Department of Pharmaceutics, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
Department of Pharmaceutics, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran; Research Center for Nanotechnology in Drug Delivery, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
Colloids Surf B Biointerfaces. 2022 Jan;209(Pt 2):112187. doi: 10.1016/j.colsurfb.2021.112187. Epub 2021 Oct 27.
Cabazitaxel (CTX) is an anti-neoplastic agent of second-generation taxane derivatives, characterized by very low water solubility. The currently marketed formulation of CTX contains high concentrations of surfactant and ethanol, which causes severe hypersensitivity reactions in patients. To deal with aforementioned side effects, our previous study attempted to develop the prodrugs of CTX with dextran. Here our approach differs through synthesizing folate containing prodrug and also investigating cytotoxicity and pharmacokinetics parameters obtained with dextran and dextran-folate nanoconjugates versus free CTX. MCF-7 with medium folate receptor expression and MDA-MB-231 as high folate receptor expression cell lines were selected for cytotoxicity assay. Pharmacokinetics properties were studied by injecting prodrugs and CTX to Wistar rats, analyzing serum and selected tissue samples and the obtained results were sibjected to data modeling study. The size of synthesized prodrugs was mostly less than 90 nm. Folate conjugates provided higher toxicity in comparison with dextran conjugates on both cell lines. In vivo non-compartmental pharmacokinetics analysis revealed enhanced area under the curve (about 3-5 fold for different samples) and longer half-life (approximately 1.3-1.8 fold higher) which led to increased serum residence time of prodrugs in comparison to free CTX. Tissue accumulation data showed that liver was the major organ with high accumulation of CTX. The accumulation of folate conjugates was remarkably higher than dextran samples (p < 0.05 in samples of 2, 10 and 24 h). Data modeling by Principal Component Analysis (PCA) and Hierarchical Cluster models showed a significant difference between pharmacokinetics properties of CTX and prodrugs. In summary, prodrugs seem to be proper and promising CTX delivery systems as substitution for the current market formulation.
卡巴他赛（CTX）是第二代紫杉烷类衍生物的抗肿瘤药物，其水溶性极低。目前市售的 CTX 制剂含有高浓度的表面活性剂和乙醇，会导致患者发生严重的过敏反应。为了应对上述副作用，我们之前的研究试图用葡聚糖制备 CTX 的前药。在这里，我们的方法不同，我们合成了含有叶酸的前药，并研究了葡聚糖和葡聚糖-叶酸纳米缀合物与游离 CTX 的细胞毒性和药代动力学参数。选择 MCF-7（中等叶酸受体表达）和 MDA-MB-231（高叶酸受体表达）细胞系进行细胞毒性测定。通过向 Wistar 大鼠注射前药和 CTX，分析血清和选定的组织样本，研究药代动力学性质，并对所得结果进行数据模型研究。合成的前药的粒径大多小于 90nm。与葡聚糖缀合物相比，叶酸缀合物在两种细胞系中均表现出更高的毒性。体内非房室药代动力学分析显示，曲线下面积增加（不同样本约增加 3-5 倍），半衰期延长（约增加 1.3-1.8 倍），与游离 CTX 相比，前药在血清中的停留时间延长。组织积累数据表明，肝脏是 CTX 积累量最大的主要器官。叶酸缀合物的积累明显高于葡聚糖样品（2、10 和 24 小时的样本中，p<0.05）。主成分分析（PCA）和层次聚类模型的数据建模显示，CTX 和前药的药代动力学性质存在显著差异。综上所述，前药似乎是 CTX 的合适且有前途的递药系统，可以替代当前的市场制剂。
