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

Sachin S. Chandran, Anjan Nan, D. Marc Rosen, Hamidreza Ghandehari, Samuel R Denmeade

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)2928-2937
Number of pages10
JournalMolecular Cancer Therapeutics
Volume6
Issue number11
DOIs
StatePublished - Nov 1 2007

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Prodrugs
Prostate-Specific Antigen
Prostatic Neoplasms
Peptides
Thapsigargin
Therapeutics
Neoplasms
N-(2-hydroxypropyl)methacrylamide
Poisons
Extracellular Fluid
Cytotoxins
Serine Proteases
Protease Inhibitors
Biological Products
Solubility
Prostate
Permeability
L12ADT
Water
Serum

ASJC Scopus subject areas

  • Oncology
  • Drug Discovery
  • Pharmacology

Cite this

A prostate-specific antigen-activated N-(2-hydroxypropyl) methacrylamide copolymer prodrug as dual-targeted therapy for prostate cancer. / Chandran, Sachin S.; Nan, Anjan; Rosen, D. Marc; Ghandehari, Hamidreza; Denmeade, Samuel R.

In: Molecular Cancer Therapeutics, Vol. 6, No. 11, 01.11.2007, p. 2928-2937.

Research output: Contribution to journalArticle

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