Drug Nanorod-Mediated Intracellular Delivery of microRNA-101 for Self-sensitization via Autophagy Inhibition

Abstract

Abstract Autophagy is closely related to the drug resistance and metastasis in cancer therapy. Nanoparticle-mediated co-delivery of combinatorial therapy with small-molecular drugs and nucleic acids is promising to address drug resistance. Here, a drug-delivering-drug (DDD) platform consisting of anti-tumor-drug nanorods as a vehicle for cytosol delivery of nucleic acid (miR-101) with potent autophagic-inhibition activity is reported for combinatorial therapy. The developed 180-nm nanoplatform, with total drug loading of up to 66%, delivers miR-101 to cancer cells, with threefold increase in intracellular level compared to conventional gene carriers and inhibits the autophagy significantly, along with above twofold reduction in LC3II mRNA and approximately fivefold increase in p62 mRNA over the control demonstrated in the results in vivo. And in turn, the delivery of miR-101 potentiates the drug’s ability to kill cancer cells, with a threefold increase in apoptosis over that of chemotherapy alone. The anti-tumor study in vivo indicates the combined therapy that enables a reduction of 80% in tumor volume and > twofold increase in apoptosis than of the single-drug strategy. In summary, via the carrier-free strategy of DDD, this work provides a delivery platform that can be easily customized to overcome drug resistance and facilitates the delivery of combined therapy of small-molecular drugs and nucleic acids.

Keywords

• Nanocrystals
• MicroRNA delivery
• Autophagy inhibition
• Cytotoxicity
• Combinatorial therapy