International Journal of Nanomedicine (Mar 2022)

Dual pH-Responsive and Tumor-Targeted Nanoparticle-Mediated Anti-Angiogenesis siRNA Delivery for Tumor Treatment

  • Zhang X,
  • Qin B,
  • Wang M,
  • Feng J,
  • Zhang C,
  • Zhu C,
  • He S,
  • Liu H,
  • Wang Y,
  • Averick SE,
  • Vo NTN,
  • Huang L,
  • Liu W,
  • Wang Z

Journal volume & issue
Vol. Volume 17
pp. 953 – 967

Abstract

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Xiangyang Zhang,1 Bin Qin,1 Min Wang,1 Junyi Feng,1 Chenglin Zhang,1 Chengshen Zhu,2 Suqin He,2 Hao Liu,2 Yaohe Wang,1 Saadyah E Averick,3 Nga TN Vo,4 Lei Huang,5 Wentao Liu,2 Zhimin Wang1 1Sino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan Province, People’s Republic of China; 2School of Material Science and Engineering, Zhengzhou University, Zhengzhou, Henan Province, People’s Republic of China; 3Neuroscience Institute, Allegheny Health Network, Allegheny General Hospital, Pittsburgh, PA, USA; 4School of Engineering, Newcastle University, Newcastle Upon Tyne, NE1 7RU, UK; 5Inflammations Immunity Research Theme, Translational and Clinical Research Institute, FMS, Newcastle University, Newcastle Upon Tyne, NE1 7RU, UKCorrespondence: Zhimin Wang; Wentao Liu, Email [email protected]; [email protected]: In order to overcome the biological barriers at all levels and enhance the delivery efficiency of siRNA, we have prepared a multifunctional siRNA delivery system (CHCE/siRNA nanoparticles) through self-assembly of the carboxymethyl chitosan modified with histidine, cholesterol, and anti-EGFR antibody (CHCE).Methods: The morphology of CHCE/siRNA NPs was detected by dynamic light scattering and scanning electron microscope. In vitro, we assessed the tumor-targeting, cellular uptake, and endosomal escape by flow cytometry and confocal laser scanning microscopy, confirming the CHCE/siRNA NPs functions in gene silencing and cell killing ability. In vivo, we examined the biodistribution of the CHCE/siRNA NPs by the IVIS imaging system and confirmed the therapeutic effect of NPs in the nude-mouse tumor model.Results: The CHCE/siRNA NPs exhibited nanosized spherical with narrow size distribution. In vitro, the CHCE/siRNA NPs incorporated a dual capability of tumor targeting and pH response that could facilitate cellular bind, cellular uptake, and endosomal escape. The CHCE/siRNA NPs could effectively silence the vascular endothelial growth factor A (VEGFA) to cause cell apoptosis and inhibit proliferation. In vivo, the CHCE/siRNA NPs could target tumor sites to knock down VEGFA and achieve a better anti-tumor effect.Conclusion: We successfully prepared a novel siRNA delivery system with the double capability of tumor targeting and pH response, which can break through the biological barriers to penetrate deep into tumors and achieve better therapeutic tumor effects, providing a new ideal delivery platform for siRNA.Keywords: multifunctional carboxymethyl chitosan, targeting delivery, endosomal escape, gene silencing, anti-tumor therapy

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