Synthesis, cytotoxicity assay, pharmacokinetics, biodistribution and modeling study of cabazitaxel-dextran nanoconjugates: targeted vs non targeted delivery

Abstract

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.