Lactate Consumption via Cascaded Enzymes Combined VEGF siRNA for Synergistic Anti‐Proliferation and Anti‐Angiogenesis Therapy of Tumors

Abstract

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.

Aggregation-Induced Emission Nanoparticles for Single Near-Infrared Light-Triggered Photodynamic and Photothermal Antibacterial Therapy

“…It is noteworthy that wound-related infections commonly induce impaired and insufficient blood vessels, which hamper the transportation of immune cells to wound sites and slow down tissue regeneration. VEGF has a significant role in promoting vascular endothelial cell proliferation and boosting angiogenesis. , The VEGF expression was significantly downregulated in the control groups, while it was dramatically overexpressed in the AIE NPs + laser groups (Figure C). Notably, CD31 is a typical biomarker that could influence the regulation of angiogenesis.…”

Co-Delivery of Repurposing Itraconazole and VEGF siRNA by Composite Nanoparticulate System for Collaborative Anti-Angiogenesis and Anti-Tumor Efficacy against Breast Cancer

“…The formation and development of endothelial cell capillary structure is a multistep process, which involving cell adhesion, migration, differentiation and growth [ 31 ]. Cancer cells can secrete various inducers into the microenvironment to regulate angiogenesis [ 32 ], we investigated the in vitro antiangiogenesis of HUVEC cells when nanoparticles were directly treated with HUVEC cells and when nanoparticles were cultured with 4T1 cells. First, to assess the direct angiogenetic inhibitory effect of the various nanoparticles, HUVECs were co-cultured with the nanoparticles and plated onto Matrigel for 24 h.…”

“…To investigate 4T1-related endothelial tube formation and angiogenesis efficiency, the 4T1 cells were seeded into 6-well plates and cultured for 24 h at a density of 1 × 10 4 cells per well [ 32 ]. Then, the cells were treated and transfected with different formulations of NPs (N/P = 30, C/N = 1/5; ITZ: 8.28%) at 100 nM VEGF siRNA and cultured for 24 h. Their media were called “conditioned medium”.…”

Nanomaterials: small particles show huge possibilities for cancer immunotherapy

“…Researchers have tried to achieve the above problem by introducing LOX (lactate oxidase) that can consume lactate, but the process of LOX catalyzing lactate to pyruvate requires oxygen consumption [ 194 ]. On the one hand, the hypoxic environment of tissues limits the action of LOX, and on the other hand, the oxygen-consuming property aggravates the lactate accumulation in tumor tissues [ 195 , 196 ]. To break the deadly cycle of LOX-catalyzed lactate, Dong et al [ 197 ] loaded Cu 2+ and LOX onto mPDA (mesoporous polydopamine nanoparticles) by ligand and electrostatic adsorption.…”