4is -H, -(Cl-6)alkyl, -R5OH, or -R6NH2, where R5and R6are each independently -(Cl-6)alkyl.

62. The compound of claim 61, wherein R1is 2-yl-6-methylheptane, n is 2, X is 12 or about 12 to provide PEG average molecular weight about 550, R2is -H, and R4is -CH3.

63. The compound of claim 61, wherein R1is 2-yl-6-methylheptane, n is 2, X is 12 or about 12 to provide PEG average molecular weight about 550, R2is -H, and R4is - CH2CH2OH.

64. A compound, comprising the structure:O-(CH2CH2O)XR4wherein R1is a substituted or unsubstituted 2-yl-6-methylheptane, X is from 7 to 56, and R4is -H, - (Cl-6)alkyl, -R5OH, or -R6NH2, where R5and R6are each independently -(Cl-6)alkyl.

65. The compound of claim 64, wherein R1is 2-yl-6-methylheptane, X is 12 or about 12 to provide PEG average molecular weight about 550, and R4is -CH3.

66. The compound of claim 64, wherein R1is 2-yl-6-methylheptane, X is 12 or about 12 to provide PEG average molecular weight about 550, and R4is - CH2CH2OH.

67. A compound, comprising the structure:O— (CH2)n— (OCH2CH2)XR5wherein R1is a substituted or unsubstituted 2-yl-6-methylheptane, n is from 2 to 4, X is from 7 to 56, R2is -H or -(Cl-6)alkyl, and R5is -OH, -O(Cl-6)alkyl, -OR6OH, or - OR7NH2, where R6and R7are each independently (Cl-6)alkyl.

68. The compound of claim 67, wherein R1is 2-yl-6-methylheptane, n is 2, X is 12 or about 12 to provide PEG average molecular weight about 550, R2is -H, and R5is -OCH3.Docket No. 018988-020W0169. The compound of claim 67, wherein R1is 2-yl-6-methylheptane, n is 2, X is 12 or about 12 to provide PEG average molecular weight about 550, R2is -H, and R5is -OCH2CH2OH.

70. A compound, comprising the structure:-C(O)-(CH2)n— NR2C(O)-(CH2)m— (OCH2CH2)xR5wherein R1is a substituted or unsubstituted 2-yl-6-methylheptane, n is from 2 to 4, X is from 7 to 56, R2is -H or -(Cl-6)alkyl, and R5is -OH, -O(Cl-6)alkyl, -OR6OH, or - OR7NH2, where R6and R7are each independently (Cl-6)alkyl.

71. The compound of claim 70, wherein R1is 2-yl-6-methylheptane, n is 2, X is 12 or about 12 to provide PEG average molecular weight about 550, R2is -H, and R5is -OCH3.

72. The compound of claim 70, wherein R1is 2-yl-6-methylheptane, n is 2, X is 12 or about 12 to provide PEG average molecular weight about 550, R2is -H, and R5is -OCH2CH2OH.

73. A compound, comprising the structure:-C(O)-(CH2)n— C(O)NR2-(CH2)m— (OCH2CH2)XR5wherein R1is a substituted or unsubstituted 2-yl-6-methylheptane, n is from 2 to 4, X is from 7 to 56, R2is -H or -(Cl-6)alkyl, and R5is -OH, -O(Cl-6)alkyl, -OR6OH, or - OR7NH2, where R6and R7are each independently (Cl-6)alkyl.

74. The compound of claim 73, wherein R1is 2-yl-6-methylheptane, n is 2, X is 12 or about 12 to provide PEG average molecular weight about 550, R2is -H, and R5is -OCH3.

75. The compound of claim 73, wherein R1is 2-yl-6-methylheptane, n is 2, X is 12 or about 12 to provide PEG average molecular weight about 550, R2is -H, and R5is -OCH2CH2OH.

76. A compound, comprising the structure:O-(CH2)n— NR2C(O)-(CH2)m— (OCH2CH2)XR5wherein R1is a substituted or unsubstituted 2-yl-6-methylheptane, n and m are each independently from 2 to 4, X is from 7 to 56, R2is -H or -(Cl-6)alkyl, and R5is -OH, -O(C1-6)alkyl, -OR6OH, or - OR7NH2, where R6and R7are each independently (Cl-6)alkyl.Docket No. 018988-020W0177. The compound of claim 76, wherein R1is 2-yl-6-methylheptane, n and m are 2, X is 12 or about 12 to provide PEG average molecular weight about 550, R2is -H, and R5is -OCH3.

78. The compound of claim 76, wherein R1is 2-yl-6-methylheptane, n and m are 2, X is 12 or about 12 to provide PEG average molecular weight about 550, R2is -H, and R5is -OCH2CH2OH.

79. A compound, comprising the structure:O-(CH2)n— C(O)NR2— (CH2)m— (OCH2CH2)xR5wherein R1is a substituted or unsubstituted 2-yl-6-methylheptane, n and m are each independently from 2 to 4, X is from 7 to 56, R2is -H or -(Cl-6)alkyl, and R5is -OH, -O(C1-6)alkyl, -OR6OH, or - OR7NH2, where R6and R7are each independently (Cl-6)alkyl.

80. The compound of claim 79, wherein R1is 2-yl-6-methylheptane, n and m are 2, X is 12 or about 12 to provide PEG average molecular weight about 550, R2is -H, and R5is -OCH3.

81. The compound of claim 79, wherein R1is 2-yl-6-methylheptane, n and m are 2, X is 12 or about 12 to provide PEG average molecular weight about 550, R2is -H, and R5is -OCH2CH2OH.

82. A process for making deciparticles composed of a complex of one or more therapeutic agents and an amphiphile, the process comprising:dissolving an amphiphile compound and one or more therapeutic agents in ethanol to form deciparticles;solubilizing the deciparticles into lactose and water for injection (WFI);filter-sterilizing the solubilized deciparticles;filling and finishing the solubilized deciparticles in a temperature-controlled environment with >98% filling weight accuracy;lyophilizing and reconstituting the deciparticles to a final concentration of 4 mg / mL for intravenous administration.

83. The process of claim 82, wherein the amphiphile is described in any one of claims 28-81.

84. The process of claim 82, wherein the amphiphile is Compound 111, Compound 111 A, Compound 111B, Compound 111X, Compound 111F, Compound 111G, or Compound 111H.Docket No. 018988-020W0185. The process of claim 82, wherein the one or more therapeutic agents is everolimus.

86. The process of claim 82, wherein the one or more therapeutic agents is paclitaxel, docetaxel, palbociclib, osimertinib, celecoxib, ritonavir, fenofibrate, carbamazepine, phenytoin, glyburide, glipizide, haloperidol, olanzapine, valsartan, semaglutide, vorinostat, carboplatin, a salt or ester form of any of the foregoing, or a combination thereof.

87. The process of claim 82, conducted under yellow light with amber vials to minimize active agent degradation.

88. The process of claim 82, wherein upon reconstitution the product is monodisperse deciparticles with average particle size from about 5 nm to about 35 nm, or from 5 nm to 20 nm, or from 5 nm to 18 nm.

89. The process of claim 82, wherein the reconstituted product retained average particle size after storage for at least one month at 5°C.

90. The process of claim 82, wherein the reconstituted product retained average particle size for at least 24 hours at 25 °C.

91. The process of claim 82, wherein the solubilized deciparticles are 1-20 g scale.

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