Spatiotemporally controlled Pseudomonas exotoxin transgene system combined with multifunctional nanoparticles for breast cancer antimetastatic therapy.

Yi Cheng, Jiafeng Zou, Muye He, Xinyu Hou, Hongtao Wang, Jiajun Xu, Zeting Yuan, Minbo Lan, Yi Yang, Xianjun Chen, Feng Gao

Journal of controlled release : official journal of the Controlled Release Society 2024 Mar

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The tumor microenvironment is a barrier to breast cancer therapy. Cancer-associated fibroblast cells (CAFs) can support tumor proliferation, metastasis, and drug resistance by secreting various cytokines and growth factors. Abnormal angiogenesis provides sufficient nutrients for tumor proliferation. Considering that CAFs express the sigma receptor (which recognizes anisamide, AA), we developed a CAFs and breast cancer cells dual-targeting nano drug delivery system to transport the LightOn gene express system, a spatiotemporal controlled gene expression consisting of a light-sensitive transcription factor and a specific minimal promoter. We adopted RGD (Arg-Gly-Asp) to selectively bind to the αvβ3 integrin on activated vascular endothelial cells and tumor cells. After the LightOn system has reached the tumor site, LightOn gene express system can spatiotemporal controllably express toxic Pseudomonas exotoxin An under blue light irradiation. The LightOn gene express system, combined with multifunctional nanoparticles, achieved high targeting delivery efficiency both in vitro and in vivo. It also displayed strong tumor and CAFs inhibition, anti-angiogenesis ability and anti-metastasis ability, with good safety. Moreover, it improved survival rate, survival time, and lung metastasis rate in a mouse breast cancer model. This study proves the efficacy of combining the LightOn system with targeted multifunctional nanoparticles in tumor and anti-metastatic therapy and provides new insights into tumor microenvironment regulation. Copyright © 2023. Published by Elsevier B.V.

Citation

Yi Cheng, Jiafeng Zou, Muye He, Xinyu Hou, Hongtao Wang, Jiajun Xu, Zeting Yuan, Minbo Lan, Yi Yang, Xianjun Chen, Feng Gao. Spatiotemporally controlled Pseudomonas exotoxin transgene system combined with multifunctional nanoparticles for breast cancer antimetastatic therapy. Journal of controlled release : official journal of the Controlled Release Society. 2024 Mar;367:167-183