Lactate Consumption via Cascaded Enzymes Combined VEGF siRNA for Synergistic Anti-Proliferation and Anti-Angiogenesis Therapy of Tumors
| Autor: | Yu Wang, Chang-hao Jia, Xue-nong Zhang, Gui Huang, Yan Tang, Hui Li, Wen-jun Wan |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
chemistry.chemical_classification
Vascular Endothelial Growth Factor A Chemistry Angiogenesis Genetic enhancement Biomedical Engineering Pharmaceutical Science Mice Nude In vitro Biomaterials Vascular endothelial growth factor chemistry.chemical_compound Mice Enzyme In vivo Cell Line Tumor Neoplasms Cancer research Tumor Microenvironment Gene silencing Animals Nanoparticles Cationic liposome Lactic Acid RNA Small Interfering |
| Zdroj: | Advanced healthcare materials. 10(19) |
| ISSN: | 2192-2659 |
| Popis: | Lactate, as the most abundant component with concentrations of 4-40 mm in tumors, contributes to the regulation of metabolic pathways, angiogenesis, and immunosuppression, exhibiting remarkable potential in cancer treatment. Therefore, a codelivery strategy that combined the cascaded enzymes Lactate oxidase/Catalase (LOx/CAT) and vascular endothelial growth factor (VEGF) siRNA (siVEGF) to suppress tumor proliferation and angiogenesis synergistically is creatively proposed. In brief, the cationic liposomes (LIP) encapsulated with LOx/CAT and siVEGF via hydrophilic interaction and electrostatic adsorption followed by coating with PEGylated phenylboronic acid (PP) is established (PPL@[LOX+CAT]). Moreover, a simple 3-aminophenylboronic acid (PBA)-shielded strategy via fructose (Fru) is applied to further enhance the targeting efficiency in the tumor site. The obtained co-encapsulated nanoparticles (NPs) can simultaneous intracellular release of LOx/CAT and siVEGF, and the collaborative use of LOx and CAT can promote lactate consumption even under a hypoxic tumor microenvironment (TME) without producing systemic toxicity. The combined application of lactate depletion and VEGF silencing demonstrated the efficient migration suppression of 4T1 cells in vitro and superior antitumor and antimetastatic properties in vivo. This work offers a promising tumor treatment strategy via integrating cascaded enzymes and gene therapy, and explores a promising therapy regimen for 4T1 triple-negative breast cancer. |
| Databáze: | OpenAIRE |
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