The Study Of Plasma Pharmacokinetics And Antitumor Pharmacodynamics Of Irinotecan Liposome

The“Updated Global Cancer Burden data 2020”shows that in 2020,the number of new cancer cases in China was accounting for 23.7%of that in the world（4.57 million in China）,ranking first in the world.In 2020,the number of breast cancer patients in China increased dramatically,reaching to 420,000 cases,and the number of deaths reaching to 120,000.Breast cancer seriously threatens women’health.Currently,the main chemotherapy drugs used in the treatment of breast cancer include paclitaxel,anthracycline,cyclophosphamide,as well as platinum（oxaliplatin）.Irinotecan（CPT-11）,as a cytotoxic drug developed by Japan,entered phase I clinical trial in 1987 and was marketed in China in March 2001.It has been proved that Irinotecan was effective against a variety of tumors,including colon cancer,pancreatic cancer,cervical cancer,ovarian cancer and other malignant tumor.Onivyde（?）（Irinotican Liposome Injection）is a long-circulating liposome for the treatment of pancreatic cancer,approved by the US FDA on October 22,2015.Irinotecan injection is a second-line drug for the treatment of breast cancer.Breast cancer is a cancer with good treatment effect,and its survival rate is improved significantly in recent years.However,there are not many optional treatment drugs for triple-negative breast cancer with the highest clinical incidence,the worst treatment effect and the highest fatality rate.The efficacy and adverse reactions of irinotecan in the treatment of breast cancer using liposome as delivery system have not been reported.Based on the experience of liposome as a drug carrier system,it can improve the stability of liposome in the circulating system,reduce drug toxicity and adverse reactions,and improve the therapeutic index of drugs.Drug liposomes improve the therapeutic targets of various drugs by changing pharmacodynamics and pharmacokinetics.Due to the complex pharmacokinetics of irinotecan liposomes in animals and humans,a large number of experimental studies are needed to determine more accurate detection methods.In this study,the content detection method of irinotecan liposome in plasma was established to study the pharmacokinetics of irinotecan liposome in rat plasma,the application of irinotecan liposomes in the treatment of breast cancer was explored and new indications for irinotecan liposomes was expanded.the The irinotecan liposome injection was injected into tail vein at the doses of 5,10,20 mg·kg^-1,respectively,and the content of irinotecan in rat plasma was determined by HPLC.The pharmacokinetic parameters were calculated and analyzed according to the non-compartmental model of the pharmacokinetic module by DAS3.0 software.SPSS 18.0 software was used for statistical analysis of pharmacokinetic parameters.The MMTV-Wnt1 breast tumor was inoculated subcutaneously into the right forelimb of nude mice to establish a nude mouse mammary tumor xenograft model.After the tumor volume reached the experimental requirements,the nude mice were randomly divided into 5 groups according to the tumor volume,namely irinotecan liposome high-dose,medium-dose and low-dose groups,irinotecan injection positive control group,and the negative control group.The drugs were administered once every 2 days,and the body weight and tumor volume were monitored every 3 days.The changes in relative tumor volume,relative tumor proliferation rate T/C（%）and tumor inhibitory growth rate IR（%）were used as evaluation indexes.The irinotecan plasma control solution has a good linearity in the range of0.20-100.02μg·m L^-1（R=0.9993）.Compared with irinotecan injection,the plasma peak concentration C max of irinotecan liposome injection was significantly increased（82times）,the mean retention time MRT（0-T）was significantly prolonged（14.6 times）,half-life T1/2 was significantly prolonged（6.5 times）,and total plasma exposure of irinotecan injection was significantly increased（748.5 times）.The statistical analysis showed a significant difference.The mean tumor volume of the three doses of irinotecan liposome(20,10,5 mg·kg^-1)and irinotecan injection on day 21 were 169mm³,155 mm³,170 mm³,273 mm³,respectively（P<0.01）.The relative growth rate（T/C）was 14.09%、11.83%、14.94%、21.33%（T/C<40%）,respectively.The tumor weight inhibition rates（IR）were 92.522%,92.781%,89.244%,79.413%,respectively（P<0.05）.Compared with irinotecan injection,the pharmacokinetics of irinotecan liposome was significantly improved,which can enhance the efficacy of irinotecan injection.Compared with the injection,the therapeutic effect of irinotecan liposomes in inhibiting breast cancer was obvious,indicating that irinotecan liposomes have excellent prospects in anti-breast cancer treatment.