Application Of Temperature-sensitive Plateletsomes For Chemotherapy In Combination With HIFU Cancer Treatment

High-intensity focused ultrasound(HIFU),a novel therapeutic tool that has emerged in recent years as a non-invasive modality for cancers treatment,could employ focused ultrasound to ablate tumor tissue.However,it is challenging for HIFU to completely eradicate tumor because of the energy attenuation in deep-seated lesions.To solve this problem,the collaboration of HIFU and chemotherapy is an excellent strategy.Nevertheless,chemotherapeutic drugs generally show short half-life time and severe side effects due to a lack of tumor selectivity.Therefore,it is urgent to develop a drug delivery vector that can enhance the synergistic effect of HIFU and chemotherapy.Biomimetic camouflage,using natural cell membranes for drug delivery,could endow the nanocarrier some advantages,such as better biocompatibility,low immunogenicity,and active tumor targeting.In this research,temperature-sensitive plateletsomes(TSPs)was developed for chemotherapy in combination with HIFU cancer treatment by employing platelet(PLT)membrane,1-stearoyl-2-hydroxysn-glycero-3-phosphoch-oline(MSPC)and 1,2-dipalmityol-sn-glycero-3-phosph-ocholine(DPPC).The characterization of TSPs was investigated in vitro.The results show that TSPs was well dispersed in PBS with a particle size distribution of 119.26±4.52 nm.The TSPs displayed high drug encapsulation efficiencies,85.27±4.12%for doxorubicin(DOX).The tumor targeting efficiency and pharmacokinetic behavior of TSPs was investigated.At 24 h after injection,TSPs exhibited a blood retention of 16.3%ID/g,which was slightly lower than that of TSLs(18.9%ID/g)but much higher than that of DMLs(2.4%ID/g).Afterwards,the bio-distribution of different vesicles in the tumors and major organs of mice was compared at different time points.All vesicles were mainly accumulated in the liver,spleen and lungs at 24h post-injection.Among the vesicles,DMLs undergo fast clearance by the liver,spleen and lungs but do not effectively accumulate in the tumor.In contrast,TSPs and TSLs had relatively slower accumulations in the organs but showed gradually increased accumulations in the tumor.Notably,TSPs exhibited nearly 2.5-,2.0-and 2.8-fold greater accumulation than TSLs at 4,12 and 24 h post injection,respectively.These results demonstrated that the incorporation of the PM not only obtained benefits in improving the blood circulation of liposomal vesicles but also significantly enhanced the tumor targeting efficacy of liposomal vesicles.The therapeutic performance of DTSPs in combination with HIFU ablation was investigated in the HeLa cell tumor-bearing mouse model.Under HIFU hyperthermia,the tumor uptake of DTSPs was approximately 1.9-fold greater than that of DTSLs,and the drug availability of DTSPs-treated tumors was nearly 2-fold and 10-fold greater than that of DTSLs and free DOX groups,respectively.Notably,a sudden increase in tumor drug availability(nearly 37.5%ID/g)was observed in the DTSPs+HIFU group at 4-10 h after HIFU ablation,due to the efficient inflammatory tumor vasculature target of the TSPs.Within 18 days after treatment,DTSLs+HIFU treatment showed a significant chemotherapeutic effect among the other groups,resulting in the smallest tuIor volume of 35 mm3.Additionally,no apparent changes were found in the histology of the main organs(liver,heart,spleen,lungs and kidney).Hematology analysis showed that the levels of white blood cells(WBCs)and PLTs were elevated after HIFU ablation but returned to normal with time.Our results indicated that TSPs can act as a more efficient chemotherapy platform in combination with HIFU treatment for tumor therapy.