A Nanocarrier that Enables Co-Delivery of Chemotherapy and siRNA Agents
Tumor cells exhibit drug resistant phenotypes that decrease the efficacy of chemotherapeutic treatments. The drug resistance has a genetic basis that is caused by an abnormal gene expression. There are several types of drug resistance: efflux pumps reducing the cellular concentration of the drug, alterations in membrane lipids that reduce cellular uptake, increased or altered drug targets, metabolic alteration of the drug, inhibition of apoptosis, repair of the damaged DNA, and alteration of the cell cycle checkpoints. siRNA is used to silence the drug resistant phenotype and prevent this drug resistance response. Of the listed types of drug resistance, pump-type resistance and apoptosis inhibition are the most frequently targeted for gene silencing. The co-delivery of siRNA and chemotherapeutic drugs has a synergistic effect, but many of the current projects do not control the drug release from the nanocarrier. This means the drug payload is released before the drug resistance proteins have degraded and the drug resistance phenotype has been silenced. Current research focuses on cross-linking the carrier's polymers to prevent premature drug release, but these carriers still rely on environmental cues to release the drug payload, and the drug may be released too early. In our study, we designed a poly(lactic acid)-b-poly(ethylene glycol)-folic acid + poly(lactic acid)-b-poly(ethylenimine) with a disulfide linker (PLA-PEG-FA+PLA-S-S-PEI) co-micellar, polymeric carrier that incorporates a gold nanorod to trigger the release of chemotherapeutic agents by near-infrared exposure. The disulfide bond is cleaved after the nanocarrier enters the lysosome and is exposed to reducing agent glutathione; at this point, the PEI and siRNA are released. After the siRNA silences the drug resistant phenotype, the gold nanorod is thermally excited by near-infrared light, and this temperature increase allows the chemotherapeutic drug to escape from the leaky poly(lactic acid) core, which is at a temperature above the PLA glass transition temperature ( ~60°C). With this method, the drug release can be triggered after the drug resistance phenotype is most heavily silenced.
Won, Purdue University.
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