Polymer-Initiating Caveolae-Mediated Endocytosis and GSH-Responsive MiR-34a Gene Delivery System for Enhanced Orthotopic Triple Negative Breast Cancer Therapy.

Autor: Han TY; Department of Pharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China., Huan ML; Department of Pharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China., Cai Z; Department of Pharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China., He W; Department of Chemistry, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China., Zhou SY; Department of Pharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China.; Key Laboratory of Pharmacology of the State Administration of Traditional Chinese Medicine, Xi'an, 710032, China., Zhang BL; Department of Pharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China.; Key Laboratory of Pharmacology of the State Administration of Traditional Chinese Medicine, Xi'an, 710032, China.
Jazyk: angličtina
Zdroj: Advanced healthcare materials [Adv Healthc Mater] 2023 Dec; Vol. 12 (32), pp. e2302094. Date of Electronic Publication: 2023 Oct 27.
DOI: 10.1002/adhm.202302094
Abstrakt: Gene therapy based on miRNAs has broad application prospects in the treatment of tumors. However, due to degradation and ineffective release during intracellular transport, current gene delivery vectors used for miRNAs limited their actual transfection efficiency. This study develops a novel nonviral vector PEI-SPDP-Man (PSM) that can simultaneously target cellular uptake pathways and intracellular responsive release for miR-34a. PSM is synthesized by connected mannitol (Man) to branched polyethylenimine (PEI) using a disulfide bond. The prepared PSM/miR-34a gene delivery system can induce and enter to tumor cells through caveolae-mediated endocytosis to reduce the degradation of miR-34a in lysosomes. The disulfide bond is sensed at high concentration of glutathione (GSH) in the tumor cells and miR-34a is released, thereby reducing the expression of Bcl-2 and CD44 to suppress the proliferation and invasion of tumor cells. In vitro and in vivo experiments show that through the targeted cellular uptake and the efficient release of miR-34a, an effective antitumor and antimetastasis profiles for the treatment of orthotopic triple negative breast cancer (TNBC) are achieved. This strategy of controlling intracellular transport pathways by targeting cellular uptake pathways in the gene therapy is an approach that could be developed for highly effective cancer therapy.
(© 2023 Wiley-VCH GmbH.)
Databáze: MEDLINE
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