Theranostics 2017; 7(14):3432-3445. doi:10.7150/thno.20297

Research Paper

The pH-Triggered Triblock Nanocarrier Enabled Highly Efficient siRNA Delivery for Cancer Therapy

Lili Du1*, Junhui Zhou2*, Lingwei Meng1, 3*, Xiaoxia Wang1, Changrong Wang2, Yuanyu Huang1, 4, Shuquan Zheng1, Liandong Deng2, Huiqing Cao1, Zicai Liang1, 5, Anjie Dong2, 5✉, Qiang Cheng1✉

1. Laboratory of Nucleic Acid Technology, Institute of Molecular Medicine, Peking University, Beijing 100871, China;
2. Department of Polymer Science and Technology, Key Laboratory of Systems Bioengineering of the Ministry of Education, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China;
3. Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China;
4. Advanced Research Institute for Multidisciplinary Science, Beijing Institute of Technology, Beijing 100081, China;
5. Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300072, China.
* These authors contributed equally to this work.

Abstract

Small interfering RNA (siRNA) therapies have been hampered by lack of delivery systems in the past decades. Nowadays, a few promising vehicles for siRNA delivery have been developed and it is gradually revealed that enhancing siRNA release from endosomes into cytosol is a very important factor for successful delivery. Here, we designed a novel pH-sensitive nanomicelle, PEG-PTTMA-P(GMA-S-DMA) (PTMS), for siRNA delivery. Owing to rapid hydrolysis in acidic environment, PTMS NPs underwent hydrophobic-to-hydrophilic transition in endosomes that enabled combination of proton sponge effect and raised osmotic pressure in endosomes, resulting in vigorous release of siRNAs from endosomes into cytosol. In vitro results demonstrated that PTMS/siRNA complexes exhibited excellent gene silencing effects in several cell lines. Their gene silencing efficiency could reach ~91%, ~87% and ~90% at the N/P ratio of 50/1 in MDA-MB-231, A549 and Hela cells respectively, which were better than that obtained with Lipofectamine 2000. The highly efficient gene silencing was then proven from enhanced siRNA endosomal release, which is mainly attributed to pH-triggered degradation of polymer and acid-accelerated siRNA release. In vivo experiments indicated that NPs/siRNA formulation rapidly accumulated in tumor sites after i.v. injection. Tumor growth was effectively inhibited and ~45% gene knockdown efficacy was determined at the siRRM2 dose of 1mg/kg. Meanwhile, no significant toxicity was observed during the whole treatment. We also found that PTMS/siRNA formulations could lead to significant gene silencing effects in liver (~63%) and skin (~80%) when injected by i.v. and s.c., respectively. This research work gives a rational strategy to optimize siRNA delivery systems for tumor treatments.

Keywords: siRNA delivery, pH-sensitive, endosomal escape, polymeric nanoparticles, cancer therapy.

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How to cite this article:
Du L, Zhou J, Meng L, Wang X, Wang C, Huang Y, Zheng S, Deng L, Cao H, Liang Z, Dong A, Cheng Q. The pH-Triggered Triblock Nanocarrier Enabled Highly Efficient siRNA Delivery for Cancer Therapy. Theranostics 2017; 7(14):3432-3445. doi:10.7150/thno.20297. Available from http://www.thno.org/v07p3432.htm