Construction Of Metal-organic Framework Nanoplatforms For Imaging And Phototherapy Of Tumors

Cancer is one of the main threats to human health.Traditional tumor treatments are not ideal due to their toxicity and side effects,which will seriously affect the compliance and survival of patients.How to innovate treatment methods,improve drug therapeutic efficacy and reduce side effects has always been the important topics in life science.Phototherapy is an emerging cancer treatment,which can exert tumor suppression effects through applying laser to excite photosensitizers or photothermal agents after they are delivered in tumor sites.It has received extensive attention owning to the non-invasiveness,high selectivity and low side effects.However,factors such as laser penetration depth and uneven heat distribution in tumor tissues will affect its therapeutic effect and limit practical application.Meanwhile,rapid development of nanotechnology and its successful combination with medicine have made nanomaterials an increasingly important role in biomedicine.Nanoscale metal-organic frameworks(n MOFs)are porous material formed by self-assembly of metal-containing nodes and organic ligands through coordination interaction.Because of their excellent drug loading capacity,adjustability of the component units and good biocompatibility,n MOFs show great potential in the field of biomedicine and have been widely utilized.In this dissertation,taking advantage of easy functionalization of n MOFs,we aim to enhance anti-tumor effect of the phototherapy platform by improving laser penetration depth,enhancing target effect,achieving imaging guidance or combination treatments.In this case,it is expected to provide new ideas and strategies for tumor diagnosis and treatment.Therefore,we developed a series of imaging-guided phototherapy platforms based on n MOFs.These nanopaltforms can accumulate in tumor sites through enhanced permeability and retention effect(EPR)or active targeting.Furthermore,the dependence on laser irradiation can reduce their toxicity and side effects on normal tissues.In vivo and in vitro experiments have shown that these systems possessed excellent imaging capacity and tumor suppression effects with great biocompatibility.The details are as follows:(1)MOF@UCNP core-satellite nanocomposite structure for imaging-guided efficient photodynamic therapyThe core-satellite nanostructures with n MOFs as core and Nd³⁺sensitive upconversion nanoparticles(UCNPs)as satellites were synthesized by a simple and controllable electrostatic self-assembly strategy.The use of Nd³⁺sensitive UCNPs could improve the penetration depth of excitation light in photodynamic therapy(PDT)while avoid the overheat problem caused by laser irradiation in the commonly used UCNPs system(980 nm excitation).Due to the high specific surface area and porous structure of n MOFs,high loading capacity of two photosensitizers(chlorin e6(Ce6)and rose bengale(RB))could be achieved.In this way,this nanopaltform could make full use of upconversion luminescence(UCL),and exhibited significantly better tumor suppressing ability than the single photosensitizer systems.Moreover,this nanopaltform had the capability of magnetic resonance(MR),UCL,and fluorescence(FL)tri-modal imaging.In vivo and in vitro experiments showed that the system had excellent anti-tumor effect under 808 nm laser irradiation,and achieved efficient PDT guided by three-modal imaging.(2)u PAR targeting photothermal metal-organic framework nanoprobes for NIR-II/MR imaging guided brain tumor treatmentBased on the MIL-101(Fe)-NH₂(MIL=materials of institute lavoisier)with MR imaging capability,a theranostic nanoprobe(CH4T@MOF-PEG-AE)was synthesized.Targeting peptide(AE105)was linked with the post-synthesis modification method to recongnize kinase plasminogen activator receptor(u PAR)and specifically target glioblastoma(GBM).And then,the second near-infrared window(NIR-II)fluorescence dye(CH4T)was loaded.This system combines the merits of magnetic resonance(MR)imaging and NIR-II fluorescence imaging,which could realize high penetration depth and spatial resolution while high sensitivity and real-time imaging at the same time,so it is possible to accurately diagnose and delineate GBM.In addition,CH4T@MOF-PEG-AE had good photothermal conversion efficiency,and excellent photothermal therapy(PTT)effect could be observed in vivo.Importantly,under the guidance of real-time NIR-II fluorescence imaging of the nanoprobe,we could realize the complete resection of orthotopic GBM.According to the results above,CH4T@MOF-PEG-AE could be applied as a multifunctional nanoprobe to integrate with multiple imaging and treatment modes for effective diagnosis and treatment of GBM.(3)Mixed-component metal-organic framework nanomaterials for multimodal imaging guided photodynamic and photothermal synergistic therapyBased on porphyrin MOFs,near infrared(NIR)dye cypate was introduced as the second ligand through a simple one-pot reaction,and the targeting molecule folic acid(FA)was connected through post-synthesis modification to obtain multifunctional n MOFs(PC₂₀-MOFs-FA).PC₂₀-MOFs-FA could target 4T1 tumors with high expression of folic acid receptor and deliver large amounts of porphyrin photosensitizers and cypate to tumor sites at the help of FA.Under 808 nm laser irradiation,cypate molecules in frameworks could convert the energy of laser into heat to increase local temperature and generate some reactive oxygen(ROS),while under 660 nm laser irradiation,porphyrin molecules in frameworks can generate a large amount of ROS,which played a synergistic role in tumor inhibition.In addition,cypate was capable of near infrared fluorescence(NIRF)and photoacoustic(PA)imaging,so it can be used for tumor imaging and guide phototherapy.Both in vivo and in vitro experimental results demonstrate that the nanoparticles exhibited excellent NIRF/PA imaging capability and anti-tumor effect,which could realize dual-modal imaging-guided efficient PDT/PTT combined therapy.Moreover,the hierarchically porous structure in the system provided the basis for loading biomolecules.