Drug delivery polymer and uses thereof

Patent metadata

Field	Value
Publication number	US-9381253-B2
Application number	US-201414249254-A
Country	US
Kind code	B2
Filing date	Apr 9, 2014
Priority date	Apr 9, 2013
Publication date	Jul 5, 2016
Grant date	Jul 5, 2016

Abstract

Described herein are platinum-based brush-arm star polymers (Pt-BASPs), or a pharmaceutical composition thereof, for delivery of platinum-based agents, such as cisplatin. Also provided are methods and kits involving the Pt-BASPs, or a pharmaceutical composition thereof, for treating proliferative diseases such as cancers (e.g., lung cancer, head-and-neck cancer, esophagus cancer, stomach cancer, breast cancer, pancreas cancer, liver cancer, kidney cancer, or prostate cancer) in a subject.

First claim

What is claimed is:

1. A macromonomer of Formula (III):

or a salt thereof, wherein:
a is an integer from 1 to 10, inclusive;
b is an integer from 1 to 5, inclusive;
c is an integer from 30 to 100, inclusive;
e is 0, 1, 2, 3, or 4;
L is —O—, —S—, —NR La —, —NR La C(═O)—, —C(═O)NR La —, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—, —OC(═O)O—, —OC(═O)NR La —, —NR La C(═O)O—, trans-CR Lb ═CR Lb —, cis-CR Lb ═CR Lb —, —C≡C—, —OC(R Lb ) 2 —, —C(R Lb ) 2 O—, —NR La C(R Lb ) 2 —, —C(R Lb ) 2 NR La —, —S(═O) 2 O—, —OS(═O) 2 —, —S(═O) 2 NR La —, —NR La S(═O) 2 —, or an optionally substituted C 1-10 hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain is replaced with —O—, —S—, —NR La C(═O)—, —C(═O)NR La —, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—, —OC(═O)O—, —OC(═O)NR La —, —NR La C(═O)O—, trans-CR Lb ═CR Lb —, cis-CR Lb ═CR Lb —, —C≡C—, —OC(R Lb ) 2 —, —C(R Lb ) 2 O—, —S(═O) 2 O—, —OS(═O) 2 —, —S(═O) 2 NR La —, or —NR La S(═O) 2 —, wherein each instance of R La is independently hydrogen, optionally substituted C 1-10 alkyl, or a nitrogen protecting group, and wherein each occurrence of R Lb is independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R Lb groups are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring, or R La and R Lb are joined to form an optionally substituted heterocyclic ring; and
M is hydrogen, or a drug or a diagnostic agent.

2. A macromonomer of Formula (III):

or a salt thereof, wherein:
a is an integer from 1 to 10, inclusive;
b is an integer from 1 to 5, inclusive;
c is an integer from 30 to 100, inclusive;
e is 0, 1, 2, 3, or 4;
M is hydrogen, or a drug or a diagnostic agent; and
L is of the formula:

wherein:
p is an integer from 1 to 10, inclusive;
each instance of R E is halogen, —CN, —NO 2 , —N 3 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted phenyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —OR A , —N(R B ) 2 , —SR A , —C(═O)R A , —C(═O)OR A , —C(═O)SR A , —C(═O)N(R B ) 2 , —C(═O)N(R B )N(R B ) 2 , —OC(═O)R A , —OC(═O)N(R B ) 2 , —NR B C(═O)R A , —NR B C(═O)N(R B ) 2 , —NR B C(═O)N(R B )N(R B ) 2 , —NR B C(═O)OR A , —SC(═O)R A , —C(═NR B )R A , —C(═NNR B )R A , —C(═NOR A )R A , —C(═NR B )N(R B ) 2 , —NR B C(═NR B )R B , —C(═S)R A , —C(═S)N(R B ) 2 , —NR B C(═S)R A , —S(═O)R A , —OS(═O) 2 R A , —SO 2 R A , —NR B SO 2 R A , and —SO 2 N(R B ) 2 ;
each R A is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
each R B is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R B groups are taken together with their intervening atoms to form an optionally substituted heterocyclic ring;
each k is independently 0, 1, 2, 3, or 4;
g is an integer from 1 to 10, inclusive; and
h is an integer from 1 to 10, inclusive.

3. The macromonomer of claim 2 , wherein the macromonomer is of Formula (III-a):

or a salt thereof.

4. The macromonomer of claim 2 , wherein the macromonomer is of Formula (III-c):

or a salt thereof.

5. The macromonomer of claim 2 , wherein the macromonomer is of Formula (III-d):

or a salt thereof.

6. The macromonomer of claim 2 , wherein M is of the formula:

7. The macromonomer of claim 2 , wherein M is of the formula:

8. The macromonomer of claim 1 , wherein L is an optionally substituted C 1-10 hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain is replaced with —O—, —NR La C(═O)—, —C(═O)NR La —, —OC(═O)—, —C(═O)O—, —OC(═O)O—, trans-CR Lb ═CR Lb —, cis-CR Lb CR Lb —, —OC(R Lb ) 2 —, —C(R Lb ) 2 O—, —S(═O) 2 O—, or —OS(═O) 2 —.

9. The macromonomer of claim 2 , wherein L is of the formula:

10. The macromonomer of claim 2 , wherein L is of the formula:

11. The macromonomer of claim 2 , wherein L is of the formula:

12. The macromonomer of claim 2 , wherein L is of the formula:

13. The macromonomer of claim 1 , wherein M is hydrogen.

14. The macromonomer of claim 1 , wherein M is a drug or a diagnostic agent.

15. The macromonomer of claim 1 , wherein M is an anti-cancer agent.

16. The macromonomer of claim 2 , wherein M is hydrogen.

17. The macromonomer of claim 2 , wherein M is a drug or a diagnostic agent.

18. The macromonomer of claim 2 , wherein M is an anti-cancer agent.

19. The macromonomer of claim 2 , wherein the macromonomer is of the formula:

or a salt thereof.

20. The macromonomer of claim 1 , further wherein L is cleavable by reduction or by hydrolysis.

21. The macromonomer of claim 1 , further wherein L is photo-cleavable.

Assignees

• Massachusetts Inst Technology

Inventors

• Johnson Jeremiah A
• Liao Longyan

Classifications

• A61K47/58

  obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin · CPC title

• A61K31/704

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

• C07F15/0093

  without a metal-carbon linkage · CPC title

• A61K47/60 Primary

  the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol · CPC title