Drug delivery polymer and uses thereof
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.
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.