Nanoscale carriers for the delivery or co-delivery of chemotherapeutics, nucleic acids and photosensitizers

Patent metadata

Field	Value
Publication number	US-10517822-B2
Application number	US-201415034799-A
Country	US
Kind code	B2
Filing date	Nov 6, 2014
Priority date	Nov 6, 2013
Publication date	Dec 31, 2019
Grant date	Dec 31, 2019

Abstract

Nanoscale coordination polymer nanoparticles for the co-delivery of multiple therapeutic agents are described. The multiple therapeutic agents can include a combination of different chemotherapeutic agents, a combination of one or more chemotherapeutic agents and one or more nucleic acids, such as small interfering RNA (siRNA) or microRNA, a combination of one or more chemotherapeutic agents and a photosensitizer (i.e., for use in photodynamic therapy), or a plurality of different siRNAs. Pharmaceutical formulations including the nanoparticles, methods of using the nanoparticles to treat cancer, and methods of making the nanoparticles are also described.

First claim

What is claimed is:

1. A nanoscale particle for co-delivery of a plurality of therapeutic agents, wherein the plurality of therapeutic agents comprise at least one non-nucleic acid chemotherapeutic agent and at least one nucleic acid therapeutic agent, said nanoscale particle comprising:
a core comprising a metal bisphosphonate coordination polymer comprising a multivalent metal ion and a bisphosphonate, wherein the bisphosphonate is a prodrug of a platinum-based chemotherapeutic agent; and
wherein the core is coated with a lipid bilayer comprising (i) a cationic lipid, wherein at least one nucleic acid therapeutic agent is attached to the cationic lipid via electrostatic interactions; or (ii) a functionalized lipid, wherein said functionalized lipid is a thiol- or dithiol-functionalized lipid covalently bonded to at least one nucleic acid therapeutic agent.

2. The nanoscale particle of claim 1 , wherein the at least one nucleic acid therapeutic agent is a siRNA, a miRNA, or an AS ODN.

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

4. The nanoscale particle of claim 1 , wherein the lipid bilayer further comprises: a passivating agent; a targeting agent; and/or an imaging agent.

5. 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.

6. The nanoscale particle of claim 1 , wherein the bisphosphonate is a cisplatin or oxaliplatin prodrug.

7. The nanoscale particle of claim 6 , wherein the bisphosphonate is an oxaliplatin prodrug.

8. The nanoscale particle of claim 6 , wherein the bisphosphonate is a cisplatin prodrug.

9. 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 .

10. The method of claim 9 , wherein the cancer is selected from lung cancer, pancreatic cancer, ovarian cancer, breast cancer and colon cancer.

11. The method of claim 9 , wherein the cancer is ovarian cancer, optionally a cisplatin resistant ovarian cancer.

12. A method of preparing a nanoscale particle of claim 1 , the method comprising:
(a) contacting a microemulsion comprising a metal ion with a microemulsion comprising a bisphosphonate, optionally wherein the bisphosphonate is a cisplatin or oxaliplatin prodrug, thereby forming a metal bisphosphonate coordination polymer nanoparticle;
(b) dispersing the nanoparticle from (a) in a solution comprising a cationic lipid and/or a functionalized lipid to form a cationic lipid-coated and/or functionalized lipid coated nanoparticle; and
(c) contacting the lipid-coated nanoparticles with a solution comprising at least one nucleic acid therapeutic agent.

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

Assignees

• Univ Chicago
• Univ North Carolina Chapel Hill

Inventors

• Lin Wenbin
• He Chunbai
• Liu Demin

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C12N2310/141

  MicroRNAs, miRNAs · CPC title

• C12N2310/11

  Antisense · CPC title

• C12N15/111

  General methods applicable to biologically active non-coding nucleic acids · CPC title