Novel Photo-responsive Gels For Combination Of Phototherapy And Immunotherapy For Postsurgical Cancer Treatment

The highly immunosuppressive microenvironment after surgery has a crucial impact on the recurrence and metastasis in cancer patients.The combination of tumor phototherapy and immunotherapy is expected to reverse the highly immunosuppressive microenviroment and inhibit tumor recurrence and metastasis after surgical treatment.In this thesis,two novel multifunctional drug-delivery depots were designed for combination of phototherapy and immunotherapy.The main research contents are as follows:1.Time-programmed delivery of sorafenib and anti-CD47 antibody via a double-layer-gel matrix for postsurgical cancer treatmentIn this study,a novel hierachically structured gel matrix with dual lipid gel(DLG)layers was designed.The outer layer of the DLG matrix was thermally responsive and loaded with sorafenib-adsorbed graphene oxide(GO)nanoparticles.GO under manually controlled near-infrared irradiation generated heat and provoked the release of sorafenib first to impede the polarization of tumor-associated macrophages(TAMs)to M2-like phenotype and promote an immunogenic tumor microenvironment.The inner layer,loaded with anti-CD47 antibody(aCD47),could maintain the gel state for a much longer time,enabling the sustained release of aCD47 for a long-term antitumor effect.2.Immunostimulant reactive oxygen species-responsive scaffold for combination of photodynamic and immunotherapy for postsurgical cancer treatmentIn this study,a novel macroscopic gel scaffold co-loaded with Chlorin e6(Ce6)and aCD47 was designed.Under 640 nm LED irradiation,the reactive oxygen species(ROS)produced by Ce6 could not only directly kill tumor cells,but also stimulated the proinflammatory effects.Moreover,the ROS could control the release of aCD47 by degrading the ROS-responsive scaffold,thus performed the immune blocking function.In vivo studies on 4T1-luc tumor-bearing mouse model demonstrated that these two strategies efficiently prevented tumor recurrence and metastasis by locally reversing the immunosuppression and synergistically blocking the CD47-dependent immune escape,thereby boosting the systemic immune responses.These two studies in this paper may provide a basis for the application of the combination of phototherapy and immunotherapy.