Candesartan Promoted The Anticancer Efficacy Of Zoledronic Acid Liposomes

Objective In this study,we prepared Zoledronic acid Liposomes by PEG(PEG-ZOL-LPs).By establishing the co-culture model of murine fibroblasts(3T3)and human breast cancer(4T1),the aim of this study was to examine the effectiveness of Angiotensin Receptor Blocker(ARB)Candesartan on murine fibroblasts.Zoledronic acid Liposomes was used to improve anticancer effificacy.Methods 1.PEG-ZOL-LPs were prepared with DSPE-PEG2000-NH2,lecithin and cholesterol by thin-film dispersion method.The appearance and characterization of PEG-ZOL-LPs were observed by transmission electron microscopy.The average particle size and Zeta potential were measured by photon correlation spectroscopy.The encapsulation efficiency and drug loading were determined by HPLC.2.The murine fibroblasts(3T3)were cultured and given candesartan(20,40,60,80?mol·L-1)for 24 h?48h?72h.And the content of tapy I collagen,hyaluronic acid and Transforming Growth Factor-?1(TGF-?1)were determined by Enzyme-linked Immunosorbent Assay(ELISA).The co-culture model of 3T3 with breast cancer cells(4T1)was constructed by using the Transwell compartment to study the effect of 3T3 cells on the invasive ability of 4T1 cells after being given candesartan.3.We established a naked mouse model of breast cancer cell.The calculation of the weight and size of tumor were measured.The content of type I collagen,hyaluronic acid and TGF-?1 in serum were determined by ELISA.The anti-tumor effect of PEG-ZOL-LPs through candesartan was studied.Results 1.The appearance of the PEG-ZOL-LPs was round and spherical with good uniformity.The average particle size was(227±11.03)nm and the Zeta potential was(0.027±0.010)mV.The encapsulation efficiency was(25.11±4.56)%,and the drug loading was(0.43±0.08)%.It met that the expected requirements and had a good stability which with the requirement of drug intravascular delivery in tumor.2.We found that candesartan(20,40,60,80 ?mol·L-1)decreased the content of type I collagen,hyaluronic acid and TGF-?1 in 3T3 after 24h?48h?72h of administration.And the present study showed that candesartan had regulating 3T3.Compared with the blank control group,the migration ability of 4T1 cells was significantly reduced by candesartan(40,60,80?mol·L-1),and the difference was statistically significant(p<0.05 or p<0.01).The results showed that candesartan inhibited milk in a dose-dependent manner adenocarcinoma cell invasion ability.With the increase of administration concentration,cell invasion ability gradually decreased.3.Through animal experiments,it was found that candesartan combined with PEG-ZOL-LPs group showed stronger tumor inhibition compared with other experimental groups(p<0.05)and was better than PEG-ZOL-LPs group(p<0.05).The contents of I collagen,hyaluronic acid and TGF-?1 in serum of nude mice of candesartan combined with PEG-ZOL-LPs group decreased significantly compared with the model control group,candesartan group and PEG-ZOL-LPs group(p<0.05 orp<0.01).Conclusion This study showed that the encapsulation efficiency,average particle size and Zeta potential of PEG-ZOL-LPs were in line with expectations and good stability.By selecting different doses of candesartan to study the regulatory effect of candesartan on mouse-derived fibroblasts,it was found that candesartan can reduce fibroblast synthesis of extracellular matrix and can inhibit the invasive ability of breast cancer cells.The co-culture model of mouse-derived fibroblasts(3T3)and breast cancer cell line(4T1)was established by constructing sequential administration of candesartan and PEG-ZOL-LPs.It was found that candesartan could reduce PEG-ZOL-LPs penetration into tumor tissue by inhibiting TGF-?1 production while reducing tapy I collagen and hyaluronic acid production Obstacles.Therefore,through the change of tumor volume,we could see that the anti-tumor effect of candesartan combined with PEG-ZOL-LPs was better than candesartan group or PEG-ZOL-LPs group.These results indicated that candesartan has the function of regulating extracellular matrix,which could improve the therapeutic effect of anti-tumor drugs and provide the basis for the development of novel anti-tumor nanologics.