Novel polymeric prodrug with multivalent components for cancer therapy - PubMed (original) (raw)
. 2006 Jun;317(3):929-37.
doi: 10.1124/jpet.105.098855. Epub 2006 Feb 9.
Affiliations
- PMID: 16469865
- DOI: 10.1124/jpet.105.098855
Novel polymeric prodrug with multivalent components for cancer therapy
Jayant J Khandare et al. J Pharmacol Exp Ther. 2006 Jun.
Abstract
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.
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