Engineering Temperature-sensitive Plateletsomes As A Tailored Chemotherapy Platform In Combination With HIFU Ablation For Cancer Treatment

High-intensity focused ultrasound(HIFU)surgery,which employs focused ultrasound to thermally and mechanically ablate target lesions,has become a powerful therapeutic methodology for cancer.Nevertheless,it is challenging for HIFU to completely eradicate a tumour because of the energy attenuation in deep-seated lesions.To improve the outcome,the coadministration of HIFU and chemotherapy is an important strategy;however,the systemic administration of chemotherapeutic drugs often causes low therapeutic efficiency and severe side effects due to a lack of tumor selectivity.In this study,temperature-sensitive plateletsomes(TSPs)composed of platelet(PLT)membrane,l-stearoyl-2-hydroxysn-glycero-3-phosphocholine(MSPC)and 1,2-dipalmityol-sn-glycero-3-phosphocholine(DPPC)has been designed to enhance the synergistic effect of HIFU and chemotherapy on tumor treatment.TSPs with well-preserved PLT biomarkers were fabricated by using DPPC and MSPC to fuse with PLT membrane in different mass ratios.Here,TSPs containing 20,35,50 and 65 wt.%DPPC and MSPC are abbreviated as TSPs-1,TSPs-2,TSPs-3 and TSPs-4,respectively.The phase transition temperature(Tm)values of TSPs-1,TSPs-2,TSPs-3 and TSPs-4 were 51.8,46.32,42.52 and 42.16?.All TSPs showed high drug encapsulation efficiencies over 80%for doxorubicin(DOX).TSPs-3,TSPs-4 can be released 83.4%and 89.33%of DOX at 42? over 2 min.Under HIFU hyperthermia at 42?,the amounts of drug released from TSPs-3 and TSPs-4 reached approximately 100%within 2 min.The cancer cell affinity of TSPs-3 was investigated in vitro.The cell uptake experiments showed that the preferential internalization of TSPs-3 by HeLa cells is attributed to the high affinity between the P-selectin and CD44 receptor.Therapeutic effect in vitro showed that TSPs-3 exhibited almost no toxicity to HeLa cells even at a high incubation concentration(200?g/mL).After drug loading,the IC50 values of TSPs-3 against HeLa cells were 12.56±1.37?M and 7.89±0.92?M at 24 h and 48 h,respectively.Combined HIFU hyperthermia(42?,2 min),The IC50 values of TSPs-3 against HeLa cells were significantly reduced by more than 50%at 24 h and 48 h.The survival rate of HeLa cells were further reduced in synergy with HIFU ablation.The results indicated that TSPs-3 could achieve better therapeutic effect under the treatment of HIFU ablation,and had certain application prospect in the treatment of HIFU tumor ablation.