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

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.

Tumor targeted combination therapeutic system for the effective treatment of drug resistant triple negative breast cancer.

Breast cancer has become the malignant tumor with the largest incidence, especially the drug resistant triple negative breast cancer (TNBC). The combination therapeutic system can play a better role in resisting drug resistant TNBC. In this study, dopamine and tumor targeted folic acid modified dopamine were synthesized as carrier materials to construct melanin-like tumor targeted combination therapeutic system. The optimized nanoparticles of CPT/Fe@PDA-FA10 with efficient loading of camptothecin and iron was achieved, which showed tumor targeted delivery ability, pH sensitive controlled release, effective photothermal conversion performance and excellent anti-tumor efficacy in vitro and in vivo. CPT/Fe@PDA-FA10 plus laser could significantly kill the drug resistant tumor cells, inhibit the growth of the orthotopic drug resistant triple negative breast cancer through apoptosis/ferroptosis/photothermal treatment, and had no significant side effects on the main tissues and organs. This strategy provided a new idea for the construction and clinical application of triple-combination therapeutic system as effective treatment for drug resistant triple negative breast cancer.

Rational design of a new near-infrared fluorophore and apply to the detection and imaging study of cysteine and thiophenol.

The development of a near-infrared fluorophore with excellent fluorescence performance, a large Stokes shift, and good biocompatibility has become a focus in the field of fluorescence imaging in recent years. Based on quantum chemistry calculations and reasonable molecular design strategies, a new NIR fluorophore was developed and characterized by simple synthesis, easy structural modification, and a large Stokes shift (105 nm). Furthermore, two new "activatable" fluorescent probes QN-Cys and QN-DNP were synthesized using a simple structural modification. The probe QN-Cys can recognize Cys with high sensitivity (LOD = 128 nM) and high selectivity, and its fluorescence intensity has a good linear relationship with the Cys concentration in the range of 5-35 µM. Furthermore, probe QN-Cys can effectively distinguish Cys from Hcy and GSH, and was successfully applied to the detection and imaging of Cys in human serum, cells, and zebrafish. The probe QN-DNP showed a good specific and sensitive (LOD = 78 nM) fluorescence response to thiophenol, and its fluorescence intensity has a good linear relationship with the thiophenol concentration in the range of 5-30 µM. Furthermore, it was successfully applied to detect thiophenol in real water samples with good recoveries (97-102%), and image thiophenol in living cells, zebrafish and mice. Notebly, the QN-DNP probe could be applied to visualize the distribution of thiophenol in the mice.