Tumor efficacy and biodistribution of linear polyethylenimine-cholesterol/DNA complexes.
Non-viral polymer/pDNA complexes were formed using linear polyethylenimine (LPEI) Mw 25 k conjugated to cholesterol in a T-shaped geometry (LPC-T) and pDNA encoding murine interleukin-12 (pmIL-12e). These complexes were subsequently injected weekly into BALB/c mice intravenously and locally for the treatment of murine renal cell adenocarcinoma (Renca) induced pulmonary metastases and subcutaneous (SC) Renca tumors, respectively. At the cessation of the pulmonary metastases study, the number of pulmonary metastases was significantly less (p < 0.001) with systemic injections of LPC-T/pmIL-12e formulations than with pmIL-12e alone or pmIL-12e complexed with LPEI, branched polyethylenimine (BPEI) Mw 25 k, or an LPEI/pEGFP control. In addition, biodistribution studies showed increased pulmonary levels of both the LPC-T carrier and pmIL-12e vector up to 3 hr after systemic injection of the LPC-T/pmIL-12e complexes into mice carrying pulmonary metastases. Furthermore, mice systemically treated with LPC-T/pmIL-12e showed a near linear profile in weight gain in the course of the pulmonary metastases study that suggests increased biocompatibility. Finally, due to favorable characteristics in vitro, LPC-T was also used for local (peritumoral) injection of SC Renca tumors. Tumor stasis and slight tumor regression were seen only with the LPC-T/pmIL-12e treated mice compared to BPEI/pmIL-12e, LPEI/pmIL-12e, and naked pmIL-12e controls. Thus, it was concluded that LPC-T is an effective carrier for passive targeting of the pulmonary tissue, treatment of Renca-induced pulmonary metastases, and local administration of Renca cell SC tumors.
Furgeson
Darin Y
DY
Department of Pharmaceutics and Pharmaceutical Chemistry, Center for Controlled Chemical Delivery, University of Utah, Salt Lake City, UT 84112-5820, USA.
Yockman
James W
JW
Janat
Margit-Maria
MM
Kim
Sung Wan
SW
D000818:Animals; D002292:Carcinoma, Renal Cell / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000031:analogs & derivatives / Q000737:chemistry / Q000627:therapeutic use*; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000737:chemistry* / Q000493:pharmacokinetics*; D006801:Humans; D018664:Interleukin-12 / Q000235:genetics*; D007680:Kidney Neoplasms / Q000473:pathology / Q000628:therapy*; D008175:Lung Neoplasms / Q000556:secondary* / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D011094:Polyethyleneimine / Q000737:chemistry / Q000627:therapeutic use*; D012878:Skin Neoplasms / Q000556:secondary / Q000628:therapy; D014018:Tissue Distribution
D018664:Interleukin-12; D011094:Polyethyleneimine; D002784:Cholesterol