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Advanced healthcare materials: jet lagged nanoparticles reshape tumor microenvironment and normalize tumor blood vessels to enhance immunotherapy

wallpapers News 2020-10-13

immunotherapy as an effective means of clinical treatment of tumor aims to enhance the body's immune system immune activity to kill tumor cells but there are still limitations in practical application. Immunotherapy is inhibited by tumor microenvironment such as high leakage of tumor blood vessels abnormal tumor glycolysis resulting in its clinical effective rate of only 30% ~ 50%. On the one h tumor blood vessels transport oxygen nutrition for tumor growth which is an important condition to maintain the exponential growth of tumor. However the abnormal structure of tumor blood vessels leads to the leakage of immune cells in the process of vascular transportation which reduces the number of immune cell infiltration. On the other h due to the low efficiency of oxygen delivery by tumor blood vessels the tumor site is in a state of hypoxia which leads to the recruitment of immunosuppressive cells (such as T-reg cells) in the tumor site finally forms a microenvironment for immunosuppressive therapy. Lactic acid the product of high glycolysis efficiency of tumor cells is secreted into tumor microenvironment enters tumor vascular endothelial cells through the "lactic acid shuttle" mechanism between cells to further promote tumor angiogenesis. In addition lactic acid is an important part of tumor acidic microenvironment which inhibits the activity of immune cells in microenvironment.

Professor Yao Jing of China Pharmaceutical University his team have constructed jet lagged nanoparticles with delayed behavior reshaped the tumor microenvironment by combining anti-tumor metabolic therapy tumor vascular normalization therapy thereby increasing the infiltration of t-immune cells reducing the number of immunosuppressive cells (T-reg) Finally it can improve the efficacy of immunotherapy drugs. The drug loaded nanoparticles (mkda / MCD) were used to construct tumor targeting endothelial cells. After the injection of jet lagged nanoparticles into the tumor vessels APA / MCP preferentially reaches the target tumor vascular endothelial cells. After endocytosis drugs are released to block the VEGF / VEGFR2 signal transduction pathway to normalize the tumor vessels. Subsequently LND / MCA enters the tumor microenvironment which is absorbed by tumor cells then released to inhibit lactic acid efflux. At the same time it strengthens the treatment of promoting vascular normalization so as to improve the infiltration of immune T cells reduce the recruitment of immunosuppressive cells (Treg cells) remodel the tumor microenvironment. After the combination of immunotherapy drug (PD-1) jet lagged nanoparticles the therapeutic effect of melanoma bearing mice was three times higher than that of free PD-1 group. In conclusion this study uses low-dose antiangiogenic drugs to promote the normalization of tumor blood vessels at the same time combined with anti metabolic therapy to interfere with tumor metabolism to induce the normalization of tumor acidic microenvironment ultimately enhance immunotherapy forming a "vascular immune" positive feedback loop to promote "treatment delivery". The researchers believe that this study will open up new therapeutic strategies for anti-tumor therapy based on immune system provide new ideas for strategies based on combination of nano drugs. This treatment strategy has a great application prospect.

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