The Construction Of Stimulus-responsive Nano-immunotherapy System And Its Applications In Antitumor Therapy

Immune checkpoint blockade(ICB)-based immunotherapy has emerged to revolutionize the traditional tumor treatment and subvertes the clinical research pattern,showing promising potentials in overcoming chemotherapy resistance and improving the survival rate of cancer patients.However,the unfavorable patient response rate,immune-related adverse events(ir AEs)and expensive costs impede the development of ICB therapy.Recent evidences suggest that cell death caused by certain treatments can induce tumor cells to generate specific tumor immunity.This immunogenic cell death(ICD),characterized by releasing of damage-associated molecular patterns(DAMPs)from dying tumor cells,is conducive to promote antigen presentation and T-cell infiltration by mean of a certain molecular mechanism.To be precise,the antigen-presenting cells(APCs)are inclined to mature once the DAMPs produced by dying cells reaches APCs,which is capable of activating the effector T-cell to response against tumor-specific antigens.The activated effector T cells are rapidly transported into the tumor and infiltrate the tumor site,leading to the death of cancer cells.This paper takes the construction of stimulus-responsive polymer prodrugs as the starting point,and aims to improve the therapeutic effect of drugs and modify the immunosuppressive microenvironment.In this paper,serveal stimulus-responsive polymeric prodrugs are designed and constructed for immunotherapy.This details are shown as follows:(1)Firstly,we reported a universal yet versatile strategy for engineering DOX-based nanogel by conjugation of hydroxyl-group-containing DOX with hydroxyl-group-containing drugs via GSH-sensitive-SS-bond linker.The formed nanogel could liberate the loaded drugs after being internalized into high GSH concentration in tumor cells for combination chemo-immunotherapy.For further proof-of-idea,we were absorbed in the development of DOX-based MAN nanogels(donated as DM NGs).Concretely,DOX could perform chemotherapy to induce ICD of the tumor cells,which manifested by released HMGB1 and exposed CRT to the cell membrane surface to cause an anti-tumor immune response.In vitro and in vivo experiments confirmed the superiority of DM NGs over other formulation at the same DOX concentration.In addition,the effects of DM NGs on TME modulation,including DCs maturation and relief of exhausted TIM3~+PD-1~+T cells,were evaluated in detail.This GSH-responsive nanogel could systematically regulate the tumor microenvironment and maximize the mannose immune effect,indicating bright application prospects in solid tumor chemotherapy and immunotherapy.(2)Next,we reported a self-amplifiable drug delivery system(DDS)by loading Ce6 in a copolymer prodrug containing thioether bonds,which can realize the GSH and ROS dual-responsive release.The CDCPT was synthesized via atom transfer radical polymerization(ATRP)with OEGMA as the hydrophilic outer layer,and the Ce6 was loaded throughπ-πstacking interaction with CPT,expert high drug loading and controlled drug release.The obtained CCNP avoid the non-specific distribution due to the high stability of thioether bonds and shows prolonged circulation time due to nano-size.ROS generated by laser irradiation triggers the degradation of nanocarriers promote the release of drugs.Furthermore,the Ce6 loaded on the CCNP can be used for fluorescence imaging,the generated ROS not only kill cells,but also can cause ICD and release HMGB1,heat shock protein 90(HSP90),while CRT was exposed on the cell membrane to induce DC maturation.Furthermore,the ability of thioether bonds can consume GSH further enhance the oxidative stress,relieves tumor hypoxia during PDT,and helps to polarize tumor-associated macrophages(TAM).The constructed imaging-guided multifunctional nano diagnosis platform not only enhances the immunogenicity of cells,but also transforms the M2-TAM into M1-TAM,realizing effective cancer diagnosis and treatment.