A prostate-specific antigen activated N-(2-hydroxypropyl) methacrylamide copolymer prodrug as dual-targeted therapy for prostate cancer.
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.
Chandran
Sachin S
SS
Department of Chemical and Biomolecular Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Nan
Anjan
A
Rosen
D Marc
DM
Ghandehari
Hamidreza
H
Denmeade
Samuel R
SR
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D003374:Coumarins / Q000378:metabolism; D016503:Drug Delivery Systems; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D006868:Hydrolysis / Q000187:drug effects; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008823:Micelles; D009928:Organ Specificity / Q000187:drug effects; D011108:Polymers / Q000737:chemistry / Q000378:metabolism*; D011109:Polymethacrylic Acids / Q000737:chemistry / Q000378:metabolism*; D011355:Prodrugs / Q000378:metabolism*; D017430:Prostate-Specific Antigen / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000628:therapy*; D019284:Thapsigargin / Q000031:analogs & derivatives / Q000494:pharmacology
C453681:7-amino-4-chloromethylcoumarin; D000970:Antineoplastic Agents; D003374:Coumarins; C476027:L12ADT; D008823:Micelles; D011108:Polymers; D011109:Polymethacrylic Acids; D011355:Prodrugs; C011533:Duxon; D019284:Thapsigargin; D017430:Prostate-Specific Antigen