Theranostics 2017; 7(7):1990-2002. doi:10.7150/thno.18136

Research Paper

Surface De-PEGylation Controls Nanoparticle-Mediated siRNA Delivery In Vitro and In Vivo

Xi Zhu1, 2*, Wei Tao1*, Danny Liu1, 3, Jun Wu1, 4, Zilei Guo1, Xiaoyuan Ji1, Zameer Bharwani1, Lili Zhao1, 5, Xiaoping Zhao2, Omid C. Farokhzad1, 6✉, Jinjun Shi1✉

1. Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA;
2. National Shanghai Center for New Drug Safety Evaluation and Research, Shanghai, 201203, China;
3. Department of Chemistry, University of Waterloo, Waterloo, Ontario N2L 3G1, Canada;
4. Department of Biomedical Engineering, School of Engineering, Sun Yet-sen University, Guangzhou, 510006, China;
5. Department of Endoscopy, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, 210029, China;
6. King Abdulaziz University, Jeddah 21589, Saudi Arabia.
* X.Z. and W.T. contributed equally to this work.


The present work proposes a unique de-PEGylation strategy for controllable delivery of small interfering RNA (siRNA) using a robust lipid-polymer hybrid nanoparticle (NP) platform. The self-assembled hybrid NPs are composed of a lipid-poly(ethylene glycol) (lipid-PEG) shell and a polymer/cationic lipid solid core, wherein the lipid-PEG molecules can gradually dissociate from NP surface in the presence of serum albumin. The de-PEGylation kinetics of a series of different lipid-PEGs is measured with their respective NPs, and the NP performance is comprehensively investigated in vitro and in vivo. This systematic study reveals that the lipophilic tails of lipid-PEG dictate its dissociation rate from NP surface, determining the uptake by tumor cells and macrophages, pharmacokinetics, biodistribution, and gene silencing efficacy of these hybrid siRNA NPs. Based on our observations, we here propose that lipid-PEGs with long and saturated lipophilic tails might be required for effective siRNA delivery to tumor cells and gene silencing of the lipid-polymer hybrid NPs after systemic administration.

Keywords: de-PEGylation, nanoparticle, self-assembly, siRNA delivery, cancer therapy.

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How to cite this article:
Zhu X, Tao W, Liu D, Wu J, Guo Z, Ji X, Bharwani Z, Zhao L, Zhao X, Farokhzad OC, Shi J. Surface De-PEGylation Controls Nanoparticle-Mediated siRNA Delivery In Vitro and In Vivo. Theranostics 2017; 7(7):1990-2002. doi:10.7150/thno.18136. Available from