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

被引：6

作者：

Han, Tian-Yan ^{[1
]}

Huan, Meng-Lei ^{[1
]}

Cai, Zedong ^{[1
]}

He, Wei ^{[2
]}

Zhou, Si-Yuan ^{[1
,3
]}

Zhang, Bang-Le ^{[1
,3
]}

机构：

[1] Fourth Mil Med Univ, Sch Pharm, Dept Pharmaceut, Xian 710032, Peoples R China

[2] Fourth Mil Med Univ, Sch Pharm, Dept Chem, Xian 710032, Peoples R China

[3] State Adm Tradit Chinese Med, Key Lab Pharmacol, Xian 710032, Peoples R China

来源：

ADVANCED HEALTHCARE MATERIALS | 2023年 / 12卷 / 32期

基金：

中国国家自然科学基金;

关键词：

caveolae-mediated endocytosis; GSH-response release; miR-34a delivery system; triple negative breast cancer; SIRNA DELIVERY; INTRACELLULAR TRAFFICKING; NANOPARTICLES; EXPRESSION; STRATEGIES;

D O I：

10.1002/adhm.202302094

中图分类号：

R318 [生物医学工程];

学科分类号：

0831 ;

摘要：

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. A nonviral vector PEI-SPDP-Man (PSM) that can simultaneously target cellular uptake pathway and intracellular responsive release for miR-34a is developed. The prepared PSM/miR-34a gene delivery system can induce and enter to tumor cells through caveolae-mediated endocytosis for the effective treatment of orthotopic TNBC. This strategy to control intracellular transport pathway is useful in the gene therapy.image

引用

页数：13