Biodistribution of HPMA copolymer-aminohexylgeldanamycin-RGDfK conjugates for prostate cancer drug delivery.

Abstract

N-(2-Hydroxypropyl)methacrylamide (HPMA) copolymer-RGD (Arg-Gly-Asp) conjugates targeting the alpha(v)beta(3) integrin present on angiogenic blood vessels and some tumor types have shown increased accumulation in solid tumors and possess properties that suggest their use for site-specific drug delivery. Geldanamycin (GDM) is a benzoquinoid ansamycin that binds to heat-shock protein 90 (HSP90), effective for the treatment of multiple cancer types including prostate, but has dose-limiting cytotoxicity. We recently reported the synthesis of HPMA copolymer-aminohexyl-geldanamycin (AH-GDM) conjugates containing RGDfK that demonstrated favorable properties of drug release, in vitro binding to the alpha(v)beta(3) integrin, cytotoxicity in human prostate cancer cells, and tolerability in nude mice greater than 2-fold equivalent free drug doses. In this study the biodistribution of 125I-radiolabeled HPMA copolymer-AH-GDM conjugates with and without RGDfK in both non-tumor-bearing and DU145 prostate tumor xenograft-bearing nude mice was evaluated. At 60 mg/kg drug equivalent polymer doses in non-tumor-bearing mice both conjugates showed fast elimination from blood and decreasing accumulation in all other organs. Kidney accumulation predominated and was higher for the conjugate containing RGDfK. In tumor-bearing mice, trace quantities of the conjugate containing RGDfK showed increased tumor accumulation as compared to the conjugate without RGDfK. Also evaluated were free drug concentrations in prostate tumor xenografts following treatments of 30 and 60 mg/kg drug-equivalent copolymer conjugates (with and without RGDfK) compared with 30 mg/kg free AH-GDM. Overall, 60 mg/kg treatment of RGDfK-containing conjugate showed significantly higher (p < 0.001) tumor drug concentrations compared with all other treatments. The targetable conjugates can effectively deliver higher amounts of geldanamycin to the tumor compared to nontargetable systems.

• Authors: Mark P Borgman, Omer Aras, Sandra Geyser-Stoops, Edward A Sausville, Hamidreza Ghandehari
• Journal: Molecular pharmaceutics (Mol Pharm) 2009 Nov-Dec Vol. 6 Issue 6 Pg. 1836-47 ISSN: 1543-8392 [Electronic] United States
• PMID: 19743884 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Acrylamides
• Benzoquinones
• Drug Carriers
• Enzyme Inhibitors
• Lactams, Macrocyclic
• Oligopeptides
• arginyl-glycyl-aspartic acid
• N-(2-hydroxypropyl)methacrylamide
• geldanamycin

Topics

• Acrylamides (chemistry)
• Animals
• Benzoquinones (chemistry, therapeutic use)
• Cell Line, Tumor
• Drug Carriers (chemical synthesis, chemistry, pharmacokinetics)
• Enzyme Inhibitors (therapeutic use)
• Female
• Humans
• Lactams, Macrocyclic (chemistry, therapeutic use)
• Male
• Mice
• Mice, Nude
• Molecular Structure
• Oligopeptides (chemistry)
• Prostatic Neoplasms (drug therapy)