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Delivery system for DNAzymes using arginine-modified hydroxyapatite nanoparticles for therapeutic application in a nasopharyngeal carcinoma model

Authors Chen Y, Yang L, Huang S, Li Z, Zhang L, He J, Xu Z, Liu L, Cao Y, Sun L

Received 15 May 2013

Accepted for publication 30 June 2013

Published 14 August 2013 Volume 2013:8(1) Pages 3107—3118


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Video abstract presented by Lifang Yang

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Yan Chen,1 Lifang Yang,1,2 Suping Huang,3 Zhi Li,1 Lu Zhang,1 Jiang He,1 Zhijie Xu,2 Liyu Liu,2 Ya Cao,2 Lunquan Sun1

1Center for Molecular Medicine, Xiangya Hospital, 2Cancer Research Institute, 3State Key Laboratory of Powder Metallurgy, Central South University, Changsha, People's Republic of China

Abstract: DNAzymes are synthetic, single-stranded, catalytic nucleic acids that bind and cleave target mRNA in a sequence-specific manner, and have been explored for genotherapeutics. One bottleneck restricting their application is the lack of an efficient delivery system. As an inorganic nanomaterial with potentially wide application, nanohydroxyapatite particles (nHAP) have attracted increasing attention as new candidates for nonviral vectors. In this study, we developed an nHAP-based delivery system and explored its cellular uptake mechanisms, intracellular localization, and biological effects. Absorption of arginine-modified nanohydroxyapatite particles (Arg-nHAP) and DZ1 (latent membrane protein 1 [LMP1]-targeted) reached nearly 100% efficiency under in vitro conditions. Using specific inhibitors, cellular uptake of the Arg-nHAP/DZ1 complex was shown to be mediated by the energy-dependent endocytosis pathway. Further, effective intracellular delivery and nuclear localization of the complex was confirmed by confocal microscopy. Biologically, the complex successfully downregulated the expression of LMP1 in nasopharyngeal carcinoma cells. In a mouse tumor xenograft model, the complex was shown to be delivered efficiently to tumor tissue, downregulating expression of LMP1 and suppressing tumor growth. These results suggest that Arg-nHAP may be an efficient vector for nucleic acid-based drugs with potential clinical application.

Keywords: hydroxyapatite nanoparticles, DNAzymes, latent membrane protein 1, transfection efficiency, cellular uptake

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