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

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 micromol/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.

• Authors: Sachin S Chandran, Anjan Nan, D Marc Rosen, Hamidreza Ghandehari, Samuel R Denmeade
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 6 Issue 11 Pg. 2928-37 (Nov 2007) ISSN: 1535-7163 [Print] United States
• PMID: 18025277 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• 7-amino-4-chloromethylcoumarin
• Antineoplastic Agents
• Coumarins
• L12ADT
• Micelles
• Polymers
• Polymethacrylic Acids
• Prodrugs
• Duxon
• Thapsigargin
• Prostate-Specific Antigen

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• Coumarins (metabolism)
• Drug Delivery Systems
• Drug Screening Assays, Antitumor
• Humans
• Hydrolysis (drug effects)
• Male
• Mice
• Mice, Nude
• Micelles
• Organ Specificity (drug effects)
• Polymers (chemistry, metabolism)
• Polymethacrylic Acids (chemistry, metabolism)
• Prodrugs (metabolism)
• Prostate-Specific Antigen (metabolism)
• Prostatic Neoplasms (therapy)
• Thapsigargin (analogs & derivatives, pharmacology)