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. However, delivery represents the main hurdle for the broad development of RNAi therapeutics.


METHODS
We 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.


RESULTS
Treatment 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).


CONCLUSIONS
This 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.
Dickerson
Erin B
EB
School of Biology, Georgia Institute of Technology, 310 Ferst Drive, Atlanta, GA 30332, USA.
Blackburn
William H
WH
Smith
Michael H
MH
Kapa
Laura B
LB
Lyon
L Andrew
LA
McDonald
John F
JF
D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D000077143:Docetaxel; D016503:Drug Delivery Systems; D066246:ErbB Receptors / Q000737:chemistry / Q000378:metabolism; D005260:Female; D005782:Gels / Q000737:chemistry*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015151:Immunoblotting; D036103:Nanotechnology / Q000379:methods*; D009369:Neoplasms / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000378:metabolism; D010455:Peptides / Q000737:chemistry; D034741:RNA, Small Interfering / Q000378:metabolism; D043823:Taxoids / Q000494:pharmacology
D000970:Antineoplastic Agents; D005782:Gels; D010455:Peptides; D034741:RNA, Small Interfering; D043823:Taxoids; D000077143:Docetaxel; D066246:ErbB Receptors