Non-viral delivery of interleukin-2 and soluble Flk-1 inhibits metastatic and primary tumor growth in renal cell carcinoma.
Treatments for renal cell carcinoma, while promising, are still limited by toxicity and cost. In the hopes of finding a novel compound or combination, we developed a plasmid containing the genes for interleukin-2 (IL-2) and soluble vascular endothelial growth factor receptor 2 (msFlk1). The plasmid, p2CMVIL2/msFlk1, demonstrated similar in vitro transgene expression of IL-2 or msFlk1 compared to their single-agent counterparts. Subcutaneous tumor growth was significantly inhibited in the p2CMVIL2/msFlk1 group when delivered locally by the non-viral water soluble polymer, WSLP and exhibited a 50% increase in survival over glucose and single-agent controls. In vivo experimentation demonstrated that WSLP/msFlk1 decreased microvessel density in pCMVmsFlk1 and p2CMVIL2/msFlk1 treated groups. Furthermore, tumor-infiltrating lymphocytes expressing CD45RO and CD68 were increased within the tumor microenvironment upon p2CMVIL2/msFlk1 treatment. To determine the effects of p2CMVIL2/msFlk1 in an experimental RENCA lung metastases model, therapeutic DNA was delivered systemically following complexation with the angiogenic endothelial-targeting polymer PEI-g-PEG-RGD. The p2CMVIL2/msFlk1 treatment significantly reduced metastases by 56% over single-agent therapy and increased survival proportions by 50% over all groups. Our work clearly demonstrates that non-viral delivery of p2CMVIL2/msFlk1 can inhibit RENCA growth in a synergistic manner and may represent a new treatment for renal carcinoma.
Yockman
J W
JW
Department of Pharmaceutics and Pharmaceutical Chemistry, Center for Controlled Chemical Delivery, University of Utah, Salt Lake City, UT 84112, USA.
Kim
W J
WJ
Chang
C-W
CW
Kim
S W
SW
D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D015214:Antigens, Differentiation, Myelomonocytic / Q000276:immunology; D002292:Carcinoma, Renal Cell / Q000276:immunology / Q000378:metabolism / Q000556:secondary / Q000628:therapy*; D003131:Combined Modality Therapy; D004337:Drug Carriers; D005260:Female; D005818:Genetic Engineering; D015316:Genetic Therapy / Q000379:methods*; D007167:Immunotherapy / Q000379:methods*; D007376:Interleukin-2 / Q000235:genetics* / Q000378:metabolism; D007680:Kidney Neoplasms / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D017493:Leukocyte Common Antigens / Q000276:immunology; D008055:Lipids / Q000008:administration & dosage; D008175:Lung Neoplasms / Q000276:immunology / Q000378:metabolism / Q000556:secondary / Q000628:therapy; D051379:Mice; D008833:Microcirculation; D009374:Neoplasms, Experimental; D009389:Neovascularization, Pathologic; D010456:Peptides, Cyclic / Q000008:administration & dosage; D011092:Polyethylene Glycols / Q000008:administration & dosage; D011094:Polyethyleneimine / Q000008:administration & dosage / Q000031:analogs & derivatives; D014162:Transfection / Q000379:methods; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics* / Q000378:metabolism; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D004337:Drug Carriers; D007376:Interleukin-2; D017493:Leukocyte Common Antigens; D008055:Lipids; D010456:Peptides, Cyclic; D011092:Polyethylene Glycols; D011094:Polyethyleneimine; D040301:Vascular Endothelial Growth Factor Receptor-2; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C507107:PEI-g-PEG-RGD; C438935:poly(ethylenimine)-co-(N-(2-aminoethyl) ethyleneimin)-co-N-(N-cholesteryloxycarbonyl-(2-aminoethyl)ethylenimine)