Manganese-based Functional Nanomaterials For Tumor Sonodynamic Therapy And Wound Healing

Sonodynamic therapy(SDT)is a non-invasive tumor therapy that depends on the reactive oxygen species(ROS)produced by ultrasound-triggered sonosensitizers against tumors.Due to its deeper tissue penetration,lower skin phototoxicity,and better controllability,SDT has become one of the most promising novel tumor treatment modalities following photodynamic therapy(PDT).However,there are still some limitations that restrict the development of SDT.Firstly,the hypoxia in the tumor microenvironment(TME)greatly compromised the SDT efficacy.Secondly,the nonbiodegradability of inorganic sonosensitizers such as titanium dioxide(TiO2)might result in long-term toxicity in vivo.Thirdly,the wounds from SDT injuries were left on the skin surface after sonodynamic treatments.Manganese-based nanomaterials,which have been widely used in the field of photocatalysis,are expected to be more suitable as sonosensitizers for clinical translation than titanium-based nanomaterials due to their controllable nano-structures and components,TME regulation property,biodegradability,and good biosafety.This thesis mainly developed two novel and highly-efficient Mn-based sonosensitizers and a Mn-based wound dressing through designing and reconstructing the structures of Mn-based nanomaterials,which aimed to compensate for the weaknesses of SDT and promote its clinical translation.The main work is summarized as follows.Firstly,in order to address the issue that the hypoxic tumor TME limited the efficacy of SDT,a hypoxia-irrelevant Fe-doped multivalent manganese oxides nanoparticle(FDMN)was constructed for enhanced SDT by vacancy engineering strategy.Compared to multivalent manganese oxides nanoparticles(MnOx NPs),FDMNs had a higher SDT efficiency.The main reason was that the abundant oxygen vacancy(OVs)defects inside FDMNs could act as electron traps,preventing the recombination of electron-hole pairs triggered by ultrasound.Even more interestingly,due to the presence of OVs,a large number of O2 molecules adsorbed on the surface of FDMNs had endowed FDMNs with hypoxia-irrelevant ROS generation ability.In addition,FDMNs had an ability of catalyzing O2 into singlet oxygen(1O2)without any exogenous stimulation and exhausting glutathione(GSH),further enhancing the ROS production efficiency of SDT.Internal and external experiments had demonstrated that FDMNs had significant anti-tumor effects under both hypoxic and normoxic conditions.This work provided a feasible strategy for the development of sonosensitizers that could overcome hypoxic limitations.Secondly in terms of the challenge that the inorganic sonosensitizers had difficulty of degrading in vivo,perovskite-type manganese vanadate(MnVO3)sonosensitizers with high ROS yield and biodegradability were successfully synthesized for SDT.Due to the inherent properties of narrow bandgap and abundant OVs in perovskites,MnVO3 had a higher ROS yield triggered by ultrasound than commercial titanium dioxide(TiO2).The presence of manganese and vanadium ions enabled MnVO3 to possess chemodynamic performance under acidic condition,catalyzing hydrogen peroxide(H2O2)in tumor into hydroxyl radical(·OH).In addition,the highly-valent vanadium endowed MnVO3 with GSH consumption ability,which could synergistically amplify the oxidative stress generated by sonodynamic and chemodynamic therapy(CDT).More importantly,owing to the degradability of perovskite materials,MnVO3 could be excreted from the body within a certain period of time after exerting their therapeutic effects,avoiding the potential toxicity caused by long-term retention in the body.Both cell and animal experiments had demonstrated that the combined treatments of SDT and CDT from FDMNs had a significant inhibitory effect on tumor growth.This new type of efficient and safe perovskite-type sonosensitizer reported in this work not only improved the SDT efficiency of sonosensitizers,but also greatly reduced the potential toxicity of inorganic sonosensitizers,thus increasing the possibility of their clinical translation.Finally,in response to the issue of wound formation on the skin surface after sonodynamic treatment,pH-responsive inj ectable hydrogel wound dressings encapsulating manganese sulfide nanoparticles(MnS NPs)were successfully prepared using Schiff base reaction.The injectable hydrogel,which used Schiff’s base bonds as the cross-linking points,exhibited good tissue adhesion,moderate tensile strength,and good biocompatibility.Due to the acidic cleavage feature of the Schiff’s base bonds,the hydrogel had an ability of pH-responsive controlled release of MnS NPs at weakly acidic wound sites.More interestingly,MnS NPs could reduce the mRNA expression levels of pro-inflammatory cytokines in Ml-type RAW264.7 cells,including interleukin-6(IL-6)and inducible nitric oxide synthase(iNOS).Animal studies had shown that hydrogel encapsulating MnS NPs could promote the mouse wound healing more effectively by facilitating cell proliferation and angiogenesis than single hydrogel without MnS NPs or single MnS NPs without hydrogel groups.This work demonstrated that manganese-based nanomaterials can be used to accelerate wound healing,expanding the application range of Mn-based nanomaterials.In summary,this thesis aims to address the challenges in the field of SDT by utilizing and improving the properties and structures of various manganese-based nanomaterials.Feasible strategies have been proposed for the design and synthesis of sonosensitizers for tumor therapy,as well as wound healing,with the hope of promoting the clinical translation of SDT.