Nano-enabled immunotherapy in cancer

Patent metadata

Field	Value
Publication number	US-12539338-B2
Application number	US-202217823044-A
Country	US
Kind code	B2
Filing date	Aug 29, 2022
Priority date	May 18, 2017
Publication date	Feb 3, 2026
Grant date	Feb 3, 2026

Abstract

In certain embodiments a platform technology for the facilitating immune therapy in the treatment of cancer is provided. In certain embodiments nanocarriers are provided that facilitate delivery of an IDO inhibitor in conjunction with an inducer of cell death (ICD-inducer). In certain embodiments the IDO inhibitor is conjugated to a component of a lipid bilayer forming a nanovesicle. In still another embodiment, methods and compositions are provided where an ICD-inducing agent (e.g., doxorubicin, oxaliplatin, mitoxantrone etc.) and an IDO pathway inhibitor (e.g., an IDO inhibitor-prodrug) are integrated into a nanocarrier (e.g. a lipid-bilayer (LB)-coated nanoparticle), that allows systemic delivery to orthotopic pancreatic cancer site.

First claim

What is claimed is:

1 . A nanovesicle drug carrier for the combined delivery of an IDO inhibitor and an inducer of immunogenic cell death (ICD), said nanovesicle drug carrier comprising:
a liposome comprising a lipid bilayer, wherein said lipid bilayer comprises cholesterol and cholesterol hemisuccinate (CHEMS), wherein the cholesterol is conjugated to the IDO inhibitor 1-methyl-D-tryptophan (indoximod); and a cargo within said liposome where said cargo comprises an agent that induces immunogenic cell death (ICD) (ICD-inducer), wherein said agent is doxorubicin loaded on a cargo trapping agent.

2 . The nanovesicle drug carrier of claim 1 , wherein said lipid bilayer comprises:
a phospholipid; and cholesterol conjugated to indoximod (Chol-IND).

3 . The nanovesicle drug carrier of claim 2 , wherein said phospholipid comprises:
a saturated fatty acid with a C14-C20 carbon chain, and/or an unsaturated fatty acid with a C14-C20 carbon chain, and/or a natural lipid comprising a mixture of fatty acids with C12-C20 carbon chains; and/or a phospholipid selected from the group consisting of phosphatidylcholine (DPPC), 1,2-dimyristoleoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-distearoyl-sn-glycero-3-phospho-rac-glycerol (DSPG), 1,2-dipalmitoyl-sn-glycero-3-phosphoglycerol (DPPG), distearoylphosphatidylcholine (DSPC), 1,2-dieicosenoyl-sn-glycero-3-phosphocholine, and diacylphosphatidylcholine (DAPC); or a natural lipid selected from the group consisting of egg phosphatidylcholine (egg PC), and soy phosphatidylcholine (soy PC); and/or distearoylphosphatidylcholine (DSPC).

4 . The nanovesicle drug carrier of claim 2 , wherein said lipid bilayer comprises an mPEG phospholipid with a phospholipid C14-C18 carbon chain, and a PEG molecular weight ranging from about 350 Da to 5000 Da.

5 . The nanovesicle drug carrier of claim 4 , wherein said lipid bilayer comprises 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-PEG (DSPE-PEG).

6 . The nanovesicle drug carrier of claim 2 , wherein said lipid bilayer comprises DSPC:Chol-IND:DSPE-PEG or DPPG:Chol-IND:DSPE-PEG.

7 . The nanovesicle drug carrier of claim 6 , wherein:
the ratio of DSPC:Chol-IND:DSPE-PEG ranges from 40-90% DSPC: 10%-50% Chol-IND: 1%-10% DSPE-PEG molar ratio; or the ratio of DSPC:Chol-IND:DSPE-PEG is about 50:40:5 molar ratio, the ratio of DPPG:Chol-IND:DSPE-PEG ranges from 40-90% DPPG: 10%-50% Chol-IND: 1%-10% DSPE-PEG molar ratio; or the ratio of DPPG:Chol-IND:DSPE-PEG is about 50:40:5 molar ratio.

8 . The nanovesicle drug carrier of claim 2 , wherein said lipid bilayer further comprises a cholesterol derivative selected from the group consisting of lysine-based cholesterol (CHLYS), and PEGylated cholesterol (Chol-PEG).

9 . The nanovesicle drug carrier of claim 2 , wherein the IDO inhibitor conjugated to cholesterol comprises a compound having the structure:

10 . The nanovesicle drug carrier of claim 1 , wherein said cargo trapping agent before reaction with the cargo drug loaded in the vesicle, is selected from the group consisting of citric acid, triethylammonium sucrose octasulfate (TEA 8 SOS), (NH4) 2 SO 4 , an ammonium salt, a trimethylammonium salt, and a triethylammonium salt.

11 . The nanovesicle drug carrier of claim 1 , wherein said drug carrier is conjugated to a moiety selected from the group consisting of a targeting moiety, a fusogenic peptide, and a transport peptide.

12 . The nanovesicle drug carrier of claim 1 , wherein the IDO inhibitor and the ICD inducer are synergistic in their activity against a cancer.

13 . A pharmaceutical formulation comprising:
a nanovesicle drug carrier of claim 1 and a pharmaceutically acceptable carrier.

14 . A method of treating a colon, pancreatic or breast cancer, said method comprising:
administering to a subject in need thereof an effective amount of a nanovesicle drug carrier of claim 1 .

15 . A method of treating a colon, pancreatic or breast cancer in a mammal, said method comprising:
administering to an intra-tumoral or peri-tumoral site an effective amount of a nanovesicle drug carrier of claim 1 .

Assignees

• Univ California

Inventors

• Nel Andre E
• Meng Huan
• Mei Kuo-Ching

Classifications

• B82Y5/00

  Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery · CPC title

• A61K47/6923

  the form being an inorganic particle, e.g. ceramic particles, silica particles, ferrite or synsorb · CPC title

• A61K47/6905

  the form being a colloid or an emulsion · CPC title

• A61K47/554

  the modifying agent being a steroid plant sterol, glycyrrhetic acid, enoxolone or bile acid · CPC title

• A61K47/551

  one of the codrug's components being a vitamin, e.g. niacinamide, vitamin B3, cobalamin, vitamin B12, folate, vitamin A or retinoic acid · CPC title