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Regulation of pathological BBB restoration via nanostructured ROS-responsive glycolipid-like copolymer entrapping siVEGF for glioblastoma targeted therapeutics

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Abstract

Glioblastoma (GBM) is one of the malignant brain tumors with high mortality and no curative treatments. Abnormally elevated vascular endothelial growth factor (VEGF) in GBM seriously disrupts the blood brain barrier (BBB) with an increased permeability, resulting in poor outcome and prognosis. RNAi interference has shown strong potential to inhibit VEGF expression, thus it is necessary to development an effective and safe gene delivery system possessing the ability to cross the BBB and target GBM cells. This study aims to explore the anti-GBM effect of angiopep-2 (Ap) peptide modified reactive oxygen species (ROS) cleavable thioketal (TK) linked glycolipid-like nanocarrier (CSTKSA) delivering anti-VEGF siRNA (R), termed as Ap-CSTKSA/R complexes. Ap functionalized modification produced an enhanced cellular uptake and a stronger bio-distribution of Ap-CSTKSA/R complexes in U87 MG cells and brain tumor tissues, respectively. Ap-CSTKSA/R complexes exhibited great superiority in GBM growth inhibition and finally translated into the longest survival period mainly via receptor-mediated targeting delivery, VEGF gene silencing accompanied with remarkable angiogenesis inhibition, and suppressed expression of caveolin-1 which is involved in BBB functional regulation in the occurrence and treatment of GBM. The study indicated that Ap functionalization on ROS-responsive glycolipid-like copolymer exhibits a promising and effective gene delivery platform for GBM targeted treatment.

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Acknowledgements

We thank Mrs. Wei Yin (Core Facilities, School of Medicine, Zhejiang University) for her assistance with confocal microscopy. The research was supported by the National Natural Science Foundation of China (No. 81973267), the National Science Foundation of Zhejiang Province, China (No. D19H30001), the Project of Gannan Medical University (No. ZD201903), and the PhD Start-up Fund of Gannan Medical University (No. QD201908).

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Authors and Affiliations

  1. National Engineering Research Center for Modernization of Tranditional Chinese Medicine-Hakka Medical Resources Branch, College of Pharmacy, Gannan Medical University, Ganzhou, 341000, China

    Lijuan Wen, Yu Peng, Shiying He, Ruiwen Xiong & Longping Wu

  2. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China

    Lijuan Wen, Kai Wang & Fuqiang Hu

  3. Department of Orthopedics, First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, China

    Fengtian Zhang

  4. Department of Orthopedics, Second Affiliated Hospital of Soochow University, Suzhou, 215004, China

    Fengtian Zhang

  5. Gannan Medical University, Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases of Ministry of Education, Ganzhou, 341000, China

    Lijuan Wen & Zhihua Huang

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  1. Lijuan Wen
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  2. Yu Peng
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  3. Kai Wang
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  8. Fengtian Zhang
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  9. Fuqiang Hu
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Correspondence to Fengtian Zhang or Fuqiang Hu.

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12274_2021_3686_MOESM1_ESM.pdf

Regulation of pathological BBB restoration via nanostructured ROS-responsive glycolipid-like copolymer entrapping siVEGF for glioblastoma targeted therapeutics

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Wen, L., Peng, Y., Wang, K. et al. Regulation of pathological BBB restoration via nanostructured ROS-responsive glycolipid-like copolymer entrapping siVEGF for glioblastoma targeted therapeutics. Nano Res. 15, 1455–1465 (2022). https://doi.org/10.1007/s12274-021-3686-3

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