Codelivery of Que and BCL-2 siRNA with Lipid–Copolymer Hybrid Nanocomplexes for Efficient Tumor Regression

Abstract

The efficacy of chemotherapy is often reduced due to the chemotherapy resistance of tumor cells, which is usually caused by abnormal gene overexpression. Herein, multifunctional nanocomplexes (Que/siBCL2@BioMICs) were developed to deliver quercetin (Que) and BCL-2 siRNA (siBCL2) to synergistically inhibit tumor growth. The nanocomplexes were composed of an amphiphilic triblock copolymer of poly(ethylene glycol) methyl ether methacrylate−poly [2-(dimethylamino) ethyl acrylate]−polycaprolactone (PEGMA−PDMAEA−PCL) and 1,2-distearoyl-sn-glycero-3-phosphoethanolaminepoly(ethylene glycol)-biotin (DSPE−PEG−biotin). Que was encapsulated into the cores through hydrophobic interactions, while negatively charged siBCL2 was loaded through electrostatic interactions. The nanocomplexes could effectively facilitate cellular uptake via biotin-mediated active targeting and cytosolic release of cargos by the "proton sponge effect" of PDMAEA. Que/siBCL2@BioMICs achieved enhanced cytotoxicity and antimetastasis activity due to a synergistic effect of Que and siBCL2 in vitro. More importantly, superior anti-tumor efficacy was observed in orthotopic 4T1 tumor-bearing mice with reduced primary tumor burden and lung metastatic nodules, while no obvious side effects to major organs were observed. In conclusion, the biotin-targeted nanocomplexes with chemotherapeutic and nucleotide agent entrapment provide a promising strategy for efficient triple-negative breast cancer (TNBC) therapy.

Construction and in vitro evaluation of pH-sensitive nanoparticles to reverse drug resistance of breast cancer stem cells

“…Although the nano drug delivery system has shown excellent tumor targeted therapy effect. However, there are still limitations to our nanocarriers [ 45 ]. First, the loading efficiency of the carrier to the drug needs to be improved.…”

Self-Augmented Reactive Oxygen Species-Responsive Nanoformulation with Efficient Curcumin Delivery for Inhibiting Triple-Negative Breast Cancer Cell Growth and Migration

“…To prepare CURencapsulated ROS-responsive nanoparticles (CUR@Bio/PE-NPs), the thin film-hydration method was adopted as described everywhere. 31 Appropriate amounts of PEG-PE-PCL-PE-PEG and Bio-PEG-DSPE (10:1, w/w) were dissolved into 10 mL of DCM, and 10 mg of CUR in methanol (1 mg/mL) was added. The solvent was removed using a rotary evaporator at 40 °C.…”

Poly(2-(dimethylamino)ethyl methacrylate)-Grafted Amphiphilic Block Copolymer Micelles Co-Loaded with Quercetin and DNA

“…In order to overcome these limitations Que has been encapsulated into various nanocarriers including polymer micelles [ 36 ]. The codelivery of Que with antigen, proteins, or RNA using emulsions [ 37 ], liposomes [ 38 , 39 ], niosomes [ 40 ], lipid [ 41 ], and lipid-copolymer [ 42 ] nanoparticles has also been described. To the best of our knowledge, there are no reports in the literature concerning the development of micelleplexes intended for the codelivery of DNA and Que.…”