Drug Nanorod-Mediated Intracellular Delivery of microRNA-101 for Self-sensitization via Autophagy Inhibition
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ARTICLE
Cite as Nano-Micro Lett. (2019) 11:82 Received: 10 July 2019 Accepted: 30 August 2019 © The Author(s) 2019
https://doi.org/10.1007/s40820-019-0310-0
Drug Nanorod‑Mediated Intracellular Delivery of microRNA‑101 for Self‑sensitization via Autophagy Inhibition Xiaofei Xin1, Xiaoqing Du1, Qingqing Xiao1, Helena S. Azevedo2, Wei He1 *, Lifang Yin1 * * Wei He, [email protected]; Lifang Yin, [email protected] Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, People’s Republic of China 2 School of Engineering and Materials Science, Institute of Bioengineering, Queen Mary, University of London, London E1 4NS, UK 1
HIGHLIGHTS • Nanosized cytotoxic drug could combat against the autophagy induced by the drug. • The drug nanorods enabled efficient intracellular delivery of the nucleic acid and the resultant autophagy inhibition in vitro and in vivo, which in turn sensitized the cancer cells to the anti-tumor nanorods.
ABSTRACT Autophagy is closely
related to the drug resistance and metastasis in cancer therapy. Nanoparticlemediated 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 (miR101) 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 Vol.:(0123456789)
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1 Introduction Despite the significant progress achieved in targeted therapies, the development of drug resistance has emerged as the next challenge for effective therapy in diverse diseases, such as tuberculosis, microbial infections and in particular cancer [1, 2]. For cancer chemotherapies, the major mechanisms of drug resistance include increased metabolic activation, elevated expression of the drug target, changed target or pathway to decrease sensitivity, reduced uptake by overexpressed efflux transpo
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