Cycloamylose‐nanogel drug delivery system‐mediated intratumor silencing of the vascular endothelial growth factor regulates neovascularization in tumor microenvironment

• DOI: 10.1111/cas.12547
• Publication Date: 2014-10-06T07:33:50Z
• Authors: Hidetaka Fujii; Masaharu Shin‐Ya; Shigeo Takeda; Yoshihide Hashimoto; Sada‐atsu Mukai; Shin‐ichi Sawada; Tetsuya Adachi; Kazunari Akiyoshi; Tsuneharu Miki; Osam Mazda
• Keywords: Vascular Endothelial Growth Factor A; 0301 basic medicine; Cyclodextrins; Neovascularization, Pathologic; Nanogels; Original Articles; Genetic Therapy; Neoplasms, Experimental; Kidney Neoplasms; Polyethylene Glycols; 3. Good health; Gene Expression Regulation, Neoplastic; Mice; 03 medical and health sciences; Drug Delivery Systems; Organ Specificity; Cell Line, Tumor; Tumor Microenvironment; Animals; Humans; Polyethyleneimine; RNA, Small Interfering; Carcinoma, Renal Cell

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.