The use of nanoparticle-mediated targeted gene silencing and drug delivery to overcome tumor drug resistance

Abstract

Overexpression of drug efflux transporters such as P-glycoprotein (P-gp) enables cancer cells to develop resistance to multiple anticancer drugs. Functional inhibitors of P-gp have shown promising efficacy in early clinical trials, but their long-term safety is yet to be established. A novel approach to overcome drug resistance is to use siRNA-mediated RNA interference to silence the expression of the efflux transporter. Because P-gp plays an important role in the physiological regulation of endogenous and xenobiotic compounds in the body, it is important to deliver P-gp targeted siRNA and anticancer drug specifically to tumor cells. Further, for optimal synergy, both the drug and siRNA may need to be temporally colocalized in the tumor cells. In the current study, we investigated the effectiveness of simultaneous and targeted delivery of anticancer drug, paclitaxel, along with P-gp targeted siRNA, using poly(D,L-lactide-co-glycolide) nanoparticles to overcome tumor drug resistance. Nanoparticles were surface functionalized with biotin for active tumor targeting. Dual agent nanoparticles encapsulating the combination of paclitaxel and P-gp targeted siRNA showed significantly higher cytotoxicity in vitro than nanoparticles loaded with paclitaxel alone. Enhanced therapeutic efficacy of dual agent nanoparticles could be correlated with effective silencing of the MDR1 gene that encodes for P-gp and with increased accumulation of paclitaxel in drug-resistant tumor cells. In vivo studies in a mouse model of drug-resistant tumor demonstrated significantly greater inhibition of tumor growth following treatment with biotin-functionalized nanoparticles encapsulating both paclitaxel and P-gp targeted siRNA at a paclitaxel dose that was ineffective in the absence of gene silencing. These results suggest that that the combination of P-gp gene silencing and cytotoxic drug delivery using targeted nanoparticles can overcome tumor drug resistance.

Advanced targeted therapies in cancer: Drug nanocarriers, the future of chemotherapy

“…Patil et al [562] achieved in vivo the active targeting of tumors coupling biotin (as a ligand for breast cancer cells) to siRNA-loaded PLGA-based nanoparticles with a PEI coating. This system was efficient in silencing the overexpression of the drug efflux transporter P-glycoprotein (Pgp), and allowed to overcome tumor drug resistance.…”

“Combo” nanomedicine: Co-delivery of multi-modal therapeutics for efficient, targeted, and safe cancer therapy

“…Drug resistance can occur through various means, which is why combating this process requires a multi-faceted approach such as combined gene and chemotherapy [187]. For example, drug resistance associated with P-glycoprotein (P-gp) drug efflux pump that is activated primarily by the MDR-1 gene can be reversed by RNA interference (RNAi) against P-gp [188].…”

Polylactide-co-glycolide nanoparticles for controlled delivery of anticancer agents

“…Biotin-conjugated nanoparticles demonstrated more tumor growth inhibition than the nontargeted nanoparticles. 144 …”