Editors' ChoiceNanomedicine

Trojan siRNA Opens the Door to Chemotherapy

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Science Translational Medicine  13 Nov 2013:
Vol. 5, Issue 211, pp. 211ec186
DOI: 10.1126/scitranslmed.3007978

Triple-negative breast cancer (TNBC) is resistant to most chemotherapeutic agents because it does not express estrogen receptor, progesterone receptor, or Her2/neu (hence, “triple-negative”). Unfortunately, most chemotherapies target one of these three receptors, making the treatment of TNBC a major clinical challenge. A new study by Deng et al. describes nanoparticles assembled from different layers of polymers for sequential delivery of small interfering RNA (siRNA), which first disables a drug-resistance pathway in tumors. After this siRNA “Trojan horse,” a chemotherapeutic agent can be released to kill the unsuspecting cancer cells.

Nanoparticles encapsulating the chemotherapeutic doxorubicin were coated with a poly-l-arginine (PLA) layer containing siRNA, followed by an outer shell layer of hyaluronic acid (HA). The particles were engineered to first release the siRNA payload targeting multidrug resistant protein 1 (MRP1), to disable tumor resistance, followed by doxorubicin, to kill the tumor cells. Together, these two layers worked to protect, target, and release the cargo more slowly over time than would a typical intravenous injection. The PLA layer enabled high siRNA loading of up to 3500 siRNA molecules per particle, with enhanced stability, better silencing efficiency, and lower cytotoxicity as compared with other polycationic materials, while the HA layer prolonged the circulation time and provided tumor-targeting by serving as a native ligand to CD44—a marker overexpressed in TNBC. Three tail vein injections of these combo nanoparticles every 5 days in human tumor-bearing mice showed significant tumor regression, whereas control animals with TNBC receiving either doxorubicin liposomes with scramble-sequenced siRNA, empty liposomes with MRP1 siRNA, or saline resisted treatment.

siRNA against MRP1 was chosen on the basis of an in vitro screen using the human TNBC cell line, MDA-MB-468, and was tested in a xenografted human tumor model, suggesting that this approach could be translated to use in people. Harnessing synergistic gene therapy and chemotherapy along with smart nanomaterials paves the way for the treatment of such aggressive cancers. However, the authors still need to examine the long-term safety, dosing, and clinical effectiveness of this platform technology. Following these studies, the system can be adapted to treat many other cancer types by substituting the drug, the siRNA, and the surface particles to target and combat tumor cells in a personalized manner.

Z. J. Deng et al., Layer-by-layer nanoparticles for systemic codelivery of an anticancer drug and siRNA for potential triple-negative breast cancer treatment, ACS Nano, published online 21 October 2013 (10.1021/nn4047925).[Abstract]

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