title: Cycloamylose-nanogel drug delivery system-mediated intratumor silencing of the vascular endothelial growth factor regulates neovascularization in tumor microenvironment.
abstract: RNAi enables potent and specific gene silencing, potentially offering useful means for treatment of cancers. However, safe and efficient drug delivery systems (DDS) that are appropriate for intra-tumor delivery of siRNA or shRNA have rarely been established, hindering clinical application of RNAi technology to cancer therapy. We have devised hydrogel polymer nanoparticles, or nanogel, and shown its validity as a novel DDS for various molecules. Here we examined the potential of self-assembled nanogel of cholesterol-bearing cycloamylose with spermine group (CH-CA-Spe) to deliver vascular endothelial growth factor (VEGF)-specific short interfering RNA (siVEGF) into tumor cells. The siVEGF/nanogel complex was engulfed by renal cell carcinoma (RCC) cells through the endocytotic pathway, resulting in efficient knockdown of VEGF. Intra-tumor injections of the complex significantly suppressed neovascularization and growth of RCC in mice. The treatment also inhibited induction of myeloid-derived suppressor cells, while it decreased interleukin-17A production. Therefore, the CH-CA-Spe nanogel may be a feasible DDS for intra-tumor delivery of therapeutic siRNA. The results also suggest that local suppression of VEGF may have a positive impact on systemic immune responses against malignancies.
authors.affiliation: Department of Immunology, Kyoto Prefectural University of Medicine, Kyoto, Kyoto Prefectural University of Medicine, Kyoto, Japan; Department of Urology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Fujii
authors.forename: Masaharu
authors.initials: M
authors.lastname: Shin-Ya
authors.forename: Shigeo
authors.initials: S
authors.lastname: Takeda
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Hashimoto
authors.forename: Sada-atsu
authors.initials: SA
authors.lastname: Mukai
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Sawada
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Adachi
authors.forename: Kazunari
authors.initials: K
authors.lastname: Akiyoshi
authors.forename: Tsuneharu
authors.initials: T
authors.lastname: Miki
authors.forename: Osam
authors.initials: O
authors.lastname: Mazda
mesh_terms: D000818:Animals; D002292:Carcinoma, Renal Cell / Q000098:blood supply / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D003505:Cyclodextrins / Q000008:administration & dosage*; D016503:Drug Delivery Systems; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy; D006801:Humans; D007680:Kidney Neoplasms / Q000098:blood supply / Q000473:pathology / Q000628:therapy*; D051379:Mice; D000080385:Nanogels; D009374:Neoplasms, Experimental; D009389:Neovascularization, Pathologic / Q000473:pathology / Q000628:therapy*; D009928:Organ Specificity; D011092:Polyethylene Glycols / Q000737:chemistry; D011094:Polyethyleneimine / Q000737:chemistry; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D059016:Tumor Microenvironment; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*
chemical_list: D003505:Cyclodextrins; D000080385:Nanogels; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; C413692:polyethylene glycol polyethyleneimine nanogel; D011092:Polyethylene Glycols; D011094:Polyethyleneimine
keywords: Drug delivery system; RNA interference; nanogel; renal cell carcinoma; vascularendothelial growth factor