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 platinum complex of Formula (I):
or a salt thereof,
wherein:
X 1 is F, Cl, Br, or I;
X 2 is F, Cl, Br, or I;
each instance of R N1 and R N2 is independently hydrogen, optionally substituted C 1-6 alkyl, or a nitrogen protecting group; or two R N1 are taken with the intervening atoms to form an optionally substituted heterocyclic ring; or two R N2 are taken with the intervening atoms to form an optionally substituted heterocyclic ring; or R N1 and R N2 are taken with the intervening atoms to form an optionally substituted heterocyclic ring; and
n is 1, 2, 3, 4, 5, or 6.
2. The platinum complex of claim 1 , wherein the complex is of Formula (II):
or a salt thereof.
3. The platinum complex of claim 1 , wherein the complex is of Formula (II-a):
or a salt thereof.
4. The platinum complex of claim 1 , wherein n is 1.
5. The platinum complex of claim 1 , wherein n is 2.
6. The platinum complex of claim 1 , wherein n is 3.
7. A method of preparing a platinum complex of claim 1 , the method comprising steps of:
(a) oxidizing a compound of Formula (s-1) with an oxidant
to give a compound of Formula (s-2):
wherein:
X 1 is F, Cl, Br, or I;
X 2 is F, Cl, Br, or I;
each instance of R N1 and R N2 is independently hydrogen, optionally substituted C 1-6 alkyl, or a nitrogen protecting group; or two R N1 are taken with the intervening atoms to form an optionally substituted heterocyclic ring; or two R N2 are taken with the intervening atoms to form an optionally substituted heterocyclic ring; or R N1 and R N2 are taken with the intervening atoms to form an optionally substituted heterocyclic ring; and
n is 1, 2, 3, 4, 5, or 6; and
(b) coupling the compound of Formula (s-2) with a compound of Formula (s-3):
to yield a platinum complex of Formula (I).
8. The method of claim 7 , wherein the oxidant used in step (a) is H 2 O 2 .
9. The method of claim 7 , wherein an activator is present in step (b).
10. The method of claim 9 , wherein the activator is N,N′-dicyclohexylcarbodiimide.
11. The platinum complex of claim 1 , wherein each of X 1 and X 2 is Cl.
12. The platinum complex of claim 1 , wherein each instance of R N1 and R N2 is independently hydrogen or optionally substituted C 1-6 alkyl.
13. The platinum complex of claim 1 , wherein each instance of R N1 and R N2 is hydrogen.
14. The platinum complex of claim 1 , wherein one R N1 and one R N2 are taken with the intervening atoms to form an optionally substituted heterocyclic ring.
15. The platinum complex of claim 1 , wherein the platinum complex is of the formula:
or a salt thereof.
16. The method of claim 7 , wherein each of X 1 and X 2 is Cl.
17. The method of claim 7 , wherein each instance of R N1 and R N2 is hydrogen.
18. The method of claim 7 , wherein one R N1 and one R N2 are taken with the intervening atoms to form an optionally substituted heterocyclic ring.
19. The method of claim 7 , wherein the platinum complex is of the formula:
20. The method of claim 9 , wherein the activator is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, diphenylphosphorylazide, carbonyldiimidazole, diethylcyanophosphonate, benzotriazole-1-yloxy-trispyrrolidinophosphonium, benzotriazole-1-yloxy-trispyrrolidinophosphonium hexafluorophosphate, 1-hydroxybenzotriazole, hydroxysuccinimide, dimethylaminopyridine, 1-hydroxy-7-azabenzotriazole, hydroxyphthalimide, pentafluorophenol, 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, 0-(7-azabenzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphonate, 0-benzotriazole-1-yl-1,1,3,3-tetramethyluronium tetrafluoroborate, or 3,4-dihydro-3-hydrodi-4-oxa-1,2,3-benzotriazine.