Multi-arm polymeric targeting anti-cancer conjugate
AssigneeBrightGene Bio-Medical Technology Co., Ltd.
InventorsJiandong Yuan, Yangqing Huang, Yunsong Song, Fang Yuan
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Abstract
Disclosed is a multi-arm targeting drug conjugate modified by a water-soluble polymer; the drug conjugate has the structural formula of (III). In formula (III), R is an organic core, POLY is a polymer, L is a multivalent linker, T is a targeting molecule, D is a camptothecin-based drug, and q is any integer between 3 and 8. The drug conjugate may improve the poor water solubility, high toxicity and low bioavailability of camptothecin-based drugs.
Claims17
A multi-branched drug conjugate having the following structural formula (III) or a pharmaceutically acceptable salt thereof:
- wherein R is an organic core, POLY is polyethylene glycol, 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 D is a camptothecin-based drug represented by the following formula:
- wherein R1 to R5 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;
- R6 is H or OR8;
- R8 is alkyl, alkenyl, cycloalkyl, halogenated alkyl, or hydroxyalkyl;
- and R7 is hydroxyl;
- the multivalent linker L is:
- 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, “%” represents an attachment point of the multivalent linker L and POLY, wherein m and m′ are any integer between 1 and 20 respectively, and l and k are any integer between 1 and 10 respectively;
- T is an “arginine-glycine-aspartic acid” sequence-containing RGD peptide, tLyp-1, Lyp-1, RPARPAR, Angiopep2, GE11, or folic acid.
A multi-branched drug conjugate having the following structure or a pharmaceutically acceptable salt thereof:
A preparation method of a multi-branched drug conjugate or a pharmaceutically acceptable salt thereof, comprising:
- wherein R is an organic core, POLY is polyethylene glycol, L is a multivalent linker, T is a targeting molecule, D is an active agent, q is any integer between 3 and 8, and D is a camptothecin-based drug represented by the following formula:
- wherein R1 to R5 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, aryl sulfonyloxy, and alkylsulfonyloxy;
- R6 is H or OR8;
- R8 is alkyl, alkenyl, cycloalkyl, halogenated alkyl, or hydroxyalkyl;
- and R7 is hydroxyl;
- the multivalent linker L is:
- 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, “%” represents an attachment point of the multivalent linker L and POLY, wherein m and m′ are any integer between 1 and 20 respectively, and l and k are any integer between 1 and 10 respectively;
- T is an “arginine-glycine-aspartic acid” sequence-containing RGD peptide, tLyp-1, Lyp-1, RPARPAR, Angiopep2, GE11, or folic acid;
- (1) the active agent D is attached to the multivalent linker L to obtain a D-L portion;
- (2) the D-L portion is attached to a multi-arm polymer RPOLY)q to obtain RPOLY-L-D)q;
- and
- (3) RPOLY-L-D)q obtained in the previous step is attached to the targeting molecule T.
Dependencies are inferred from the claim text.