Construction And Antitumor Therapy Research Of Paclitaxel Nano-Prodrug Delivery System

Objective:Malignant tumors remain one of the most serious diseases that threaten the life and health of human beings.Tumors are one of the major challenges in clinical medicine,because they are characterized by rapid proliferation and growth compared to normal tissues.Tumor cells have a specific microenvironment with high levels of oxidative stress,high concentration of GSH,low levels of oxygen,micro-acidity and the over-expression of certain enzymes.The main methods of clinical treatment are surgical resection,chemotherapy and radiotherapy.However,surgical resection is difficult and prone to recurrence.Pharmacological chemotherapy remains the mainstay of treatment.However,most chemotherapeutic drugs have drawbacks,such as poor water solubility,low bioavailability,poor pharmacokinetics and toxic side effects.These drawbacks limit their clinical application.Therefore,it is crucial to find efficient and safe ways to rationally design effective drug delivery systems for improving the efficacy of oncology treatment.Methods:In this thesis,we have modified PTX as a dimeric and polymeric prodrug and systematically investigated the effect of the prodrug strategy on the drug loading and the combination therapy of tumors.Due to the structural complexity and micro-preparation of drug analysis objects,it is particularly important to choose the right analytical method for separation purposes and to improve sensitivity.Therefore,the structure of the compound was detected by LC-MS and the drug delivery system was prepared by dialysis.Particle size and surface potential were measured with a Malvern particle sizer,particle size and morphology observed by transmission electron microscopy,in vitro drug release measured by dialysis and HPLC,cytotoxicity measured by CCK-8 and MTT,apoptosis measured by Annexin V-FITC/PI,and drug distribution in model animals observed by a small animal in vivo fluorescence imaging system.The distribution of the drug in the model animals was further investigated by enrichment of the drug delivery system at the tumor site.The biocompatibility of the drug was studied by means of a haemolysis test and histopathological analysis with H&E staining.Results:Construction of cascaded multi-stimulus-responsive metal-phenol network prodrug delivery systems(di PTX@Fe&TA):a simple,green hybrid method was used to construct a metalphenol network-based drug delivery system with a hydrodynamic diameter of 152.6 ± 1.2 nm,good stability,drug loading capacity of up to 24.7%,good biocompatibility,inhibition of early drug release and high anti-tumor capacity.Construction of paclitaxel nano-prodrug delivery system with ultra-high DLC(di PTK@DP):It was prepared by prodrug di PTK into a micellar hydrophobic nucleus through hydrophobic interaction using the amphiphilic polymer m PEG-DSPE as a carrier.It has been demonstrated that di PTK@DP has a high DLC when used at different dosage ratios.106.0±1.0,while the drug loading capacity and drug loading efficiency were as high as 49.43% and 98.86%,respectively.The vector has high physiological stability.It can not only be efficiently taken up by tumor cells,but also release PTX prodrugs to specific tumor cell microenvironment.The results of cellular assay also verified its antitumor activity.The dimer strategy fully demonstrates its high DLC.It has important implications for the use of nanomedicines in tumor therapy.Construction of cascade amplification multidrug nanosystem(IR780@PMPTP): m PEGTK-PTX,a reactive oxygen-sensitive polymeric prodrug,was synthesized and self-assembled with photosensitizer IR780.In the tumor microenvironment,the prodrug PTX can be released to exert chemotherapeutic effects;At the same time,controlled photothermal treatment under light is also achieved through the stacking interaction with IR780,promoting the encapsulation of IR780.69.0°C and an increase in apoptosis from 27.99% to 73.75% compared to PTX chemotherapy.The anti-tumor effect of the combination treatment was remarkable.Conclusion:In brief,we construct three PTX-based nano-prodrug delivery systems that utilize a prodrug strategy to improve drug delivery of chemotherapeutic drugs,which can reduce toxicity and side effects,and avoid premature drug release.Most importantly,the nano-prodrug can act as a vehicle to co-deliver another drug used in combination therapy,thus providing synergistic treatment.In conclusion,this work provides a new strategy for the treatment of tumors.It offers new therapeutic options for future anti-tumor research.