Multi-arm targeting anti-cancer conjugate
A multi-branched drug conjugate of formula (I) or a pharmaceutically acceptable salt thereof. In the formula, R is an organic center, POLY is a polymer, L is a multivalent linker, T is a targeting molecule, D is an active agent, and q is any integer between 3 and 8. The symbol “*” in L represents a junction point of the multivalent linker L and the targeting molecule T, “#” represents a junction point of the multivalent linker L and the active agent D, and “%” represents a junction point of the multivalent linker L and POLY. 1 is any integer between 2 and 20, and m and n are each an integer between 0 and 10. T is iRGD, cRGD, tLyp-1, Lyp-1, RPARPAR, Angiopep2, or GE11. D is a camptothecin drug.
1. A multi-branched drug conjugate having the following structural formula (I) or a pharmaceutically acceptable salt thereof:
R is an organic core, POLY is a polymer, L is a multivalent linker, T is a targeting molecule, D is an active agent, and q is any integer between 3 and 8, wherein L is
a symbol “*” represents an attachment point of the multivalent linker L and the targeting molecule T, “#” represents an attachment point of the multivalent linker L and the active agent D, and “%” represents an attachment point of the multivalent linker L and POLY, wherein I is any integer between 2 and 20, and m and n are any integer between 0 and 10 respectively;
T is an RGD peptide containing a sequence of “arginine-glycine-aspartic acid”, tLyp-1, Lyp-1, RPARPAR, Angiopep2, or GE11;
D is a camptothecin-based drug as represented by formula (II):
wherein R 1 to R 5 are selected from the following groups independently from each other: hydrogen, halogen, acyl, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, alkynyl, cycloalkyl, hydroxyl, cyano, nitro, azido, amido, hydrazine, amine group, substituted amine group, hydroxycarbonyl, alkoxycarbonyl, alkoxycarbonyloxy, carbamoyloxy, arylsulfonyloxy, and alkylsulfonyloxy; R 6 is H or OR 8 ; R 8 is alkyl, alkenyl, cycloalkyl, halogenated alkyl, or hydroxyalkyl; and R 7 is hydroxyl.
2. The multi-branched drug conjugate or the pharmaceutically acceptable salt thereof according to claim 1 , wherein T is cRGD or iRGD.
3. The multi-branched drug conjugate or the pharmaceutically acceptable salt thereof according to claim 1 , wherein POLY is polyethylene glycol.
4. The multi-branched drug conjugate or the pharmaceutically acceptable salt thereof according to claim 3 , wherein POLY is
wherein “ ” represents a site for attachment of atoms, an oxygen atom marked with “&” is the atom attached to the organic core “R”, k is an integer in a range of 50 to 200, and r is any integer between 1 and 10.
5. The multi-branched drug conjugate or the pharmaceutically acceptable salt thereof according to claim 4 , which is as represented by structural formula (III), (IV), or (V):
6. The multi-branched drug conjugate or the pharmaceutically acceptable salt thereof according to claim 5 , wherein POLY is
7. The multi-branched drug conjugate or the pharmaceutically acceptable salt thereof according to claim 6 , which is
8. The multi-branched drug conjugate or the pharmaceutically acceptable salt thereof according to claim 7 , wherein k has an average value of 113.
9. The multi-branched drug conjugate or the pharmaceutically acceptable salt thereof according to claim 8 , wherein L is
10. The multi-branched drug conjugate or the pharmaceutically acceptable salt thereof according to claim 9 , wherein D is irinotecan, SN-38, 10-hydroxycamptothecin, or rubitecan.
11. The multi-branched drug conjugate or the pharmaceutically acceptable salt thereof according to claim 10 , which is
12. The multi-branched drug conjugate or the pharmaceutically acceptable salt thereof according to claim 11 , which is
13. A pharmaceutical composition, comprising the multi-branched drug conjugate or the pharmaceutically acceptable salt thereof according claim 1 , and a pharmaceutically acceptable excipient.
14. A method for treating a cancer selected from the group consisting of colon cancer, lung cancer, breast cancer, ovarian cancer, pancreatic cancer, gastric cancer, brain glioma, and a malignant sarcoma, a cancer and a lymphoma of breast, ovary, colon, kidney, bile duct, lung and brain, comprising administering to a subject in need thereof a therapeutic effective amount of the multi-branched drug conjugate or the pharmaceutically acceptable salt thereof according to claim 1 .
15. A method for treating a cancer selected from the group consisting of colon cancer, lung cancer, breast cancer, ovarian cancer, pancreatic cancer, gastric cancer, brain glioma, and a malignant sarcoma, a cancer and a lymphoma of breast, ovary, colon, kidney, bile duct, lung and brain, comprising administering to a subject in need thereof a therapeutic effective amount of the pharmaceutical composition according to claim 13 .
16. A pharmaceutical composition, comprising the multi-branched drug conjugate or the pharmaceutically acceptable salt thereof according to claim 5 , and a pharmaceutically acceptable excipient.
17. A pharmaceutical composition, comprising the multi-branched drug conjugate or the pharmaceutically acceptable salt thereof according to claim 11 , and a pharmaceutically acceptable excipient.
18. A pharmaceutical composition, comprising the multi-branched drug conjugate or the pharmaceutically acceptable salt thereof according to claim 12 , and a pharmaceutically acceptable excipient.