Targeted Photodynamic Cancer Therapy With An Autophagy-inhibiting Porphyrin Metal-organic Framework

Photodynamic therapy(PDT)has a long history,but was not widely used at first.Later on,due to the research and development of photosensitizers,photodynamic therapy was again taken seriously.Currently,photodynamic therapy(PDT)has the advantages of minimally invasive,controllable,low toxicity and reproducible treatment,and has become an indispensable treatment method in clinical medicine.PDT consists of photosensitizer,light,and oxygen.These components are not toxic to the tumor when they are alone,but chemically react when they are combined to produce highly active ROS and singlet oxygen.PDT therapy is the intracellular generation of ROS and singly linear oxygen(1O2)to induce cancer cell death,with different modes of death depending on the localisation of the photosensitiser within the cell.However,for autophagy,it is caused by the damage of endoplasmic reticulum or lysosome induced by photosensitive agents.Tumor cells can degrade the damaged cellular proteins and organelles by their protective autophagy behavior,thus reducing the efficacy of PDT.Therefore,we should minimize autophagy and promote other tumor-killing modalitiesIn this study,a porphyrin metalorganic framework material with autophagy inhibition and targeting function was constructed in a simple and convenient way.By loading autophagy inhibitor hydroxychloroquine sulfate(HCQ)on MOF material PCN-224 and modifying its surface with folic acid(FA),the specific tumor targeting effect and autophagy inhibition function were achieved.The experimental results showed that the targeted autophagy inhibition MOF material was successfully synthesized with uniform particle size and good nanometer size.In vitro experiments showed that HCQ could be released from MOF in lysosomal environment and was stable in MOF under neutral conditions.Pharmacodynamic tests showed that cells with folate receptors on the surface had good uptake of synthetic drugs,which could promote the generation of intracellular reactive oxygen species and enhance the generation of singlet oxygen.Further experiments showed that the drug had a good tumor killing effect under the photodynamic action,and the killing effect was better than that of PCN-224 without HCQ modification.This effect was achieved because HCQ produced autophagy inhibition in cells.We continued to study the mechanism of drug action through GC-MS-based metabolomics.Through the analysis of metabolomic data,it was found that the differential metabolites were mainly involved in amino acid metabolism,glucose metabolism,pyruvate metabolism and the tricarboxylic acid cycle,and the metabolites were all up-regulated to a certain extent.We hypothesize that the accumulation of metabolites is caused by the drug inhibiting the energy generation pathway of tumor cells to promote tumor death.In conclusion,we successfully synthesized a targeted metalloorganic framework material with autophagy inhibition,which has a good effect on tumor killing.The mechanism of action may be to achieve therapeutic effect by inhibiting the energy metabolism pathway of the tumor itself.