Paclitaxel prodrugs with sustained release and high solubility in poly(ethylene glycol)-b-poly(ε-caprolactone) micelle nanocarriers:: Pharmacokinetic disposition, tolerability, and cytotoxicity
Paclitaxel prodrugs with sustained release and high solubility in poly(ethylene glycol)-b-poly(ε-caprolactone) micelle nanocarriers:: Pharmacokinetic disposition, tolerability, and cytotoxicity
复制标题
DOI：
10.1007/s11095-007-9451-9
复制
发表时间：
2008-01-01
影响因子：
3.7
通讯作者：
Davies, Neal M.
中科院分区：
文献类型：
--
作者：
Forrest, M. Laird;Yanez, Jaime A.;Davies, Neal M.
目的。采用聚乙二醇-聚己内酯两亲嵌段共聚物胶束(PEGb-PCL)制备无溶剂、含乳油的紫杉醇制剂，并对其释放度、溶解性、细胞毒性、耐受性和释放性进行表征。为了克服紫杉醇在聚乙二醇-b-聚乙二醇单甲醚胶束中的载药量较低的问题，采用DCC/DMAP或酸酐化学方法合成了紫杉醇疏水前药。采用共溶剂萃取法制备了胶束。给大鼠静脉注射紫杉醇前药胶束制剂(PAX7‘C-6)10 mg/kg，并与相同剂量的紫杉醇(Taxol，R)和CrEL：Etoh中的PAX7’C-6作对照。测定药代动力学参数和组织分布。紫杉醇前药在PEG-b-PCL胶束中的溶解度为-5 mg/ml。所得的聚乙二醇b-聚乙二醇酯胶束含有17-22%w/w的前药，其直径小于50 nm。PEG-b-PCL胶束在几天内释放紫杉醇前体药物，t(1/2)和gt；3d，只有紫杉醇最短的7‘-己酸酰基衍生物(PAX7’C-6)保持了与未修饰紫杉醇相似的细胞毒活性。PAX7‘C-6胶束的曲线下面积、半衰期和平均滞留时间增加，总清除量和分布体积减小。紫杉醇前体药物在聚乙二醇b-PCL胶束纳米载体中增加了处置和耐受性，为进一步研究肿瘤的疗效奠定了基础。
Purpose. Develop a Cremophor((R)) and solvent free formulation of paclitaxel using amphiphilic block co-polymer micelles of poly(ethylene glycol)-b-poly(epsilon-caprolactone) (PEG-b-PCL) and characterize their release, solubility, cytotoxicity, tolerability, and disposition.Methods. Hydrophobic prodrugs of paclitaxel were synthesized via DCC/DMAP or anhydride chemistry to overcome the poor loading (< 1% w/w) of paclitaxel in micelles of PEG-b-PCL. Micelles were prepared by a co-solvent extraction technique. A micellar formulation of paclitaxel prodrug (PAX7'C-6) was dosed intravenously to rats (10 mg/kg) and compared to Taxol((R)) (paclitaxel in CrEL:EtOH) and PAX7'C-6 in CrEL:EtOH as controls at the same dose. Pharmacokinetic parameters and tissue distribution were assessed.Results. Paclitaxel prodrugs had solubilities > 5 mg/ml in PEG-b-PCL micelles. Resulting PEG-b-PCL micelles contained 17-22% w/w prodrug and were less than 50 nm in diameter. PEG-b-PCL micelles released paclitaxel prodrugs over several days, t(1/2)> 3 d. Only the 7'derivative of paclitaxel with the shortest acylchain 7'hexonoate (PAX7'C-6) maintained cytotoxic activity similar to unmodified paclitaxel. PAX7'C-6 micelles demonstrated an increase in area under the curve, half-life, and mean residence time while total clearance and volume of distribution decreased.Conclusions. Paclitaxel prodrugs in PEG-b-PCL micelle nanocarriers augment the disposition and increase tolerability making further studies on tumor efficacy warranted.