The Construction Of Self-targeting Theranostic Nanoplatforms And Their Applications In The Chemo-sonodynamic Oncotherapy

Sonodynamic therapy(SDT)has attracted wide attention as a noninvasive therapy due to its deep tissue penetration.However,the majority of sonosensitizers often suffer from poor physiological stability,short half-life in vivo and nonspecific targeting,hence it is an urgent scientific issue that optimizing the performance of sonosensitizers to improve the effect of tumor treatment.Inspired by the concept of active targeted nano-drug delivery,we combined the dual-functional targeted chemotherapeutic drug small molecule pemetrexed(PEM)and the amphiphilic polymer D-α-tocopherol polyethylene glycol 1000 succinate(TPGS)to form self-targeting TPGS-PEM prodrug through the esterification reaction,then the sonosensitizer indocyanine green(ICG)was loaded in it by self-assembly technology to build the TPGS-PEM-ICG theranostic nanoplatform(TPI)to address issues faced by sonodynamic therapy.In vitro performance evaluation experiments showed that the synthesized TPI could not only significantly improve the physiological stability of the sonosensitizer ICG,but also achieve on demand drug release under the stimulation of endogenous lysosomal acid,esterase and exogenous ultrasound,thereby reducing the potential toxicity and side effects on normal cells and tissues.Laser confocal microscopy and flow cytometry analysis results proved that TPI had good selectivity for tumor cells with high folate receptor expression.In vitro cytotoxicity,apoptosis,living and death cell staining experiments jointly proved that TPI had a significant killing effect on tumor cells with high folate receptor expression under the stimulation of ultrasound.In the in vivo experiments,we not only visually verified the excellent tumor enrichment effect of TPI but also determined the best sonodynamic therapy time point through fluorescence/photoacoustic imaging experiments.In addition,we adopted photoacoustic imaging technology to discover that highly toxic ROS can significantly down-regulate the blood oxygen saturation signal in the tumor microenvironment for the first time.Finally,in vivo anti-tumor experiments and pathological analysis systematically explained that TPI has excellent chemo-sonodynamic synergistic therapeutic effects under ultrasound signal stimulation.In general,this thesis not only provides a new method for sonodynamic therapy of tumors,but also is expected to provide an experimental basis for preclinical tumor diagnosis,prognosis,and targeted therapy.