Study On The Preparation,Characterization,Pharmacokinetics And Acute Toxicity Of A New Paclitaxel Loaded Stabilized And Targeted Liposomes

Objective: This paper aims to design and prepare a new type of long-circulating targeted paclitaxel liposome preparation.Based on the characteristics of estrogen receptor over-expressed on the surface of breast cancer cells,the drug is specifically targeted to breast cancer cells.Prolong the half-life of drugs,increase the bioavailability of drugs,increase the uptake of drugs by tumor cells,and reduce the toxic and side effects of drugs.The characterization,pharmacokinetics,and acute toxicity of long-circulating paclitaxel liposome formulations were investigated.Methods:(1)Preparation of paclitaxel general liposome(L-PTX)and paclitaxel long-acting targeted liposome(ES-SSL-PTX)preparations by thin film hydration method.HPLC method for the determination of paclitaxel was established.The characterization of plastid preparations was studied: dynamic light scattering particle size analyzer was used to determine the liposomal particle size distribution and Zeta potential.The low-speed centrifugation was used to determine the liposomal encapsulation efficiency and drug loading.(2)HPLC method for paclitaxel production in mice was established.Pharmacokinetics experiments were performed using ICR mice as an animal model.The concentrations of paclitaxel,paclitaxel,liposomes,paclitaxel,and long-circulating targeted liposomes at different times were measured.The concentration of organ,statistical analysis of t1/2,AUC,MRT and other pharmacokinetic parameters,and analyze the distribution of the three paclitaxel formulations in mice within 48 hours.(3)Using ICR mouse as a model,acute toxicity experiments of three preparations of paclitaxel injection,paclitaxel common liposome and paclitaxel long-circulating targeted liposome were performed.The LD50 and maximal tolerated dose(MTD)of three drugs against ICR mice were investigated.The symptoms,weight changes,major hematological parameters,and differences in doses after administration of mice were investigated.The safety of different paclitaxel formulations.RESULTS:(1)In this study,a long-acting paclitaxel-targeted paclitaxel-targeting strategy was developed using the membrane hydration method,which contained ES-PEG2000-DSPE targeting fragment and DSPE-mPEG2000 long-acting fragment.Liposomal preparations,the preparation method is simple and easy,the obtained liposome particle size in the range of 120-140 nm,uniform stability,with a certain negative charge,the encapsulation rate is about 86%,drug loading in 6.0 Between % and 7.4%,the entrapment efficiency and drug loading are high,and the release rate at 4°C for 48 hours is less than 10%,which has the potential in clinical application.(2)Pharmacokinetics experiments showed that the elimination half-lives of PTX,L-PTX and ES-SSL-PTX groups were 1.79,2.26,and 20.98 hours,respectively.The elimination half-life of paclitaxel long-acting targeted liposomes was 11.1 and 9.3 times that of free paclitaxel and paclitaxel ordinary liposomes,respectively,and the elimination half-life was significantly prolonged.The AUC0-? of paclitaxel long-acting targeted liposomes was 107.69 mg/L*h,which was significantly improved by 5.2-fold and 3.8-fold bioavailability of free paclitaxel and paclitaxel common liposomes,respectively.In addition,the long-acting targeted liposome clearance CL of paclitaxel was significantly reduced,and the mean residence time(MRT)was significantly prolonged.(3)The LD50 value of long-acting targeting liposomes for ICR mice was 166.39 mg/kg,which was 4.6 times that of paclitaxel injection and significantly higher than that of paclitaxel common liposomes;ICR mice to paclitaxel The maximum tolerated dose was 20 mg/kg for paclitaxel injection,and increased to 80 mg/kg for paclitaxel and liposomal liposomes and long-circulating targeted liposomes,indicating that long-circulating targeted liposomal formulations can effectively reduce paclitaxel injections.The toxic side effects.Conclusion: This study selected a high expression of estrogen receptor in breast cancer as a long-acting targeted liposome target.The pharmacokinetics experiment and acute toxicity experiment proved that the long-circulating targeted paclitaxel liposome preparation prepared in this article can prolong the action time of the drug,increase its bioavailability,and reduce its toxic and side effects.The long-acting targeted paclitaxel liposome ES-SSL-PTX has great potential for the treatment of clinical breast cancer,and it is expected to significantly improve the clinical efficacy of paclitaxel and reduce its toxic and side effects,thereby improving the patient's life and quality of life.