Focused Ultrasound Combined With Bionic Targeted Drug Delivery Platform In Brain Tumors Treatment

Glioblastoma(GBM)is the most common primary brain tumor.It is difficult for multiple chemotherapy drugs to reach tumor owing to the blood-brain barrier(BBB),which also becomes the biggest obstacle to GBM treatment.Focused ultrasound(FUS)can open BBB reproducibly by means of mediating microbubble(MB)cavitation,which provides great convenience and flexibility for GBM treatment.However,MBs are not sufficiently targeted in vivo,affecting the concentration of drugs released in tumor.In addition,industrially produced MBs has low biocompatibility and will be recognized by the autoimmune monitoring system during transportation in vivo,resulting in excessive wastage and even immunological rejection.Therefore,it is necessary to strengthen MB stability and targeting to effectively improve the drug release concentration and maximize the therapeutic effect on tumors.In this study,bionic MBs prepared using cell membrane not only improve the targeting efficiency to tumor through membrane protein,but also improve the biocompatibility and prolong MB stability in vivo,so that drugs can be released efficiently and in sufficient quantities to effectively treat brain tumors.Firstly,bionic MBs are constructed by hybrid brain microvascular cell membrane with lipid components,loaded with magnetic drugs synthesized by iron oxide particles and doxorubicin,and finally prepare into Fe DOX@cell MBs.On the basis of not losing the functional characteristics of each component,Fe DOX@cell MBs greatly improve the stability in vivo 12 and 24 hours after treatment.Under the combined FUS and magnetic field,Fe DOX@cell MBs can open BBB and releases sufficient drugs into tumor,thus improving GBM treatment.On this basis,the bionic targeted MB drug delivery platforms combined with FUS are used to develop a "two-stage rocket" mode drug delivery system,which realize transfection in vivo.Moreover,the system effectively reversed resistance of GBM to temozolomide(TMZ)by inhibiting the expression of Yes1 associated transcriptional regulator(YAP1),which provides a new idea and strategy for GBM treatment in clinic.First of all,it was found that YAP1 was highly expressed in tumor tissues of glioma patients,and was correlated with the survival time of GBM patients.In addition,YAP1 was correlated with the expression of MGMT,a key factor of TMZ resistance through bioinformatics analysis on public databases and literature learning.Therefore,YAP1 is selected as the key regulatory factor of GBM resistance to TMZ.It is verified and confirmed that siYAP1 can become a targeted gene therapy drug to reverse TMZ resistance in vitro.Subsequently,the nucleotide gene therapy drug TDN-AS1411-siYAP1 was synthesized by connecting siYAP1 with tumor-targeting penetration aptamer AS1411 in tetrahedral nucleic acid framework in order to maximize the function of siYAP1 in reversing TMZ resistance.In vivo imaging system proved that the bionic MBs of microglia cell membrane hybrid effectively improved the nucleic acid drugs stability time.Finally,the bionic targeted drug delivery platform TDN-AS1411-siYAP1@cell MBs is prepared by connecting TDN-AS1411-siYAP1 with the cation-modified bionic targeting MBs of microglia cell membrane hybrid through electrostatic action.The platform cooperated with FUS to accurately transport siYAP1 to the tumor,achieving GBM transfection in vivo and reversing TMZ resistance.In summary,this study prepares new bionic targeted drug-carrying MBs through the hybridized cell membrane,effectively opened BBB in collaboration with FUS,improving GBM treatment.On this basis,aiming at the clinical problems of extensive drug resistance to TMZ,explore TMZ resistance mechanism and screen new therapeutic targets.The bionic targeted drug delivery platform TDN-AS1411-siYAP1@cell MBs is developed,and a "two-stage rocket" booster drug delivery system is formed in coordination with FUS,effectively achieving GBM transfection in vivo,and reversing TMZ resistance through inhibiting YAP1 expression.Therefore,this new model of bionic targeted drug delivery platform can be built as a multi-functional drug delivery platform for targeted imaging and treatment of other solid tumors.On the other hand,it can also provide new ideas and methods for the targeting and imitation modification of other tumors,which has great clinical transformation value and potential.