Novel polymeric prodrug with multivalent components for cancer therapy.
We designed, synthesized, and evaluated in vitro and in vivo a novel targeted anticancer polymeric prodrug containing multiple copies of tumor targeting moiety [synthetic luteinizing hormone-releasing hormone (LHRH) peptide, analog of LHRH] and anticancer drug (camptothecin). One, two, or three molecules of the targeting peptide and anticancer drug were covalently conjugated with bis(2-carboxyethyl) polyethylene glycol polymer using citric acid as a multivalent spacer. We showed that LHRH peptide was bound to extracellular receptors and localized in plasma membrane of cancer cells. The designed tumor-targeted prodrug increased the solubility of anticancer drug and offered cytoplasmic and/or nuclear delivery of drug to cancer cells expressing LHRH receptors. The multicomponent prodrug containing three copies of the targeting peptide and drug was almost 100 times more cytotoxic and substantially had enhanced antitumor activity compared with the analogous nontargeted prodrug and prodrugs containing one or two copies of active components.
Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA.
Jayant J
JJ
Khandare
Pooja
P
Chandna
Yang
Y
Wang
Vitaly P
VP
Pozharov
Tamara
T
Minko
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D002166:Camptothecin / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004337:Drug Carriers / Q000737:chemistry*; D015195:Drug Design; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000737:chemistry*; D006801:Humans; D015394:Molecular Structure; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D010051:Ovarian Neoplasms / Q000473:pathology; D011108:Polymers; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D051381:Rats; D023041:Xenograft Model Antitumor Assays
D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D011108:Polymers; D011355:Prodrugs; D007987:Gonadotropin-Releasing Hormone; D002166:Camptothecin