| Objective: To investigate whether the ultrasound targeted microbubble destruction(UTMD)in combination with mild hyperthermia(MH)can further improve the extravasation of chemotherapeutic drugs.Methods:Establishing the animal model of rabbit,with VX2 tumors transplanted into the superficial muscle of the hind limb;Twelve rabbits with VX2 tumors were randomly divided into 2 groups : 41 ? MH+ pegylated liposomal doxorubicin(PLD)group(n=6)and 43 ? MH+PLD group(n=6).To achieve complete tumor remission,multiple high-dose administrations(5 mg/kg,once per week for a total of 3 weeks)were given.An embedded ultrasound tumor hyperthermia instrument was used to induce local hyperthermia.The antitumor efficacy of rabbit VX2 tumor intervened by combination of 41? or 43? MH and PLD were assessed by the tumor weight,the AST,LDH and CPK value in peripheral blood,and the Vascular Index(VI);Nine rabbits with VX2 tumors were randomly divided into 3 groups : DOX(n=3);DOX+ intravenous injection MBs(IVMBs)group(n=3)and DOX+ intratumor injection MBs(ITMBs)group(n=3).Bolus intravenous injection of MBs(0.2ml/kg)through ear vein or intratumor injection of MBs(0.2 ml/kg)wasfollowed by injection of DOX(5mg/kg,5 minutes),real-time three-dimensional ultrasound was performed to irradiate the tumor for 10 minutes.The rabbits were sacrificed by overdose of anesthesia four hours after the treatment.Tumors,organs and tissue homogenates were analyzed by Ultra high performance liquid chromatography(UPLC)to determine drug concentrations,in order to explore the optimal microbubbles dosing way on UTMD mediated extravasation of chemotherapeutic drugs;Twenty-four rabbits tumor modle were randomly assigned to the following 4 treatment groups:(1)DOX(n=6),(2)DOX+IVMBs(n=6),(3)DOX+MH(n=6)and(4)DOX+MH+IVMBs(n=6).Embedded ultrasound tumor hyperthermia instrument was used to perform ultrasound MH under 41 ? for 30 min or false MH instantly after injection of DOX(5mg/kg,5 minutes)through ear vein.After bolus injection of MBs or normal saline(0.2mg/kg)through ear vein,real-time three-dimensional ultrasound was performed to irradiate the tumor for 10 minutes.The rabbits were sacrificed by overdose of anesthesia four hours after the treatment.Tumors,organs and tissue homogenates were analyzed by UPLC to determine drug concentrations.The system toxicity and chemotherapy response were assessed by the drug concentration of the liver,heart,kidney and the tumor tissue,while targeted property of drug delivery to tumor was estimated by the DOX drug ratios of tumor tissues compared to tumor tissue-adjacent muscles.Results: At the studyendpoint,the vascular index(VI),the tumor weight,and the AST,LDH and CPK value in peripheral blood,the vascular index(VI),and the tumor weight in PLD+41?MH group was significantly lower than that of PLD+43?MH group(P<0.05);Drug concentration in the tumor tissue of intratumoral injection MBs was higher than that of intravenous injection MBs group,but has no statistical differences(P>0.05);In terms of the drug concentration in the tumor tissues,and the relative drug concentration of tumor tissue and tumor tissue adjacent muscles,DOX+MH+IVMBs group was significantly higher than that of DOX,DOX+IVMBs,and DOX+MH groups,while the drug concentration in liver was the lowest.Conclusions: In comparison with 43? 30 min,the thermal dose of 41? 30 min could significantly improve the antitumor efficacy,as well as reduce system toxicity.Under the irradiation of real-time 3D diagnostic ultrasound,the two dosing way(intravenous injection or intratumoral injection)have no difference on the effect of UTMD promote the extravasation of chemotherapeutic drugs;UTMD in combination with local MH can further promote the extravasation of chemotherapeutic drugs,reduce the toxicity of system. |
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