Indoleamine 2,3-dioxygenase Inhibitors Loaded Hyaluronic Acid Based Photosensitive Micelles For Cancer Combination Photo-Immunotherapy

The incidence and mortality of malignant tumors in China are increasing year by year,which seriously endanger the human's lives and health.Traditional tumor treatment methods are not effective in preventing metastasis and recurrence.Photodynamic therapy not only can kill tumor cells but also can activate the anti-tumor immune response.However,the immune-supressive microenviroment greatly weakens the effect of immune anti-tumor effiency.Indoleamine 2,3-dioxygenase 1 overexpressed in cancer cells can deplete the tryptophan and accumulate kynurenine to suppress the T cell immune response.Thus,the nanocomplex with the function of PDT and immune-therapy would provide an ideal strategy to kill the primary tumor.This thesis aimed to construct a targeted nanomicelle coloaded with IDO1 inhibitor and photosentitizer for the PDT-immuno combination therapy.Hyaluronic acid(HA)was utilized as the skeleton material,and Ce6 was grafted to HA via amide bond using ADH as a linker to yield a hydrophilic conjugate HA-Ce6.Then the hydrophobic IDO inhibitor NLG919 was loaded into self-assembled micelle by ultrasonic emulsification.Its hydrodynamic diameter is about 175 nm and its drug loading rate is about 14.7%.Micelles can be endocytosed by 4T1 tumor cells through specifically binding to CD44 overexpressed on the surface of tumor cells.Under laser irradiation,NLG919@HA-Ce6 killed tumor cells through ROS,and CRT exposure and ATP section showed that PDT induced effective immunogenic cell death.Meanwhile,the level of kynurenine decilined,which confirmed that NLG919 has the ability to inhibit the activity of IDO1,restoring the tryptophan level in tumor microenvironment and promoting T cell proliferation.Furthermore,the results of in vivo fluorescence imaging and therapy of mice showed that photosensitizers were effectively accumulated in 4T1 mouse breast cancer models.The results of serum levels of cytokines showed enhanced PDT-mediated immune responses.Ultimately,the primary tumors are effectively suppressed by NLG919@HA-Ce6.The study verified that NLG919@HA-Ce6 are promising photo-immuno agents against breast cancer,suggesting its potency for the combination therapy of cancer.