Construction Of MOF-based Sonosensitizers For Biomedical Application

Sonodynamic therapy（SDT）is a novel strategy for disease treatment with the involvement of ultrasound（US）and sonosensitizers,which offers the advantages of non-invasiveness,precision,and high tissue penetration.Currently,the therapeutic mechanism of SDT is mainly proposed based on the cavitation effect generated under US irradiation,including the mechanical effect and the production of reactive oxygen species（ROS）,but its exact mechanism remains unclear,which seriously restricts the rational design of efficient sonosensitizers and the clinical translation of SDT.In addition,due to the complex disease microenvironment,sonosensitizers with a single function do not provide optimal therapeutic efficacy and are prone to side effects,and the application of SDT is often limited to superficial tissues.Metal–organic frameworks（MOF）have unique crystalline and porous structures.Their well-controlled metal coordination compositions facilitate the exploration of conformational relationships and guide the design of MOF-based materials,showing great potential in the biomedical field.Thanks to the unique advantages of MOF-based nanomaterials,this thesis systematically investigates the biological effects of MOF-based sonosensitizers.The thesis is studies from three aspects,namely exploring the sonodynamic mechanism,rational design of sonosensitizers and developing novel SDT technology,as follows.（1）To address the unclear mechanism of SDT,the sonodynamic of zeolite imidazolium framework-8 nanocrystals（ZIF-8 NCs）with specific metal–nitrogen active sites was explored and their therapeutic efficiency in tumors was verified in combination with their bioactivity.Density functional theory calculations combined with experiments revealed that the unsaturated zinc–nitrogen active sites on the surface of ZIF-8 NCs allow an enhanced electron transfer via ligand to metal charge transfer bands（LMCT）from the highest occupied molecular orbitals（HOMO）to the lowest unoccupied molecular orbitals（LUMO）.This process is critical for the generation of ROS by MOF under US irradiation.In addition,ZIF-8 NCs are susceptible to biodegradation to release zinc ions triggered by the weakly acidic tumor microenvironment,demonstrating the bioactivity to induce apoptosis.In vivo experiments indicate that ZIF-8 NCs exhibit high tumor inhibition efficiency（84.6%）as both a bioactive anticancer agent and a sonosensitizer.（2）To address the problem that tumor hypoxia severely limits the efficiency of SDT,a multifunctional sonosensitizer with self-O₂ generation capability was rationally designed for the efficient cancer treatment.A double-layer hollow manganese silicate nanoparticle（DHMS）was simply constructed by using ZIF-8 as a template,which could convert H₂O₂to O₂ in the disease microenvironment and thus improve the therapeutic efficiency of O₂-dependent SDT.In addition,the presence of Mn elements not only improves the electron-hole separation efficiency of DHMS under US irradiation,but also confers its US imaging and magnetic resonance imaging capabilities.In vivo experiments showed that DHMS-mediated SDT effectively inhibited tumor growth（tumor inhibition rate of 92.0%）under the guidance of multimodal imaging.（3）A novel SDT-based antimicrobial technology was developed for the application of SDT to deep disease tissues.We develop ZIF-8-derived carbon@titanium dioxide nanoparticles（ZTN）as inhalable sonosensitizers for multidrug-resistant（MDR）bacterial pneumonia.Upon US irradiation,ZTN exhibit an excellent efficacy to produce ROS and thereby to kill Gram-negative MDR bacteria in vitro.Taking advantage of aerosolized intratracheal inoculation,ZTN can be precisely delivered to lung infection sites,and the application of US further facilitates the diffusion of the ZTN in the lungs.This SDT-based antimicrobial technique achieved effective clearance of Gram-negative MDR bacteria in a lethal mouse model of pneumonia,resulting in a100%survival rate.In addition,ZTN have no obvious toxicity at both cellular and animal levels.In summary,this thesis systematically explores the therapeutic efficiency of MOF-based sonosensitizers in cancer and bacterial infections,using MOF-based nanomaterials as a starting point to address the bottlenecks currently hindering the development of SDT.This thesis firstly explores the mechanism of ZIF-8-mediated SDT,providing theoretical guidance for the development of effective sonosensitizers.In addition,MOF-based sonosensitizers designed for the disease hypoxic microenvironment are predicted to give a new way for the simple construction of sonosensitizers with self-O₂ production capability.Finally,the new SDT technology developed based on the strong tissue penetration capability of US provides a new idea for the treatment of MDR bacterial infections in deep tissues.The above research content was carried out in terms of mechanism exploration,rational design,and technology development,which is conducive to expanding the nanomedical applications of sonosensitizers and accelerating the clinical translation of SDT.