Chemosensitization of cancer cells by siRNA using targeted nanogel delivery

Abstract

BackgroundChemoresistance 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. However, delivery represents the main hurdle for the broad development of RNAi therapeutics.MethodsWe report here the use of core/shell hydrogel nanoparticles (nanogels) functionalized with peptides that specially target the EphA2 receptor to deliver small interfering RNAs (siRNAs) targeting EGFR. Expression of EGFR was determined by immunoblotting, and the effect of decreased EGFR expression on chemosensitization of ovarian cancer cells after siRNA delivery was investigated.ResultsTreatment of EphA2 positive Hey cells with siRNA-loaded, peptide-targeted nanogels decreased EGFR expression levels and significantly increased the sensitivity of this cell line to docetaxel (P < 0.05). Nanogel treatment of SK-OV-3 cells, which are negative for EphA2 expression, failed to reduce EGFR levels and did not increase docetaxel sensitivity (P > 0.05).ConclusionThis study suggests that targeted delivery of siRNAs by nanogels may be a promising strategy to increase the efficacy of chemotherapy drugs for the treatment of ovarian cancer. In addition, EphA2 is a viable target for therapeutic delivery, and the siRNAs are effectively protected by the nanogel carrier, overcoming the poor stability and uptake that has hindered clinical advancement of therapeutic siRNAs.

STAT3 inhibitor enhances chemotherapy drug efficacy by modulating mucin 1 expression in non-small cell lung carcinoma

“…Previous studies have shown that sensitizing cancer cells to chemotherapeutic agents can reduce the side effects as well as balance the efficacy and toxicity of chemotherapy [30]. Molecular pathways driving cancer progression or essential for the cancer cell survival could be targeted to sensitize the cells for chemotherapy.…”

Nanocarriers for siRNA delivery to overcome cancer multidrug resistance

“…Nanogels are able to be loaded with siRNA via "breathing-in" manner besides electrostatic attraction [94]. Dickerson et al [95] investigated core/shell nanogels composed of poly (N-isopropylmethacrylamide) (pNIPMAm) cross-linked with N,N′-methylene(bisacrylamide) to deliver siRNA targeting epidermal growth factor receptor (EGFR). Knockdown of (EGFR) contributes to the overcoming of MDR in cancer cells [96].…”

RNAi Therapeutic Potentials and Prospects in CNS Disease

“…It is also suggested a possible therapeutic effect of direct introduction of siRNA to CD44 into some human solid tumors with high expression of the CD44 gene [146]. Although the role of epidermal growth factor receptor (EGFR) in altering tumor chemosensitivity has not yet been fully elucidated, selectively targeting EGFR supplies the reversal possibility of chemoresistance in many tumor types [147]. Reduction of EGFR expression and increased chemosensitivity to docetaxel are emerging an effective strategy for the sensitization of cancer cells to taxane chemotherapy [147].…”

“…Although the role of epidermal growth factor receptor (EGFR) in altering tumor chemosensitivity has not yet been fully elucidated, selectively targeting EGFR supplies the reversal possibility of chemoresistance in many tumor types [147]. Reduction of EGFR expression and increased chemosensitivity to docetaxel are emerging an effective strategy for the sensitization of cancer cells to taxane chemotherapy [147]. siRNA-PG-Amine polyplexes can be systemically delivered to tumors in mice [148], and siRNA-nanocarrier system can efficiently inhibit expression of a specific gene in tumor cells.…”