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Intravital Microscopy of Tumor-associated Vasculature Using Advanced Dorsal Skinfold Window Chambers on Transgenic Fluorescent Mice
Published on: January 19, 2018
Exploiting eNOS activation to achieve tumor vascular normalization via endothelial transcytosis of lipid
Huisong Hao1, Yunfei Yi1,2, Yanan Fu1
1School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China.
Abstract:
Abnormal tumor vasculature greatly accelerates tumor progression and diminishes antitumor treatments. Restoring perivascular NO gradients is available to maintain tumor vessel homeostasis and promote tumor vascular normalization. However, exogenously delivering NO strategies lacks the durability to maintain precise NO localization around tumor vessels. Herein, we design a lipid nano delivery system (MC@L) and exploit endothelial transcytosis to deliver metformin (Met) and CaO2 into tumor vascular endothelial cells (ECs) and tumor cells for achieving tumor vascular normalization-boosted antitumor immunotherapies. The Ca2+ and Met released in ECs could restore perivascular localization of NO by activating endothelial NOS (eNOS). Additionally, MC@L internalized by tumor cells could cause CaO2-induced immunogenic cell death (ICD), together with hypoxia relief and acid neutralization mediated by O2 generation and H+ consumption during CaO2 degradation, thus further improving the immune effector cell functions under the accompaniment of Met-mediated inhibition of tryptophane uptake in tumor cells. Such a lipid nano delivery system greatly increases the susceptibility of 4T1 tumor-bearing mice to PD-L1 blockade efficacy.
Insights
This study introduces a novel lipid nanodelivery system (MC@L) that restores nitric oxide (NO) levels in tumor vasculature. This approach enhances tumor vascular normalization and boosts the efficacy of immunotherapy in preclinical models.
Area of Science:
- Biomedical Engineering
- Cancer Research
- Nanotechnology
Background:
- Abnormal tumor vasculature accelerates cancer progression and hinders treatment efficacy.
- Restoring perivascular nitric oxide (NO) gradients is crucial for tumor vascular normalization.
- Current NO delivery methods lack durability and precise localization.
Purpose of the Study:
- To develop a lipid nanodelivery system (MC@L) for co-delivering metformin and calcium peroxide (CaO2) to normalize tumor vasculature.
- To enhance anti-tumor immunotherapies by improving tumor microenvironment and immune cell function.
Main Methods:
- MC@L system designed for endothelial transcytosis to deliver metformin and CaO2 into endothelial cells and tumor cells.
- Investigated CaO2-induced immunogenic cell death (ICD) and its effects on tumor microenvironment (hypoxia, acidity).
- Assessed metformin's role in restoring NO gradients and inhibiting tryptophan uptake.
Main Results:
- MC@L restored perivascular NO localization by activating endothelial nitric oxide synthase (eNOS).
- CaO2 induced ICD in tumor cells, relieved hypoxia, and neutralized acidity.
- Metformin enhanced immunogenic cell death and inhibited tryptophan uptake, improving immune effector cell function.
- The nanodelivery system significantly sensitized 4T1 tumor-bearing mice to PD-L1 blockade therapy.
Conclusions:
- The MC@L system effectively normalizes tumor vasculature and enhances anti-tumor immunity.
- This nanodelivery strategy represents a promising approach for combination cancer therapy.
- MC@L boosts immunotherapy efficacy by modulating the tumor microenvironment and cellular metabolism.
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