Construction Of Tumor Acidic And NIR-responsive Polydopamine Drug Delivery System And Study On The Photothermal To Activate Ferroptosis

As nanotechnology continues to evolve,so does its range of applications.The mature application of nanomaterials in biomedicine makes it a great help for human to overcome diseases.Based on the study of mussels,researchers have developed a variety of polydopamine（PDA）nanomaterials,including PDA nanoparticles,mesoporous PDA,hollow PDA capsules,PDA nanowires,PDA nanosheets,etc.The synthesis of PDA nanoparticles is relatively simple,and the particles can be formed by oxidation and self-polymerization in alkaline aqueous solution.And the polymerization process of PDA is affected by solvent,p H,oxidant,temperature,substrate concentration and other factors.Researchers don’t have a clear conclusion on the polymerization mechanism of PDA.A more widespread explanation is that PDA is oxidized to form quinones,which are further cross-linked to PDA through Michael addition reaction.There are abundant chemical groups on PDA nanoparticles,which can react with amino and sulfhydryl groups in Schiffer base reaction or Michael addition reaction.Phenolic hydroxyl groups on the PDA can also coordinate with transition metal ions and radioisotopes.The metal ions chelated into the PDA can be used as contrast agent,radiotherapy agent or chemotherapy agent.PDA’sπ-πstacking structure also allows it to bind to a large number of hydrophobic chemical molecules.At the same time,PDA can convert 808 nm near-infrared light（NIR）into heat energy,and the photothermal conversion rate reaches about 40%,which is an excellent photothermal therapeutic agent.Its strong fluorescence absorption ability allows it to quench fluorescent molecules.PDA is unstable and degradable in acidic p H and thermal environments.PDA also has excellent biocompatibility,its monomer material is from the body,so it can exist in the biological body for a long time without toxic side effects.It can be inferred that PDA is an ideal combination therapy vector.A large number of drug delivery systems have been constructed and used for the treatment of cancer diseases with a high mortality rate.PDA is an ideal carrier for drug delivery.The discovery of Ferroptosis provides a good opportunity for tumor treatment.The essence of Ferroptosis is the peroxidation of polyunsaturated fatty acids caused by iron ions,which leads to the damage of plasma membrane.Researchers have found a number of small molecule drugs that can induce Ferroptosis.There are also a large number of Ferroptosis-based nano-drug delivery systems that have been developed,all of which have excellent anti-tumor effects.In summary,PDA is used as a drug carrier in this paper,which is loaded with LAP and Fe²⁺and modified with targeted molecule cRGD,to get the nanoparticles Fe（Ⅱ）PDA@LAP-PEG-c RGD,Under low power 808 nm NIR irradiation,PDA particles produce mild photothermal effects and trigger the release of LAP and Fe²⁺,which have the effect of promoting Ferroptosis.In the meanwhile,the photothermal effect induced by NIR can also activate the Heat shock response of cells,resulting in the up-regulation of Heat shock 70 k Da protein（HSP70）.The expression of NQO-1 is up-regulated by HSP70/NAD（P）H dehydrogenase and Quinone 1（NQO-1）pivot.The up-regulated expression of NQO-1catalyzes the formation of more H₂O₂ by LAP in cells.The released Fe²⁺will catalyze the accumulation of H₂O₂ in the cell to produce lipid peroxidation,which will damage the cell membrane,which represents the occurrence of Ferroptosis,Moreover,as a chemotherapy drug,LAP itself has a relatively strong ability to promote tumor cell apoptosis.This paper mainly obtains the following experimental results:（1）We have designed and synthesized a targeted nanoparticle Fe（Ⅱ）PDA@LAP-PEG-c RGD with about 200 nm of drug loading.It is also verified that the nanoparticles have good photothermal conversion ability,acid/photothermal degradation ability,drug release ability and H₂O₂ decomposition ability.（2）We demonstrated that the drug-loaded nanoparticles have a good ability to target B16F10 cells.At the same time,it also leads to severe Ferroptosis and apoptosis of tumor cells.In vivo biological verification shows that the granule has excellent tumor tissue growth inhibition ability,and has good biocompatibility,will not cause the damage of the normal cells.By combining the photothermal effect with iron death,we can accurately control the occurrence of iron death.This powerful strategy to activate and enhance the effect of iron death in vivo provides hope for the treatment of multiple tumor indications in the clinical context.