Platycodon Grandiflorum Combined With Doxorubicin In The Treatment Of Breast Cancer Lung Metastases In Mice With Increased Efficacy And Attenuated Effects And Pharmacokinetics

Objective:To observe the effect of platycodon grandiflorum combined with adriamycin on tumor growth and progression in mice with lung metastasis of breast cancer,explore the mechanism of platycodon grandiflorum anti-lung metastasis and reduce cardiac toxicity,and verify the scientific nature of the theory of traditional Chinese medicine.Methods:Pharmacodynamic experiments:70 Balb/c mice were randomly divided into normal group?Normal?,control group?Control?,adriamycin group?ADM?,adriamycin plus platycodon grandiform low-dose group?ADM+PG 0.5 g/kg?,adriamycin plus platycodon grandiform middle-dose group?ADM+PG 1 g/kg?,adriamycin plus platycodon grandiform high-dose group?ADM+PG 2 g/kg?,adriamycin plus dexrazoxane?ADM+DEX 25 mg/Kg?,10 each group after the successful establishment of mouse lung cancer lung metastasis model,except for the normal group were modeled.Each group started dosing on the 14th day after tumor inoculation.Adriamycin 2.5mg/kg was intraperitoneally injected every other day for a total of 7 times,with a total dose of17.5mg/kg.The low,medium and high dose groups of platycodon grandiflorum were given 0.5 g/kg,1 g/kg?equivalent to 6 g of platycodon grandiflorum for human use?,and2 g/kg dose by feeding once a day for 14 consecutive days.The normal group and the control group were fed with 0.9%normal saline for 14 consecutive days.The adriamycin plus dexrazoxane group was intraperitoneally injected with 25 mg/kg dexrazoxane once every other day for a total of 7 times.The mice were treated with color Doppler ultrasound,tumor in situ and lung nodules number after the last dose detecting the levels of ROS,MDA,CK-MB,c Tn I in serum and the expression of collagen I and III in myocardial tissue.Pharmacokinetic experiments:Use LC-MS/MS Studying the effects of platycodon grandiflorum on the pharmacokinetics and tissue distribution of adriamycin in mice with Lung Metastasis from Breast Cancer.After the successful establishment of the animal model of lung metastasis of breast cancer in mice,100 female Balb/c mice were randomly divided into adriamycin group and adriamycin plus platycodon grandiflorum group,with50 mice in each group.The two groups started to be dosed on the 14th day after inoculation of the tumor.The two groups were given intraperitoneal injection of adriamycin 10 mg/kg on the 21st and 28th days after tumor inoculation,a total of two times,with a cumulative dose of 20 mg/kg.In adriamycin plus platycodon grandiflorum group,the platycodon grandiflorum?1 g/kg?was fed once a day for 14 days.Plasma,heart,lung and tumor tissues of mice in the two groups were collected at 0,0.083,0.5,1,2,4,6,12,24,and 36h after the last dose of mice to determine the content of mycin.Results:1.Platycodon grandiflorum slice were soaked,refluxed,filtered and concentrated to prepare extract of platycodon grandiflorum.The contents of luteolin and platycodon grandiflorum saponins D in extract of platycodon grandiflorum were determined by HPLC and UPLC-MS/MS method for quality control.2.Establishment of a animal model of lung metastasis from breast cancer in mice,continuous intraperitoneal injection of adriamycin?2.5 mg/kg?for 2 weeks,the occurrence of myocardial damage caused by doxorubicin.3.Pharmacodynamic experiments suggest.Compared with the adriamycin group,adriamycin combined with platycodon grandiflorum group could increase the tumor inhibition rate in a concentration-dependent manner?p<0.05?.Adriamycin combined with platycodon grandiflorum in low-dose group can reduce heart weight index?p<0.05?.adriamycin combined with high-dose group of platycodon grandiflorum can significantly reduce the number of lung nodules?p<0.01?.cardiac pathological sections of adriamycin combined with platycodon grandiflorum showed that the degree of inflammatory infiltration was similar,the degree of myocardial space was decreased,the degree of myocardial edema was reduced,and no obvious hypertrophy and necrosis of cardiomyocytes were observed.The CK-MB of adriamycin combined with platycodon grandiflorum was significantly decreased and dose-effect relationship?p<0.01?.the c Tn I of adriamycin combined with low dose of platycodon grandiflorum was significantly decreased?p<0.01?;MDA in the serum of adriamycin combined with platycodon grandiflorum was significantly decreased and showed a dose-effect relationship?p<0.01?;adriamycin combined with platycodon grandiflorum and high dose group can significantly inhibit collagen I expression?p<0.01?;Adriamycin combined with platycodon grandiflorum can significantly inhibit the expression of collagen III,presents a concentration-dependent?p<0.01?.4.Pharmacokinetic experiments showed that the AUC_0-t of adriamycin combined with platycodon grandiflorum was 562.15±120.30 ng h m L-1,which was 1.3 times higher than that of the adriamycin group?441.98 97.88 ng h ml-1?.The C_max of adriamycin combined with platycodon grandiflorum group was 673.27±162.45 ng/m L,1.1 times higher than that of adriamycin group?618.70±308.82 ng/m L?.The total clearance rate of Cl/F in adriamycin combined with platycodon grandiflorum group was 16.21±2.71 L kg1 h 1,which was 20%lower than that in the adriamycin group 20.02±4.01 kg^-1 h^-1.5.Pharmacokinetic experiments suggest that the platycodon grandiflorum can promote the transport of adriamycin to the targeted tissue lungs and slow the elimination of the adriamycin compared with the adriamycin group,and reduce the transport of non-targeted tissues to heart tissues and speed up the elimination,while the transport to tumor tissues decreased but slowed down the elimination.Conclusions:Platycodon grandiflorum combined with adriamycin can significantly inhibit the growth and lung metastasis of lung cancer in mice with lung metastasis,and protect cardiac function and the mechanism may be related to inhibition of myocardial oxidative stress.Platycodon grandiflorum did not affect the pharmacokinetic process of adriamycin in mice;Platycodon grandiflorum can enhance the accumulation of adriamycin in the lungs and reduce the distribution in the heart,thereby synergize the effect and reduce the side effects of the heart,verifying the scientific nature of the Platycodon grandiflorum as a messenger drugs.