Chemosensitization of cancer cells by siRNA using targeted nanogel delivery.

Background: Chemoresistance is a major obstacle in cancer treatment. Targeted therapies that enhance cancer cell sensitivity to chemotherapeutic agents have the potential to increase drug efficacy while reducing toxic effects on untargeted cells. Targeted cancer therapy by RNA interference (RNAi) is a relatively new approach that can be used to reversibly silence genes in vivo by selectively targeting genes such as the epidermal growth factor receptor (EGFR), which has been shown to increase the sensitivity of cancer cells to taxane chemotherapy.

Peptide-functionalized nanogels for targeted siRNA delivery.

A major bottleneck in the development of siRNA therapies is their delivery to the desired cell type or tissue, followed by effective passage across the cell membrane with subsequent silencing of the targeted mRNA. To address this problem, we describe the synthesis of core/shell hydrogel nanoparticles (nanogels) with surface-localized peptides that specifically target ovarian carcinoma cell lines possessing high expression levels of the Eph2A receptor. These nanogels are also demonstrated to be highly effective in the noncovalent encapsulation of siRNA and enable cell-specific delivery of the oligonucleotides in serum-containing medium.

Size Controlled Synthesis of Monodispersed, Core/Shell Nanogels.

Small, monodispersed nanogels (~ 50-nm radius) were synthesized by free-radical precipitation polymerization and characterized using a suite of light scattering and chromatography methods. Nanogels were synthesized with either N-isopropylacrylamide or N-isopropylmethacrylamide as the main monomer, with acrylic acid or 4-acrylamidofluorescein as a co-monomer and N, N'-methylenebis(acrylamide) as a cross-linker. By varying the surfactant and initiator concentrations, particle size was controlled while maintaining excellent monodispersity.