Research Article

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2019, 12(4): 889–896

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https://doi.org/10.1007/s12274-019-2319-6

Regulation of the cellular uptake of nanoparticles by the orientation of helical polypeptides

Chong Zhang1,2,§, Jianhua Lu1,2,§, Falin Tian3,§, Lindong Li1,4, Yingqin Hou1,2, Yaoyi Wang1,2, Lingdong Sun1,4 (*), Xinghua Shi3 (*), and Hua Lu1,2 (*)

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1 Beijing National Laboratory for Molecular Sciences, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China
2 Center for Soft Matter Science and Engineering, Key Laboratory of Polymer Chemistry and Physics of Ministry of Education, Peking University, Beijing 100871, China
3 CAS Key Laboratory of Nanosystem and Hierarchical Fabrication, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, China
4 State Key Laboratory of Rare Earth Materials Chemistry and Applications, PKU-HKU Joint Laboratory in Rare Earth Materials and Bioinorganic Chemistry, Peking University, Beijing 100871, China
§ Chong Zhang, Jianhua Lu, and Falin Tian contributed equally to this work.

Keywords: helix, orientation, polypeptides, cellular uptake, gold nanoparticles
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  • Abstract
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Controlling the cellular interaction and internalization of polymer-modified nanoparticles (NPs) is of central importance to the development of promising nanomedicines. Here, we describe the use of synthetic polypeptides for NP surface coating and regulation of their cellular uptake behaviors by simply switching the conformation and anchoring orientation. Our results show that gold NPs (AuNPs) coated with a helical poly(γ-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)esteryl L-glutamate) (L-P(EG3Glu)50) from the C-terminus ((L-C)-AuNPs) exhibit greater zeta potential and more cellular uptake (2.0–5.5 fold higher) than those coated with the same polypeptide but anchored from the N-terminus ((L-N)-AuNPs), or from both the C- and N-terminus at a 1/1 molar ratio ((L-C/L-N)-AuNPs). A similar orientation-regulated cellular internalization pattern is observed in D-P(EG3Glu)50 but not the unstructured DL-P(EG3Glu)50-modified AuNPs, suggesting an important and universal role of the helix-derived macrodipole in cellular uptake. Moreover, this orientation-governed internalization is successfully reproduced in P(EG3Glu)50-coated gold nanorods (AuNRs), and applied to the design of doxorubicin-loaded polypeptide micelles. Simulation study offers time-resolved insights regarding the NP–membrane interactions and membrane remodeling. Thus, our study provides a delicate way of regulating the surface chemistry of NPs and the subsequent NP–cell interactions. Moreover, the results highlight the uniqueness of polypeptides in NP surface engineering, and urge a more careful consideration on the polymer orientation effect.
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Regulation of the cellular uptake of nanoparticles by the orientation of helical polypeptides. Nano Res. 2019, 12(4): 889–896 https://doi.org/10.1007/s12274-019-2319-6

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