Self-assembled Nano-prodrug Micelles Based On IDO Pathway Inhibition For MR Imaging-guided Tumor Synergistic Therapy

At present,the early diagnosis and effective treatment of malignant tumors still face many challenges.Although the introduction of photodynamic therapy（PDT）in cancer treatment field can reduce the concerns of some patients,it is still likely to face the risk of postoperative recurrence after PDT.Therefore,it is particularly important to use immune adjuvant to activate the body’s immune system to inhibit tumor recurrence and metastasis.The effective combination of PDT and immunotherapy is also a general trend in the field of cancer treatment.However,most photosensitizers and immune adjuvants have encountered problems such as poor water solubility and low specificity.Therefore,in terms of the delivery of hydrophobic drugs,researchers also need to actively explore safe and effective carriers to improve the water solubility of drugs,avoid the degradation of drugs in the process of blood circulation,and achieve effective delivery of the target site.Nanomicelles with their easy functionalized modifications,good drug-loading capacity and blood circulation ability have received the widespread attention in the field of cancer diagnosis and treatment.Especially,the tumor microenvironment（TME）responsiveness nano-prodrug micelles not only have good multiple drug loading capacity,but also achieve specific drug release,increase drug utilization,and further improve the therapeutic effect.Therefore,in this study,a p H/GSH dual-responsive nano-prodrug micelle（NLG919/PGA-Cys-PPA@Gd）was prepared by self-assembly for effective delivery of indoleamine 2,3-dioxygenase（IDO）inhibitor NLG919 and photosensitizer pheophorbide A（PPA）to achieve T₁-weighted MRI guided tumor photodynamic immunotherapy.When the micelles self-assembled in aqueous solution,the micelles were in a photo-quenched state due to the self-quenching effect PPA molecules.However,since the amide bond in PGA-Cys-PPA and the disulfide bond in cystamine（Cys）are sensitive to p H and GSH,respectively.TME-triggered photoactivity recovery and effective release of PPA and NLG919 occurred in the nanomicelles after accumulation at the tumor site.In this design,the ingenious combination of photosensitizer and IDO inhibitor could effectively induce cell apoptosis induced by PDT and block the immunosuppressive IDO pathway,as well as enhance the therapeutic effect of cancer.In addition,the micelles also had high relaxivity(r₁=29.85m M^-1 s^-1),which could effectively enhance the contrast of tumor T₁-weighted MRI and had good imaging ability.Based on the above responsive drug release ability and adjustable photoactivity mechanism,we injected the intelligent dual-drug delivery system into tumor-bearing mice through the tail vein for imaging and treatment.In vivo results showed that tumor growth of mice was significantly inhibited after treatment,and the transformation of tryptophan（Trp）to kynurenine（Kyn）in mice was reduced,indicating that IDO pathway was effectively blocked.Meanwhile,the content of immune-related cytokines TNF-αand IL-6 in blood of mice increased,which helped stimulate T cell proliferation and promote cytotoxic T lymphocytes to tumor killing effect.At 12 h post-injection,MR signal of the tumor site was significantly enhanced.The weights of mice were not affected.Hemolysis test,blood routine analysis and H&E staining analysis further indicated that the micelle had good blood compatibility and biosafety,it could be served as an effective reagent for MRI-guided combination therapy of cancer.