Nanoparticles for chemotherapy, targeted therapy, photodynamic therapy, immunotherapy, and any combination thereof

Patent metadata

Field	Value
Publication number	US-11246877-B2
Application number	US-201716302185-A
Country	US
Kind code	B2
Filing date	May 22, 2017
Priority date	May 20, 2016
Publication date	Feb 15, 2022
Grant date	Feb 15, 2022

Abstract

Prodrugs containing lipid moieties attached to drug derivatives, such as anti-cancer drug derivatives, via linkers comprising disulfide groups are described. Also described are nanoparticles coated with a lipid layer containing the prodrugs, formulations comprising the nanoparticles, and the use of the nanoparticles in methods of treating diseases, such as cancer, alone or in combination with additional drug compounds, targeting agents, and/or immunotherapy agents, such as immunosuppression inhibitors that target the CTLA-4, PD-1/PD-L1, IDO, LAG-3, CCR-7 or other pathways, or multiple immunosuppression inhibitors targeting a combination of such pathways. Optionally, the nanoparticles can comprise a photosensitizer or a derivative thereof and can be used in methods involving photodynamic therapy. Synergistic therapeutic effects result from combinations of multiple modalities provided by the disclosed nanoparticles and/or nanoparticle formulations.

First claim

What is claimed is:

1. A nanoscale particle for delivery of therapeutic agents, said nanoscale particle comprising:
a core comprising a metal bisphosphonate coordination polymer comprising a multivalent metal ion and a bisphosphonate, wherein said bisphosphonate comprises a cisplatin and/or oxaliplatin prodrug; and
a coating layer covering at least a portion of an outer surface of the core, wherein said coating layer comprises an asymmetric lipid bilayer wherein said asymmetric lipid bilayer comprises a prodrug comprising: (a) a monovalent drug moiety, wherein said monovalent drug moiety is a monovalent derivative of an anticancer drug compound selected from the group consisting of Etoposide (ET), Paclitaxel (PTX), NLG919, OTS167, OTSC41, dihydroartemisin, Camptothecin (CPT), Docetaxel, Mitoxantrone, and Artesunate, (b) a monovalent lipid moiety, and (c) a bivalent linker comprising a disulfide bond, wherein said monovalent drug moiety and said monovalent lipid moiety are linked through the bivalent linker.

2. The nanoscale particle of claim 1 , wherein the monovalent lipid moiety is a monovalent derivative of cholesterol, oleic acid, a lyso-lipid, or phosphocholine.

3. The nanoscale particle of claim 2 , wherein the monovalent lipid moiety is a cholesterol derivative and the monovalent lipid moiety and the bivalent linker moiety together have the structure:

4. The nanoscale particle of claim 2 , wherein the monovalent lipid moiety is an oleic acid derivative and the monovalent lipid moiety and the bivalent linker moiety together have the structure:

5. The nanoscale particle of claim 2 , wherein the monovalent lipid moiety is a lyso-lipid derivative and the monovalent lipid moiety and the bivalent linker moiety together have the structure:

where R is selected from oleyl, stearyl, or palmitoleyl.

6. The nanoscale particle of claim 1 , further comprising at least one nucleic acid chemotherapeutic agent.

7. The nanoscale particle of claim 6 , wherein the nucleic acid chemotherapeutic agent is a siRNA, a miRNA, or an AS ODN.

8. The nanoscale particle of claim 6 , wherein the at least one nucleic acid is selected from the group consisting of survivin siRNA, ERCC-1 siRNA, P-glycoprotein siRNA (P-gp siRNA), Bcl-2 siRNA, and a mixture thereof.

9. The nanoscale particle of claim 1 , further comprising at least one additional non-nucleic add chemotherapeutic agent incorporated in the core, wherein said additional non-nucleic acid chemotherapeutic agent is selected from the group consisting of gemcitabine, methotrexate, leucovorin, pemetrexed disodium, doxorubicin, vinblastine, vincristine, vindesine, cytarabine, azathioprine, melphalan, imatinib, anastrozole, letrozole, carboplatin, paclitaxel, docetaxel, etoposide, and vinorelbine.

10. The nanoscale particle of claim 1 , wherein the cisplatin and/or oxaliplatin prodrug is cis, cis, trans-Pt(NH 3 ) 2 Cl 2 (OEt)(O 2 CCH 2 CH 2 COOH), optionally wherein the core comprises between about 10 weight % and about 50 weight % of the cisplatin and/or oxaliplatin prodrug.

11. The nanoscale particle of claim 1 , wherein the nanoscale particle has an average diameter of between about 20 nm and about 140 nm.

12. The nanoscale particle of claim 1 , wherein the asymmetric lipid bilayer comprises a cationic lipid and/or a functionalized lipid, wherein said functionalized lipid is a lipid functionalized with a group that can bond to a nucleic acid, and wherein at least one nucleic acid is covalently bonded to the functionalized lipid and/or attached to the cationic lipid via electrostatic interactions.

13. The nanoscale particle of claim 1 , wherein the asymmetric lipid bilayer comprises a mixture comprising one or more of a thiol- or dithiol- functionalized 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (SSPE), 1,2-dioleoyl-3-trimethylammonium propane (DOTAP), and 1,2-dioleoyl-sn- glycero-3-phosphocholine (DOPC).

14. The nanoscale particle of claim 1 , wherein the coating layer further comprises at least one of a passivating agent, wherein said passivating agent is optionally a hydrophilic polymer; a targeting agent, wherein said targeting agent is optionally a RGD peptide; and an imaging agent, wherein said imaging agent is optionally a fluorescent moiety.

15. The nanoscale particle of claim 1 , wherein the asymmetric lipid bilayer further comprises one or more of 1,2-dioleoyl-sn-glycero-3- phosphate sodium salt (DOPA), cholesterol, and pegylated-DSPE.

16. The nanoscale particle of claim 1 , wherein the multivalent metal ion is selected from the group consisting of Ca 2 + , Mg 2 + , Mn 2 + , Zn 2 + , and combinations thereof.

17. The nanoscale particle of claim 1 , wherein the monovalent drug moiety of the prodrug is a monovalent derivative of dihydroartemisin (DHA).

18. The nanoscale particle of claim 17 , wherein the bisphosphonate is a bisphosphonate ester of cis, cis-trans- [Pt(NH 3 ) 2 Cl 2 (OH) 2 ] (a cisplatin prodrug) or cis, trans-[Pt(dach)Cl 2 (OH) 2] .

19. The nanoscale particle of claim 1 , wherein the multivalent metal ion is Zn 2 + .

20. The nanoscale particle of claim 1 , wherein the core comprises between about 40 and about 50 weight % of bisphosphonate.

21. The nanoscale particle of claim 1 , wherein one or more of survivin siRNA, P-gp siRNA, and Bcl-2 siRNA are attached to the coating layer.

22. The nanoscale particle of claim 1 , wherein the nanoscale particle has a diameter between about 20 nm and about 180 nm.

23. The nanoscale particle of claim 1 , wherein the nanoscale particle has a diameter between about 90 nm and about 180 nm.

24. The nanoscale particle of claim 1 , wherein the monovalent drug moiety is a monovalent derivative of a drug compound selected from the group consisting of Etoposide (ET), Paclitaxel (PTX), NLG919, OTS167, OTSC41, dihydroartemisin, Camptothecin (CPT), Mitoxantrone, and Artesunate.

25. The nanoscale particle of claim 1 , wherein the monovalent lipid moiety is a monovalent derivative of cholesterol.

26. A pharmaceutical formulation comprising a composition comprising a nanoscale particle of claim 1 and a pharmaceutically acceptable carrier.

27. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a composition comprising a nanoscale particle of claim 1 .

28. The method of claim 27 , wherein the cancer is selected from lung cancer, pancreatic cancer, ovarian cancer, breast cancer, and colon cancer.

29. The method of claim 27 , wherein the cancer is ovarian cancer, optionally a cisplatin resistant ovarian cancer.

30. The method of claim 27 , further comprising administering to the subject an immunotherapy agent.

31. The method of claim 30 , wherein the immunotherapy agent is selected from the group consisting of an anti-CD52 antibody, an anti-CD2O antibody, anti-CD47 antibody, an anti-GD2 antibody, a cytokine, and polysaccharide K.

32. The method of claim 30 , wherein the immunotherapy agent is selected from the group consisting of Alemtuzumab, Of

Assignees

• Univ Chicago

Inventors

• Lin Wenbin
• Duan Xiaopin
• Chan Christina
• Han Wenbo

Classifications

• C12N2310/141

  MicroRNAs, miRNAs · CPC title

• A61K31/357

  having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel · CPC title

• C12N2310/11

  Antisense · CPC title

• A61K31/4745

  condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48) · CPC title

• A61P35/00

  Antineoplastic agents · CPC title