Research On Pharmacokinetics,Tissue Distribution And Acute Toxicity Of Estrogen-targeted PEGylated Liposomes Loading Oxaliplatin

Oxaliplatin?OXA?is a third-generation platinum-based chemotherapeutic drug.Oxaliplatin slows cisplatin's nephrotoxicity and carboplatin's myelosuppression,but clinical oxaliplatin still has serious toxic side effects.This preparation of non-toxic targeted long circulating nanocarriers has become a necessary choice to solve its toxic side effects.Studies have shown that some tumor cells express high levels of estrogen.Our laboratory has synthesized an estrogen-targeting fragment to prepare estrogen-targeted long-circulating oxaliplatin liposomes?ES-SSL-OXA?.The liposome can effectively inhibit tumor cell proliferation in vitro and in vivo.A series of studies were conducted to explore the pharmacokinetics,tissue distribution and acute toxicity of ES-SSL-OXA in vivo.High-performance liquid chromatography?HPLC?is an efficient,rapid,and sensitive detection method that uses the principle of UV to detect sample components.Oxaliplatin in plasma samples and tissue samples is complexed with silver diethyldithiocarbamate?DETC?to form platinum complexes.The content of the complex can be specifically detected by HPLC,and then the Austrian complex can be calculated.Saliplatin content.HPLC conditions:C₁₈ reverse column,column length150 mm,column diameter 4.6 mm,column center diameter 5?m,mobile phase composition methanol:water=78:22?v:v?,injection volume 20?L,mobile phase flow rate 1 mL/min,the detection wavelength is 254 nm.Using this analytical method,plasma and tissue sample recovery was determined.The recoveries of plasma and tissue were between 92.4%and 100.14%,and the standard curve R² was more than 0.9992.At the same time,plasma and tissue concentrations of free oxaliplatin were measured to obtain plasma drug concentration curves.DAS 2.0 was used to process the data of plasma concentration over time,and the area under the curve of the drug was obtained,as well as other pharmacokinetic parameters.The plasma drug-time curve area?ACU?0-???ES-SSL-OXA group was4.05 times that of the OXA group and 2.25 times that of the L-OXA group.The plasma clearance?CL?of the ES-SSL-OXA group was 0.082 L/h/kg,and that of the OXA group was 0.332 L/h/kg.The CL of the ES-SSL-OXA group was only about 1/4of that of the OXA group.Tissue distribution data showed that the oxaliplatin concentration in the ES-SSL-OXA group was higher than that in the free drug group and the L-OXA group,indicating that estrogen-targeted long-circulating liposomes can reduce the plasma protein and oxaliplatin The combination increases the tissue distribution of oxaliplatin,effectively prolongs the cycle time of oxaliplatin in vivo,and improves the bioavailability of oxaliplatin.In the oxaliplatin acute toxicity test,the LD₅₀ value in the OXA group was 14.78 mg/kg,the LD₅₀ in the L-OXA group was16.313 mg/kg,and the LD₅₀ value in the ES-SSL-OXA group was 19.095 mg/kg.The LD₅₀ of ES-SSL-OXA was 1.29 times that of the OXA group.In the whole blood analysis data,there was no difference in the hematological parameters of the ES-SSL-OXA group when compared with the normal group when the dose was 16mg/kg.The number of white blood cells?p<0.05?,neutrophils?p<0.05?,monocytes?p<0.05?,and platelets were significantly lower in the OXA group than in the normal group?p<0.001?.This indicates that oxaliplatin caused significant myelosuppression at this dose,whereas there was no significant bone marrow suppression in the ES-SSL-OXA group.There was no significant difference in blood urea nitrogen and creatinine levels at this dose.The creatinine level was significantly higher in the OXA group than in the normal control group,indicating that oxaliplatin was free at this dose.The drug causes nephrotoxicity,and the liposome group can significantly reduce nephrotoxicity.