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.
Highlights
Chemoresistance is a major obstacle in cancer treatment
Down-regulation of epidermal growth factor receptor (EGFR) in erythropoietin-producing hepatocellular receptor A2 (EphA2)+ ovarian cancer (Hey) cells by targeted small interfering RNA (siRNA)-loaded nanogels By coupling a peptide-mimetic (YSAYPDSVPMMS) of the EphA2 receptor’s ephrin-A1 ligand to core/shell nanogels, we demonstrated previously the ability to target the delivery of siRNA to ovarian cancer (Hey) cells expressing the EphA2 receptor [26]
Because of the observed differences in EphA2 expression levels, we hypothesized that the level of EGFR siRNA delivery and the subsequent decrease in EGFR expression in the cell lines would depend upon the presence of the EphA2 receptor as well as the concentration of siRNA loaded-nanogels added to the cells
Summary
Targeted therapies that enhance cancer cell sensitivity to chemotherapeutic agents have the potential to increase drug efficacy while reducing toxic effects on untargeted cells. Chemoresistance and subsequent tumor recurrence are often the outcome of such therapies An example of this all too common event is the use of taxanes (paclitaxel and its semi-synthetic analogue, docetaxel) in the treatment of a variety of cancers including ovarian, breast, prostate, and non-small cell lung cancers [1,2]. Novel targeted therapies that interfere with specific molecular signaling pathways affecting cancer cell survival are being developed as potential treatment options to render cancer cells more sensitive to cytotoxic chemotherapy. Targeted therapies that increase cancer cell sensitivity to chemotherapies offer the benefits of lowering unwanted side effects and increasing the likelihood of destroying resistant cells while avoiding healthy cells where there is little or no expression of the targeted entity
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