title: Targetable HPMA copolymer-aminohexylgeldanamycin conjugates for prostate cancer therapy.
abstract: OBJECTIVE
  This study focuses on the synthesis and characterization of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-cyclo-RGD (Arg-Gly-Asp) conjugates for delivery of geldanamycin to prostate tumors.
  
  
  METHODS
  HPMA copolymers containing aminohexylgeldanamycin (AH-GDM) with and without the targeting peptide RGDfK were synthesized and characterized. Drug release from copolymers was evaluated using cathepsin B. Competitive binding of copolymer conjugates to alpha(v)beta(3) integrin was evaluated in prostate cancer (PC-3) and endothelial (HUVEC) cell lines and in vitro growth inhibition was assessed. The maximum tolerated dose for single i.v. injections of free drug and the conjugates was established in nude mice.
  
  
  RESULTS
  HPMA copolymers containing AH-GDM and RGDfK showed active binding to the alpha(v)beta(3) integrin similar to that of free peptide. Similarly, growth inhibition of cells by conjugates was comparable to that of the free drug. Single intravenous doses of HPMA copolymer-AH-GDM-RGDfK conjugates in mice were tolerated at 80 mg/kg drug equivalent, while free drug caused morbidity at 40 mg/kg. No signs of toxicity were present in mice receiving HPMA copolymer-AH-GDM-RGDfK over the 14-day evaluation period.
  
  
  CONCLUSIONS
  Results of in vitro activity and in vivo tolerability experiments hold promise for the utility of HPMA copolymer-AH-GDM-RGDfK conjugates for treatment of prostate cancer with greater efficacy and reduced toxicity.
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland, Baltimore, MD 21201, USA.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Borgman
authors.forename: Abhijit
authors.initials: A
authors.lastname: Ray
authors.forename: Rohit B
authors.initials: RB
authors.lastname: Kolhatkar
authors.forename: Edward A
authors.initials: EA
authors.lastname: Sausville
authors.forename: Angelika M
authors.initials: AM
authors.lastname: Burger
authors.forename: Hamidreza
authors.initials: H
authors.lastname: Ghandehari
mesh_terms: D000178:Acrylamides / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D016227:Benzoquinones / Q000008:administration & dosage* / Q000378:metabolism / Q000633:toxicity; D002401:Cathepsin B / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D003164:Competitive Bidding; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D006801:Humans; D039001:Integrin alpha Chains / Q000378:metabolism; D039641:Integrin beta Chains / Q000378:metabolism; D047029:Lactams, Macrocyclic / Q000008:administration & dosage* / Q000378:metabolism / Q000633:toxicity; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D018675:Toxicity Tests
chemical_list: D000178:Acrylamides; D016227:Benzoquinones; D039001:Integrin alpha Chains; D039641:Integrin beta Chains; D047029:Lactams, Macrocyclic; D010456:Peptides, Cyclic; C099250:cyclic (arginyl-glycyl-aspartyl-phenylalanyl-lysyl); D002401:Cathepsin B; C032976:N-(2-hydroxypropyl)methacrylamide; C001277:geldanamycin