Evaluation of doxorubicin-containing nanoparticle thermosensitive gel composite system on its extended release in vivo,antitumor,and intratumor retention
Objective To investigate the extended release performance in vivo,anti-tumor effect and intratumor retention performance of doxorubicin-loaded nanoparticles thermosensitive gel(DOX-NPs-Gel)composite system.Methods Eighteen SD male rats were randomly divided into doxorubicin(DOX)group,DOX-iodine oil group(1 mL 4 g/L DOX solution mixed with 1 mL iodine oil on site,5 mL/kg)and DOX-NPs-Gel group(5 mg/kg DOX+2 g/L DOX);then subjects received intraperitoneal injection;blood was taken through the fundus venous plexus at different time points after administration of drugs;the concentration of DOX in plasma was detected by ultra-performance liquid chromatography-tandem mass spectrometry(UPLC-MS/MS),and the main pharmacokinetic parameters were fitted by WinNonLin 8.1 software[half life period(t1/2),Cmox,area under the curve(AUC),clearance(CL),mean residence time(MRT)].Rats hepatocarcinoma strain H22 was cultivated and collected for suspension;single vaccination was performed in right axilla subcutaneous part of 90 male ICR rats for load tumor.Such experiment was divided into two parts:part one,36 rats with load tumor were evenly divided into normal saline group(injected with normal saline,5 mL/kg),blank NPs-Gel group(100 mg blank NPs lyophilized powder distributed in 1 mL blank Gel,5 mL/kg),iodine oil group(iodine oil,5 mL/kg),DOX group(2 g/L DOX,5 mL/kg),DOX-iodine oil group(1 mL 4 g/L DOX mixed with 1 mL iodine oil on site,5 mL/kg)and DOX-NPs-Gel group(2 g/L DOX,5 mL/kg);intratumor injected for one time and observed for 10 d,body mass was measured every two days after drug administration and calculated changes of body mass ration of all groups;the size and length of tumor was measured after weighing and tumor volume(V)was calculated;all the mice were sacrificed by neck removal after observation finished,tumor tissue was stripped,tumor mass was weighed and tumor inhibition rate was calculated;histological features of tumor tissue was observed by slicing and HE staining.Part two,54 load tumor mice were evenly divided into DOX group,DOX-iodine oil group,and DOX-NPs-Gel group;all subjects followed the same pattern of dosage and experiment method.At 12,24,48,72,96,and 120 h after drug administration,three mice from each group were sacrificed by neck removal,tumor tissue was stripped,UPLC-MS/MS was adopted to detect DOX intratumor retention rate of tumor tissue at different time points.Results Compared with other groups,in vivo extended-release performance study showed that the half-life(t1/2)of DOX-NPs-GEL group was prolonged,and CL rate decreased(P＜0.05).Findings of anti-tumor effect study indicated that,the growth of tumor tissues in DOX-NPs-Gel group was the slowest,the tumor weight decreased(P＜0.05),the tumor inhibitory rate was the highest(76.55％)compared with other treatment group.After HE staining,the tumor tissues showed large scale apoptosis and necrosis.The results of intratumor retention showed that the retention rate of DOX-NPs-Gel was(44.14±3.84)％on the 5th day,and the retention rate of other groups dropped to 0％on the 4th day.Conclusion Compared with DOX and DOX-iodide,DOX-NPs-Gel showed stronger extended-release properties,antitumor effects and intratumor retention in animals.
维普
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