Tumor-targeted HPMA copolymer-(RGDfK)-(CHX-A''-DTPA) conjugates show increased kidney accumulation.
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.
Borgman
Mark P
MP
Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland-21201, USA.
Coleman
Tomika
T
Kolhatkar
Rohit B
RB
Geyser-Stoops
Sandra
S
Line
Bruce R
BR
Ghandehari
Hamidreza
H
D000178:Acrylamides / Q000008:administration & dosage / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D000818:Animals; D001667:Binding, Competitive; D018827:Carcinoma, Lewis Lung / Q000000981:diagnostic imaging / Q000378:metabolism*; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical; D004337:Drug Carriers; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D006801:Humans; D007205:Indium Radioisotopes; D007275:Injections, Intravenous; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D017879:Isothiocyanates / Q000008:administration & dosage / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D007668:Kidney / Q000000981:diagnostic imaging / Q000378:metabolism*; D008657:Metabolic Clearance Rate; D051379:Mice; D008810:Mice, Inbred C57BL; D008970:Molecular Weight; D009368:Neoplasm Transplantation; D004369:Pentetic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D011877:Radionuclide Imaging; D014018:Tissue Distribution
D000178:Acrylamides; D004337:Drug Carriers; D007205:Indium Radioisotopes; D039302:Integrin alphaVbeta3; D017879:Isothiocyanates; D010456:Peptides, Cyclic; C099250:cyclic (arginyl-glycyl-aspartyl-phenylalanyl-lysyl); C085678:N-(2-amino-3-(4-isothiocyanatophenyl)propyl)cyclohexane-1,2-diamine-N,N',N',N'',N''-pentaacetic acid; D004369:Pentetic Acid; C032976:N-(2-hydroxypropyl)methacrylamide