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Research Articles: Therapeutics, Targets, and Development

A prostate-specific antigen–activated N-(2-hydroxypropyl) methacrylamide copolymer prodrug as dual-targeted therapy for prostate cancer

¹ Department of Chemical and Biomolecular Engineering, The Johns Hopkins University Whiting School of Engineering; ² Department of Pharmaceutical Sciences and Center for Nanomedicine and Cellular Delivery, University of Maryland-Baltimore; and ³ The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, Maryland

Requests for reprints: Samuel R. Denmeade, Department of Oncology, The Johns Hopkins University School of Medicine, CRB I 1M43, 1650 Orleans Street, Baltimore, MD 21231. Phone: 410-955-8875; Fax: 1-410-614-8397. E-mail: Denmesa{at}jhmi.edu

Abstract

Prostate cancer targeted peptide prodrugs that are activated by the serine protease activity of prostate-specific antigen (PSA) are under development in our laboratory. To enhance delivery and solubility of these prodrugs, macromolecular carriers consisting of N-(2-hydroxypropyl) methacrylamide (HPMA)–based copolymers were covalently coupled to a PSA-activated peptide prodrug. HPMA copolymers are water-soluble, nonimmunogenic synthetic carriers that exhibit promise for drug delivery applications. These macromolecular copolymers enter the interstitium of solid tumors by the enhanced permeability and retention effect. The PSA-activated peptide substrate imparts selectivity because it is specifically hydrolyzed to release a cytotoxin at the site of prostate tumor. Enzymatically active PSA is present in high amounts in the extracellular fluid of a tumor, but PSA is inactivated in blood by binding to serum protease inhibitors. As an initial proof of concept, the HPMA copolymer was synthesized with a peptide substrate (HSSKLQ) bound to a fluorophore, 7-amino-4-methylcoumarin (AMC). PSA cleavage of the HPMA-HSSKLQ-AMC copolymer was observed, which led to the synthesis of an HPMA-based copolymer with the prodrug SSKYQ-L12ADT [HPMA–morpholinocarbonyl-Ser-Ser-Lys-Tyr-Gln-Leu-12-aminododecanoyl thapsigargin (JHPD)]. L12ADT is a potent analogue of the highly cytotoxic natural product thapsigargin. HPMA-JHPD was hydrolyzed by PSA in vitro and was toxic to prostate cancer cells in the presence of active PSA. The HPMA-JHPD produced no systemic toxicity when given at a 500 µmol/L L12ADT equivalent dose. Analysis of tumor tissue from mice treated with a single or multiple dose of the HPMA-JHPD copolymer showed release and accumulation of the L12ADT toxin within the tumor tissue. [Mol Cancer Ther 2007;6(11):2928–37]

Grant support: National Cancer Institute Prostate Specialized Programs of Research Excellence grant P50CA58236 (S.R. Denmeade) and National Institute of Biomedical Imaging and Bioengineering grant R01 EB007171 (H. Ghandehari).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁴ Unpublished data.

Received 6/13/07; revised 8/28/07; accepted 9/27/07.