Functional PLA-PEG copolymers, the nanoparticles thereof, their preparation and use for targeted drug delivery and imaging

Patent metadata

Field	Value
Publication number	US-9364444-B2
Application number	US-201314381197-A
Country	US
Kind code	B2
Filing date	Feb 28, 2013
Priority date	Feb 28, 2012
Publication date	Jun 14, 2016
Grant date	Jun 14, 2016

Abstract

Functional PLA-PEG copolymers, the nanoparticles thereof, their preparation and use for targeted drug delivery and imaging The present invention concerns novel functional PEG-PLA containing copolymers, the nanoparticles containing the same, their process of preparation and their use for site specific targeted drug delivery and imaging.

First claim

The invention claimed is:

1. A compound of formula (A)

where:
PLA represents a polylactic acid rest;
PEG represents a polyethylene glycol rest;
the linker PEG′ is a polyethylene glycol rest; and
Ligand is a functional ligand rest.

2. The compound of formula (A) according to claim 1 , wherein PEG′ is of formula

where:
n′ is the number of units and is comprised between 1 to 10
(1) is the attachment of the bond to the —(CH 2 )-triazole group;
(2) is the attachment of the bond to the ligand.

3. The compound of formula (A) according to claim 1 , wherein PLA is of formula:

where:
(3) is the attachment of the bond to the PEG moiety; and
m is the number of units and is comprised between 1 and 500.

4. The compound of formula (A) according to claim 1 , wherein PEG is of formula:

where:
(4) is the attachment of the bond to -PLA;
(5) is the attachment of the bond to the nitrogen atom of

 and
n is the number of units and is comprised between 1 and 300.

5. The compound of formula (A) according to claim 1 , wherein Ligand is chosen from rests of homing devices, diagnostic agents, imaging agents, stimuli-sensitive agents, docking agents, cell penetrating agents, detoxifying agents, and drugs.

6. The compound of formula (A) according to claim 5 , wherein said homing device is a membrane recognition ligand.

7. The compound of formula (A) according to claim 1 , wherein Ligand is chosen from:
a membrane recognition ligands selected from an oestrogen receptor antagonist, an androgen receptor antagonist, folic acid, anisamide, an antibody cabable of recognising the corresponding surface antigen, a RGD sequence that binds to α v β 3 integrins overexpressed on tumor angiogenic endothelium, hyaluronic acid, transferrin, peptide targeted gene vectors, aptamers, and tumor necrosis factor,
diagnostic/imaging agents selected from iron oxide, gadolinium complexes, indocyanin green, near infra-red fluorescent probes, and positron emitters,
stimuli responsive substances selected from iron oxide nanoparticles, gold nanoparticles, and any radiation-activable substances,
docking agents selected from oligopeptides,
a cell penetrating agent selected from Transactivator of transcription (TAT) sequences, penetratin, polyarginine sequences, and VP22 protein sequences,
a detoxifying agent selected from cobalamin, cobinamide, rhodanese enzyme, an organophosphorus hydrolyzing enzyme, naloxone, atropine, and antibodies/antibody fragments recognizing a specific toxin; and
a drug selected from an antibiotic, anti-cancer agent, antiviral agent, anti-inflammatory agent, a vaccine antigen, and a nutraceutical.

8. A nanoparticle comprising one or more identical or different compounds of formula (A) according to claim 1 .

9. The nanoparticle according to claim 8 which further comprises one or more compounds of formula (I′):
PLA_PEG_OR  (I′)

where PLA represents a polylactic acid rest; PEG represents a polyethylene glycol rest; and R is H or a C 1 -C 6 alkyl.

10. A process for the preparation of the nanoparticle according to claim 8 comprising reacting a nanoparticle comprising one or more identical or different compounds of formula (I)
PLA_PEG_N 3   (I)

where PLA represents a polylactic acid rest; and PEG represents a polyethylene glycol rest,

with one or more compounds of formula (XI)

where PEG′ represents a polyethylene glycol rest and Ligand is chosen from rests of homing devices, diagnostic agents, imaging agents, stimuli-sensitive agents, docking agents, cell penetrating agents, detoxifying agents and drugs, optionally followed by non-covalent encapsulation or covalent conjugation of a drug.

11. A process for the preparation of the nanoparticle according to claim 8 , comprising nanoprecipitating one or more compounds of formula (A)

where PLA represents a polylactic acid rest; PEG represents a polyethylene glycol rest; the linker PEG′ is a polyethylene glycol rest; and Ligand is a functional ligand rest, optionally in the presence of a compound of formula (I′)
PLA_PEG_OR  (I′)

where PLA represents a polylactic acid rest; PEG represents a polyethylene glycol rest; and R is H or a C 1 -C 6 alkyl, optionally followed by non-covalent encapsulation or covalent conjugation of a drug.

12. The nanoparticle according to claim 8 which comprises a drug.

13. The nanoparticle according to claim 12 , wherein the drug is a cytotoxic agent.

14. The nanoparticle according to claim 12 , wherein the drug is a taxoid.

15. The nanoparticle according to claim 12 , wherein the drug is docetaxel.

16. The nanoparticle according to claim 12 , wherein the drug is non-covalently encapsulated with the nanoparticle.

17. The nanoparticle according to claim 12 , wherein the drug is covalently conjugated to the nanoparticle.

18. A pharmaceutical composition, which comprises at least one compound of formula (A) according to claim 1 , optionally in the form of a nanoparticle comprising one or more identical or different compounds of formula (A).

19. A pharmaceutical composition, which comprises, as active principle, a compound of formula (A) according to claim 1 , optionally in the form of a nanoparticle comprising one or more identical or different compounds of formula (A) and at least one pharmaceutically acceptable excipient.

20. A process for the preparation of a compound of formula (A) according to claim 1 comprising coupling:
a compound of formula (I):
PLA_PEG_N 3   (I)

with
a compound of formula (XI):

where
PLA represents a polylactic acid rest;
PEG represents a polyethylene glycol rest;
PEG′ is a polyethylene glycol rest; and
Ligand is a functional ligand rest.

21. The process according to claim 20 , wherein said coupling is made by click chemistry.

22. The process according to claim 20 , wherein said coupling reaction is carried out according to the Huisgen reaction, in organic or aqueous conditions.

23. The process according to claim 21 , wherein said click chemistry coupling reaction is carried out in the presence of CuBr and PMDETA (N,N,N′,N′,N″-pentamethyldiethylenetriamine).

24. The process according to claim 21 , wherein said click chemistry coupling reaction is carried out in the presence of water, CuSO 4 5H 2 O, and sodium ascorbate.

Assignees

• Sanofi Sa

Inventors

• Bazile Didier
• Couvreur Patrick
• Lakkireddy Harivardhan Reddy
• Mackiewicz Nicolas
• Nicolas Julien

Classifications

• A61K9/5138

  obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates · CPC title

• A61K9/51

  Nanocapsules; {Nanoparticles; (nanotubes A61K9/0092; polymeric micelles A61K9/1075; polymersomes A61K9/1273; pure drug nanoparticles A61K9/14; drug nanoparticles with adsorbed surface modifiers A61K9/141; conjugates, e.g. between drug and non-active nanoparticles, A61K47/50; preparations for in vivo diagnosis A61K49/00; with radioactive substances A61K51/00)} · CPC title

• A61K31/337

  having four-membered rings, e.g. taxol · CPC title

• C08G63/664 Primary

  derived from hydroxy carboxylic acids · CPC title

• C08G63/91

  Polymers modified by chemical after-treatment · CPC title