Metal Organic Framework-Based Core-Shell Nanocomposites For Radiotherapy Sensitization And Anti-Tumor Immunotherapy

Radiation therapy(RT)is a widely used for more than 50%of tumor patients in local cancer therapy.Theoretically,RT can activate systemic anti-tumor immune responses to inhibit tumor metastases(termed as the abscopal effects)by inducing immunogenic cell death(ICD),accompanied by the release of damage-associated molecular patterns(DAMPs)including adenosine triphosphate(ATP),calreticulin(CRT)and high mobility group box 1(HMGB1).These DAMPs will stimulate the maturation and migration of dendritic cells(DCs),and then further stimulate the proliferation and differentiation of T cells,eventually leading to the abscopal effects.Unfortunately,RT-mediated abscopal effects are very rare and insufficient to meet clinical needs due to the tumor microenvironment(TME).Oxygen plays an important role in tumor progression and tumoral response to RT.However,the overactive oxygen metabolism during the abnormal proliferation process of tumor cells,leading to serious hypoxia in the TME,thus making oxygen-dependent therapeutics ineffective,typically for RT.In order to resist the high level of oxidative stress in tumor,tumor cells have a strong ability to scavenge reactive oxygen species(ROS)by developing adaptive antioxidant mechanisms,for example,glutathione(GSH),to make RT ineffective.In addition,tumor-associated macrophages(TAMs),as influenced by the suppressive tumor immune microenvironment(TIME),are mostly M2 phenotype.M2 macrophages severely inhibits RT-mediated systemic immune responses.This thesis mainly focuses on "how to enhance RT-mediated systemic anti-tumor immune responses via TME modulation and radiosensitization to inhibit primary and distant tumors".1)Combining TME modulation and mutually reinforced ferroptosis and radiotherapy for improved anti-tumor immunity,we designed and constructed a core-shell nanocomposites of UiO@Mn3O4(UM)by coating Mn3O4 particles on the surface of nanoscale UiO-66(Hf)-NH2(denoted as UiO).To enable its use in biomedical applications,polyacrylic acid(PAA)was coated on the surface of UM to form the nanocomposite of UiO@Mn3O4@PAA(denoted as UMP).The obtained UMP could serve as an efficient nanoregulator for alleviating hypoxia via endogenous hydrogen peroxide(H2O2)consumption,and inducing oxidative stress via GSH depletion-enhanced Fenton-like reaction and redox reaction.Therefore,UMP re-assorted cell cycle distribution(i.e.,at the gap 2/mitosis(G2/M)phases),consequently contributing to enhanced tumoral radiosensitivity.Upon low-dose irradiation,UiO could serve as a radiosensitizer to give substantial amounts of ROS.The integration of ROS enhancement,GSH depletion,and oxygen production,eventually amplified UMP-mediated ferroptosis and radiotherapy to induce a workable ICD effect,resulting in polarization of M2 macrophages to M1 phenotype,maturation of DCs,activation of CD8+T cells,secretion of inflammatory cytokines TNF-α and IFN-γ,and ultimately initiation of strong anti-tumor immune responses.Thus,UMP demonstrated satisfactory efficiency in eliminating both primary and metastatic tumors.This work provides a combining TME modulation and mutually reinforced ferroptosis and radiotherapy approach for eminent antitumor therapeutic efficacy,which is expected to shed light on the design of TME-reshaping via multiple strategies to reinforce the synergistic therapeutic outcome and facilitate the development of effective cancer nanomedicine.Although in part 1)we alleviated tumor hypoxia by Mn3O4-catalyzed oxygen production from H2O2.However,limited by insufficient endogenous H2O2 in the TME and abnormal proliferation of tumor cells that continuously consume large amounts of oxygen,the method of overcoming tumor hypoxia by increasing oxygen supply via H2O2 consumption may be not effective.In contrast to the oxygen supply strategy,inhibition of tumor oxygen consumption by small molecule compounds is a more promising approach to improve tumor oxygenation.Meanwhile,ferroptosis is limited by insufficient H2O2 level to achieve durable and effective antitumor effects,which is also a great challenge for current chemodynamic therapy(CDT).Therefore,to further enhance anti-tumor effects of CDT and RT,we conducted part 2)of the thesis.2)In order to exert the synergistic effect of hydrogen sulfide(H2S)-mediated gas therapy(GT)and Mn2+-mediated CDT in RT to enhance anti-tumor immunity,we designed a core-shell nanosensitizer UiO@MnS(US).Firstly,a hafnium-based metal organic framework UiO-66(Hf)-NH2(UiO)was constructed to enhance X-ray deposition.Then a manganese sulfide(MnS)nanoshell was constructed on the UiO surface to obtaine US.In acidic TME,MnS released H2S and Mn2+.On the one hand,the generated H2S destroyed the mitochondrial electron transfer chain by inhibiting cytochrome c oxidase(complex Ⅳ,COX Ⅳ),which has a destructive effect on the aerobic respiration and energy supplement,and then causes "chemical asphyxia" of cells,thus reducing the expression of HIF-1α to intensify RT efficacy.On the other hand,H2S also inhibited the activity of catalase(CAT)to increase H2O2 level,which subsequently enhances Mn2+-mediated CDT,ultimately arresting the cell cycle in the G2/M phase to improve the sensitivity of RT.Combined with US mediated-GT/CDT/RT,this synergistic effect induced workable ICD,resulting in polarization of M2 macrophages to M1 phenotype,maturation of DCs,activation of CD4+and CD8+T cells,secretion of inflammatory cytokines TNF-α and IFN-γ,and ultimately initiation of strong anti-tumor immune responses.Thus,US demonstrated satisfactory efficiency in eliminating both primary and metastatic tumors.Such a synergistic strategy would have great potential in optimizing RT-mediated systemic anti-tumor immune responses to inhibit metastasis.