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.