Bio-reducible self-assembled liquid crystalline block copolymer for drug delivery

Patent metadata

Field	Value
Publication number	US-9975983-B2
Application number	US-201515519085-A
Country	US
Kind code	B2
Filing date	Oct 15, 2015
Priority date	Oct 15, 2014
Publication date	May 22, 2018
Grant date	May 22, 2018

Abstract

The disclosure provides biodegradable amphiphilic liquid crystalline copolymers that can readily self-assemble to nanoparticles in aqueous solutions and also allow for encapsulation of hydrophobic pharmaceutically active molecules.

First claim

We claim:

1. A copolymer comprising:
a first block, which is of formula:

and a second block, which is of formula:

wherein
m is an integer about 3 to about 500;
A is independently selected from the group consisting of polyacrylate, polymethacrylate, polynorbonene, polycyclopentene, polycyclooctene, polysiloxane, polyester, and polypeptide, or combinations thereof;
R 1 is a steroid moiety optionally comprising a linker R 11 ;
R 2 is polyalkylene oxide, polyester, or polypeptide moiety; and
R 3 is a disulfide linker moiety.

2. The copolymer of claim 1 , wherein the steroid moiety comprises cholesterol, cholic acid, deoxycholic acid, taurocholic acid, lanosterol, estradiol, testosterone, bile acid, dexamethasone, secosteroid, phytosterol, or combinations thereof.

3. The copolymer of claim 1 , wherein R 11 is

a polylactone, or an oligomer of siloxane.

4. The copolymer of claim 1 , wherein A is independently polyacrylate, polymethacrylate, polyester, or a combination thereof.

5. The copolymer of claim 1 , wherein the first block is of formula:

6. The copolymer of claim 1 , wherein R 2 is a polyalkylene oxide moiety.

7. The copolymer of claim 6 , wherein the polyalkylene oxide moiety comprises polyethylene oxide, polyethylene oxide thiolate, polypropylene oxide, or polypropylene oxide thiolate.

8. The copolymer of claim 1 , wherein R 3 is of formula:

9. The copolymer of claim 1 , wherein the copolymer further comprises a chain terminus X:

10. The copolymer of claim 9 , wherein X is a trithiocarbonate, dithiocarbamate, or dithioester.

11. The copolymer of claim 9 , wherein X is —SC(S)S—C 12 H 25 .

12. The copolymer of claim 9 , comprising the structure:

wherein
m is an integer between about 5 and about 200; and
n is an integer between about 5 and about 100.

13. The copolymer of claim 1 , wherein m is between about 10 and about 100.

14. The copolymer of claim 1 , wherein the molecular weight of the copolymer is about 5,000 Da to about 200,000 Da.

15. The copolymer according to claim 1 , wherein the copolymer is in a core/shell nanoparticle form.

16. A nanoparticle comprising the copolymer of claim 15 and a pharmaceutically active molecule.

17. The nanoparticle of claim 16 , wherein the molecule is doxorubicin, daunorubicin, vincristin, paclitaxel, docetaxel, cisplatin, camptothecin, irinotecan, 5-fluorouracil, methotrexate, or dexamethasone.

18. The nanoparticle of claim 15 , further comprising one or more metal nanoparticles or quantum dots (e.g., near infrared (NIR) quantum dot).

19. A method of delivering a pharmaceutically active molecule, or of treating a disease or disorder comprising administering to a subject in need thereof the nanoparticle according to claim 16 .

20. A process for preparing the nanoparticle according to claim 15 , comprising: (a) dissolving a copolymer in an organic solvent to obtain a copolymer solution; and (b) mixing the copolymer solution in an aqueous solution to form a nanoparticle; wherein the copolymer comprises:
a first block, which is of formula:

and a second block, which is of formula:

wherein
m is an integer about 3 to about 500;
A is independently selected from the group consisting of polyacrylate, polymethacrylate, polynorbonene, polycyclopentene, polycyclooctene, polysiloxane, polyester, and polypeptide, or combinations thereof;
R 1 is a steroid moiety optionally comprising a linker R 11 ;
R 2 is polyalkylene oxide, polyester, or polypeptide moiety; and
R 3 is a disulfide linker moiety.

Assignees

• Univ Connecticut

Inventors

• Lu Xiuling
• Kasi Rajeswari
• Tran Thanh-Huyen
• Nguyen Chi Thanh

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/704

  attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin {(digitoxin A61K31/7048)} · CPC title

• A61K9/5146

  obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides · CPC title

• A61K9/5192

  Processes · CPC title

• C08F2438/03

  Use of a di- or tri-thiocarbonylthio compound, e.g. di- or tri-thioester, di- or tri-thiocarbamate, or a xanthate as chain transfer agent, e.g . Reversible Addition Fragmentation chain Transfer [RAFT] or Macromolecular Design via Interchange of Xanthates [MADIX] · CPC title