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.

Nanogels: An overview of properties, biomedical applications and obstacles to clinical translation

“…Subsequently, DeSimone and coworkers used inverse miniemulsion polymerization of 2-acryloxyethyltrimethylammonium chloride and 2-hydroxyethylacrylate with PEG-diacrylate crosslinker to synthesize biocompatible nanogels with controlled size, morphology, and composition capable of forming stable ODN complexes and enhancing cellular delivery of ODNs in vitro [16]. Nowadays, a variety of cationic nanogel particles have been actively adapted to deliver siRNA molecule [81,120-128]. For example, Anderson and coworkers synthesized a library of 1,536 structurally distinct core-shell nanogels for siRNA complexation and delivery with great variability in the chemical nature of the protonizable amine-based core and a shell with variation in polymer length and chemical properties [129].…”

Preparation, characterization and anticancer activities of resveratrol loaded redox-sensitive F127-SS-TOC micelles

“…1,2 Surgery, chemotherapy and radiotherapy are the major and common treatments for breast cancer, occasionally, some side effects may occur without being expected, such as postoperative trauma, gastro-intestinal reactions, alopecia, etc. An increasing number of drug delivery systems (DDS) have attracted more attention for improving therapeutics via designing multifunctional drug vehicles including polymeric micelles, 3 nanoparticles, 4 liposomes, 5 nanogels, 6 et al Polymeric micelles can encapsulate poorly water-soluble drugs with a narrow size distribution, high drug loading capacity and the ability of extending systemic circulation. 7,8 Moreover, the polymeric micelles are amphiphilic block copolymer and formed the micelles structure with hydrophobic inner core and hydrophilic outer shell selfassembling in water.…”

Structural Dissection of the Maltodextrin Disproportionation Cycle of the Arabidopsis Plastidial Disproportionating Enzyme 1 (DPE1)

“…DPE1 can be used in vitro to produce large ring cycloamyloses with degrees of polymerization (DP) in the range of 16–50 ( 11 , 14 ), although there is no evidence for this occurring in vivo . Cycloamyloses have a number of biotechnological applications, including drug ( 15 ) or gene ( 16 ) delivery, and in the removal of detergents following protein refolding experiments ( 17 ). Plant disproportionating enzymes have also been used to transfer glucans from cheap donor molecules onto acceptor molecules ( e.g.…”