Tumor Microenvironment-Specific Chemical Internalization for Enhanced Gene Therapy of Metastatic Breast Cancer.

Yun Zhou,Mian Yu,Chenyi Huang,Hairong Zheng,Meiying Wu,Junqing Wang,Lin Mei,Yang Deng,Changjun Tie,Fan Zhang,Yunfei Yi

doi:10.34133/2021/9760398

Abstract

Benefiting from treating diseases at the genetic level, gene therapy has been considered a new revolution in the biomedical field. However, the extracellular and intracellular barriers during gene transport such as enzymatic degradation and endo-/lysosomal sequestration significantly compromise the therapeutic efficacy. Though photochemical internalization (PCI) has emerged as a promising approach for causing endo-/lysosomal leakage with translocation of the internalized molecules into the cytosol, its effect is still unsatisfactory due to the insufficient light penetration depth. Here, we develop tumor microenvironment-specific enhanced gene delivery by means of ROS generated from the in situ cascaded catalytic reactions in tumors involving GOx-mediated redox reaction and Mn2+-mediated Fenton-like reaction. The efficient enzymatic protection and successful endo-/lysosomal escape of cargo gene complexes have been demonstrated. Moreover, anti-Twist siRNA-loaded G@MMSNs-P exhibit tumor-specific biodegradation, excellent T1-weighted MR imaging, and significant inhibitory effects against breast cancer growth and pulmonary metastasis.

Highlights

Gene therapy has emerged as an attractive technique for treating various genetic and acquired disorders [1,2,3], which is implemented by transporting therapeutic nucleic acids into cells to correct or modify a specific genetic target responsible for the manifestation of a disease [4]
tumor microenvironment (TME)-triggered enhanced chemical internalization was successfully realized by taking full advantage of the specific TME, which was significantly different from Photochemical internalization (PCI)
The constructed GR@MMSNs-P could remarkably elevate reactive oxygen species (ROS) production due to the cascaded catalytic reactions involving Glucose oxidase (GOx)-mediated redox reaction and Mn2+-mediated Fentonlike reaction, which was independent of exogenous laser irradiation

Summary

Introduction

Gene therapy has emerged as an attractive technique for treating various genetic and acquired disorders [1,2,3], which is implemented by transporting therapeutic nucleic acids into cells to correct or modify a specific genetic target responsible for the manifestation of a disease [4]. Numerous nonviral vectors have been substantially advanced to overcome the extracellular and intracellular barriers during gene transport [8, 9], such as enzymatic degradation [10], cellular internalization [11], and endo-/lysosomal sequestration [12]. The gene transfection efficiencies of these vectors are still not satisfactory, hindering their further application. Photochemical internalization (PCI), a spatiotemporally controllable technology [13], has been developed for enhancing cytosolic release of trapped molecules in endocytic vesicles by photochemical disruption of the endo-/lysosomal membrane using light and photosensitizers [14,15,16]. PCI has exhibited significant improvement in gene transfection efficiency, its clinical application is limited by the insufficient light penetration depth. Chemodynamic therapy (CDT) is a newly developed tumor therapeutic modality that could convert intracellular hydrogen peroxide (H2O2) into highly toxic ROS through the Research

Methods

Results

Conclusion