Therapy Drug Delivery System For Cancer Combined Design Of Caspase-3 Enzyme-responsive Nano

Traditional tumor treatment methods such as chemotherapy,radiotherapy,and surgery have been unable to meet clinical needs due to various defects.In recent years,photodynamic therapy(PDT),photothermal therapy(PTT)and immunotherapy have developed rapidly,especially the combination therapy based on these methods,which has become a hotspot of cancer treatment research.This thesis starts with a caspase enzyme,based on the tumor microenvironment,research and design a caspase-3 enzyme response nano-drug loading system.The detailed contents and main results are described as follows: 1.Caspase-3 Responsive Chimeric Peptide for Chemo/Photodynamic Therapy.A chimeric peptide based on caspase-3 enzyme response in the tumor microenvironment is designed for combined chemotherapy / photodynamic therapy to reduce systemic toxicity.A solid-phase synthesis method was used to synthesize chimeric peptide sequences with doxorubicin(DOX)and photosensitizer pheophorbide-a(pha)at both ends.In vitro experiments showed that DOX can only be released when incubated with caspase-3 enzyme,and the cytotoxicity treated with chimeric peptide micelles after light reached 25%,which was comparable to that of the control significant difference.The results of confocal experiments and flow cytometry analysis showed that the chimeric peptides in the experimental group had the highest proportion of apoptosis.The flow cytometry analysis results in the experimental group showed up to 61% of late apoptosis and 20% of early apoptosis.In vivo treatment experiments have shown excellent combined treatment effects.Blood routine and biochemical indicators also prove that the chimeric peptide has low systemic toxicity.This caspase-3 enzyme-responsive nano drug-loaded system has great potential for tumor therapy in combination therapy based on chemotherapy.2.Caspase-3 enzyme responsive chimeric peptide for the photodynamic/photothermal therapy and photoacoustic imaging.Conventional PDT and PTT combination therapy is mostly a combination of photosensitizer and photothermal material,or adding imaging molecules,loaded in nanoparticles,to complete the treatment and imaging.Using the chimeric peptides synthesized here under different p H conditions,the degree of aggregation is different,which enhances the endocytosis of nanomaterials in tumor cells.Transmission electron microscopy,ultraviolet,fluorescence,and flow fluorescence analysis all proved that the enrichment of the chimeric peptide nanomaterials in cells increased.The confocal fluorescence experiment and the in vitro photothermal experiment proved that the pha aggregated after caspase-3 incubation and realized the transformation from photodynamic therapy to photothermal therapy.Small animal photoacoustic imaging experiments show that it has a good photoacoustic effect in tumor models.This method of using chimeric peptides to enhance cell endocytosis under the difference of slightly acidic tumors,and according to the difference between hydrophilicity and hydrophobicity of photosensitizers,it has achieved the transformation of photodynamic therapy and photothermal therapy.The photosensitizer in the state of photothermal properties also has the effect of photoacoustic imaging,which realizes the visualization of tumor treatment.This kind of diagnosis and treatment strategy that integrates multiple treatments and imaging functions provides a new idea for the integration of tumor diagnosis and treatment.