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.
Subject(s)
Acrylamides/chemistry , Benzoquinones/chemistry , Drug Carriers/chemistry , Drug Carriers/pharmacokinetics , Lactams, Macrocyclic/chemistry , Oligopeptides/chemistry , Prostatic Neoplasms/drug therapy , Animals , Benzoquinones/therapeutic use , Cell Line, Tumor , Drug Carriers/chemical synthesis , Enzyme Inhibitors/therapeutic use , Female , Humans , Lactams, Macrocyclic/therapeutic use , Male , Mice , Mice, Nude , Molecular StructureABSTRACT
N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-RGDfK conjugates targeting the alpha(v)beta(3) integrin have shown increased accumulation in solid tumors and promise for selective delivery of radiotherapeutics to sites of angiogenesis- or tumor-expressed alpha(v)beta(3) integrin. An unresolved issue in targeting radiotherapeutics to solid tumors is toxicity to non-target organs. To reduce toxicity of radiolabeled conjugates, we have synthesized HPMA copolymer-RGDfK conjugates with varying molecular weight and charge content to help identify a polymeric structure that maximizes tumor accumulation while rapidly clearing from non-targeted organs. Endothelial cell binding studies showed that copolymer conjugates of approximately 43, 20 and 10 kD actively bind to the alpha(v)beta(3) integrin. Scintigraphic images showed rapid clearance of indium-111 ((111)In) radiolabeled conjugates from the blood pool and high kidney accumulation within 1 h in tumor bearing mice. Biodistribution data confirms images with high accumulation in kidney (max 210% ID/g for 43 kD conjugate) and lower tumor accumulation (max 1.8% ID/g for 43 kD conjugate). While actively binding to the alpha(v)beta(3) integrin in vitro, HPMA copolymer-RGDfK conjugates with increased negative charge through increased CHX-A''-DTPA chelator content in the side chains causes increased kidney accumulation with a loss of tumor accumulation in vivo.
Subject(s)
Acrylamides/pharmacokinetics , Carcinoma, Lewis Lung/metabolism , Drug Carriers , Integrin alphaVbeta3/metabolism , Isothiocyanates/pharmacokinetics , Kidney/metabolism , Pentetic Acid/analogs & derivatives , Peptides, Cyclic/pharmacokinetics , Acrylamides/administration & dosage , Acrylamides/blood , Acrylamides/chemical synthesis , Animals , Binding, Competitive , Carcinoma, Lewis Lung/diagnostic imaging , Cell Line, Tumor , Chemistry, Pharmaceutical , Endothelial Cells/metabolism , Female , Humans , Indium Radioisotopes , Injections, Intravenous , Isothiocyanates/administration & dosage , Isothiocyanates/blood , Isothiocyanates/chemical synthesis , Kidney/diagnostic imaging , Metabolic Clearance Rate , Mice , Mice, Inbred C57BL , Molecular Weight , Neoplasm Transplantation , Pentetic Acid/administration & dosage , Pentetic Acid/blood , Pentetic Acid/chemical synthesis , Pentetic Acid/pharmacokinetics , Peptides, Cyclic/administration & dosage , Peptides, Cyclic/blood , Peptides, Cyclic/chemical synthesis , Radionuclide Imaging , Tissue DistributionABSTRACT
Recent advances in positron emission tomography (PET) instrumentation have paralleled those of multichannel computed tomography (CT) for cardiac applications. Whereas multichannel CT angiography provides information on the presence and extent of anatomical luminal narrowing of epicardial coronary arteries, stress myocardial perfusion PET provides information on the downstream functional consequences of such anatomic lesions. With the advent of hybrid PET/CT systems, such complementary information of anatomy and physiology can be realized immediately at the same imaging session. By acquiring dynamic, gated myocardial perfusion data, PET studies provide insight into impairment of regional coronary blood flow reserve and microvascular endothelial dysfunction. This paper presents recent developments in PET detector materials, acquisition modes, combined PET/CT scanners, rubidium-82 (Rb-82) gated myocardial perfusion studies and analysis methods for absolute myocardial blood flow quantification.
