Abstract
Usage of combination therapies to deliver multiple therapeutics to increase treatment efficacy has shown promising results in the clinic. In an effort to maximize the synergistic effect of co-delivery of a drug and siRNA, we have developed a time-dependent sequential drug delivery system (DDS) based on a disulfide-linked chitosan-based nanocarrier (CS-ss-SA) for the co-delivery of paclitaxel (PTX) and Bcl-2 specific siRNA (siBcl-2). This CS-ss-SA nanocarrier is able to transport both drug and siRNA by entrapment of PTX and adsorption of siRNA on the shell by electrostatic attraction. We show that this nanocarrier transports siRNA into tumor cells via its glycolipid-like spatial structure and releases a hydrophobic model drug, Nile Red 8-11 h later. Next, when siRNA and the hydrophobic drug PTX were co-delivered to tumor cells, a synergistic effect was observed in both cell cycle arrest and cell viability. Ultimately, the co-delivery of PTX and siBcl-2 by CS-ss-SA may prove to be more efficacious and may even help overcome drug resistance.
Highlights
In recent years, advances in nanotechnology and biotechnology have opened up unprecedented opportunities for controlled drug delivery and novel codelivery strategies [1, 2]
In an effort to maximize the synergistic effect of co-delivery of a drug and siRNA, we have developed a timedependent sequential drug delivery system (DDS) based on a disulfide-linked chitosanbased nanocarrier (CS-ss-Stearic acid (SA)) for the co-delivery of paclitaxel (PTX) and Bcl-2 specific siRNA
We proposed a disulfide-linked glycolipid-like nanocarrier as the co-delivery system
Summary
Advances in nanotechnology and biotechnology have opened up unprecedented opportunities for controlled drug delivery and novel codelivery strategies [1, 2]. The ideal codelivery carrier with an optimized drug releasing sequence should first release the siRNA to achieve knock-down of the target gene, leading to a transient window of increased cytotoxin sensitivity. The cytotoxin will gradually release from www.impactjournals.com/oncotarget the core into the cytoplasm, exerting its cytotoxic effects This nanocarrier would allow for the sequential delivery of therapeutic agents. In this manuscript, we report the development of a glycolipid-like nanocarrier based on chitosan (CS-ss-SA) for the co-delivery of a Bcl-2 specific siRNA (siBcl-2) and the hydrophobic antitumor drug paclitaxel (PTX). We demonstrate time dependent sequential drug delivery achieves synergetic effects and potentially can be used to treat drug resistant cell lines (Scheme 1)
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