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

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.

STAT4 facilitates PD‐L1 level via IL‐12R/JAK2/STAT3 axis and predicts immunotherapy response in breast cancer

“…Photographs of scratches were taken after 24 and 48 h for generating statistics through ImageJ software. In Transwell assay, 1 × 10 5 transfected cells were suspended in 200 μL of serum‐free medium and were transplanted to the upper Transwell chamber (Corning, Inc., 0.8 μm pore) covered with Matrigel (Corning, Inc.) 47 . Complete medium of RPMI 1640 (500 μL) was added to the lower chamber.…”

“…In Transwell assay, 1 × 10 5 transfected cells were suspended in 200 μL of serum-free medium and were transplanted to the upper Transwell chamber (Corning, Inc., 0.8 μm pore) covered with Matrigel (Corning, Inc.). 47 Complete medium of RPMI 1640 (500 μL) was added to the lower chamber. After 24 h, the cells were washed with phosphatebuffered saline buffer, fixed with 4% paraformaldehyde, stained with 0.1% crystal violet and counted via ImageJ.…”

Microfluidic Droplet-Assisted Fabrication of Vessel-Supported Tumors for Preclinical Drug Discovery

“…Most drug candidates that pass the preclinical development fail in phase I clinical trials . Particularly, the accurate predictive ability of preclinical physiological models is one of the important factors affecting the efficiency of drug development. − In recent years, multicellular tumor spheroid has been increasingly used as in vitro model for drug screening assays. − Compared with the traditional two-dimensional (2D) cellular monolayer model, the three-dimensional (3D) spheroids can exhibit more similar in vivo physiological characteristics, including hypoxic core, pondus hydrogenii gradient distribution, cellular metabolism, and gene expression, thus providing a more realistic drug response . Accordingly, the manufacturing technology of tumor spheroids has also been continuously improved and developed. − Among them, droplet-based techniques stand out for their capability to generate uniform spheroids at a high-throughput manner. − As a relatively automated production method, microfluidic droplet technology breaks the device limitations of traditional well-array plates and can mass-produce identical tumor spheroids for drug screening in a time-dependent manner .…”

Polypyrrole Nanoenzymes as Tumor Microenvironment Modulators to Reprogram Macrophage and Potentiate Immunotherapy

“…[ 2 ] The altered redox stability not only contributes to tumor development and progression, but also increases the susceptibility of tumor cells to oxidative damage. [ 3 ] Therefore, the elevation of ROS in tumor microenvironment (TME) by ROS‐scavenging enzymes or increasing ROS generation presents a new era for tumor therapy.…”