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Enhanced endosomal escape of dendrigraft poly-L-lysine polymers for the efficient gene therapy of breast cancer

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Abstract

Dendrimer, such as dendrigraft poly-L-lysine (DGL) polymers, with high surface charge density, well-defined structure, and narrow poly-dispersity is often employed as a gene vector, but its transfection efficiency is still partially inhibited due to poor endosomal escape ability. Herein, we used a surface modification strategy to enhance the endosomal escape ability of DGL polymers, and thus improved its gene transfection efficiency. A library of phenylboronic acid (PBA) modified DGL polymers (PBA-DGLs) was designed to screen efficient small interfering RNA (siRNA) vectors. The lead candidate screened from the library shown a capability of inducing nearly 90% gene silencing in MDA-MB-231 cells. The study of the transfection mechanism revealed that PBA modification not only improves siRNA cellular uptake, but, more importantly, endows DGL polymers the ability of endosomal escape. One of the top candidates from polyplexes was further shielded with hyaluronic acid to construct targeted nanoparticles, and the yielding nanoparticles significantly suppressed the tumor growth in a breast cancer model by effective siRNA delivery. This research provides a general and effective strategy to enhance the endosomal escape and transfection efficiency of dendrimer.

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Acknowledgements

We appreciate the grants from the National Natural Science Foundation of China (Nos. 81771968, 21704061, and 82003166), Natural Science Foundation of Shanghai (No. 21ZR1439200), Shanghai Sailing Program (No. 17YF1411000), Shanghai Municipal Education Commission-Gaofeng Clinical Grant Support (No. 20181705), Shanghai Municipal Commission of Health and Family Planning (No. 201840020). and the Medical-Engineering Joint Funds from the Shanghai Jiao Tong University (Nos. ZH2018ZDA05 and YG2016QN54).

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  1. Li Ye, Hongmei Liu, and Xin Fei contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China

    Li Ye, Hongmei Liu, Qianyun Tang & Peifeng Liu

  2. Central Laboratory, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China

    Hongmei Liu, Xin Fei, Ding Ma, Xiaozhen He, Xue Zhao, Hanbing Zou, Xiaojing Chen, Xianming Kong & Peifeng Liu

  3. Shanghai University of Medicine and Health Sciences, Shanghai, 201318, China

    Xianming Kong

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  1. Li Ye
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Correspondence to Xianming Kong or Peifeng Liu.

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Ye, L., Liu, H., Fei, X. et al. Enhanced endosomal escape of dendrigraft poly-L-lysine polymers for the efficient gene therapy of breast cancer. Nano Res. 15, 1135–1144 (2022). https://doi.org/10.1007/s12274-021-3616-4

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