A Novel Strategy for Liposomal Drug Separation in Plasma by TiO2 Microspheres and Application in Pharmacokinetics

Yue-yang Yu,1,2 Mei Yuan,1 Wei-jie Qin,3 Hai-hong Bai,4 Hong-zhuo Liu,2 Jin-jing Che1 1Beijing Institute of Pharmacology and Toxicology, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing, People’s Republic of China; 2Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, People’s Republic of China; 3State Key Laboratory of Proteomics, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing, People’s Republic of China; 4Phase I Clinical Trial Center, Beijing Shijitan Hospital of Capital Medical University, Beijing, People’s Republic of ChinaCorrespondence: Hong-zhuo Liu, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, People’s Republic of China, Tel/Fax +86 13236637187, Email liuhongzhuo@syphu.edu.cn Jin-jing Che, Beijing Institute of Pharmacology and Toxicology, No. 27 Taiping Road, Beijing, People’s Republic of China, Tel/Fax +86 01066930633, Email chejinjing80@126.comPurpose: Liposomes are nano-scale materials with a biofilm-like structure. They have excellent biocompatibility and are increasingly useful in drug delivery systems. However, the in vivo fate of liposomal drugs is still unclear because existing bioanalytical methods for quantitation of total and liposomal-encapsulated drugs have limits. A novel strategy for liposomal-encapsulated drug separation from plasma was developed via the specific coordinate binding interaction of TiO2 microspheres with the phosphate groups of liposomes.Methods: Liposomal-encapsulated docetaxel was separated from plasma by TiO2 microspheres and analyzed by the UPLC-MS/MS method. The amount of TiO2, pH of the dilutions, plasma dilution factors and incubation time were optimized to improve extraction recovery. The characterization of the adsorption of liposome-encapsulated drugs by TiO2 microspheres was observed by electron microscopy. For understanding the mechanism, pseudo-first and the pseudo-second order equations were proposed for the adsorption process. The study fully validated the method for quantitation of liposomal-encapsulated in plasma and the method was applied to the pharmacokinetic study of docetaxel liposomes.Results: The encapsulated docetaxel had a concentration range of 15– 4000 ng/mL from the plasma sample using a TiO2 extraction method. Successful method validation proved the method was sensitive, selective and stable, and was suitable for quantitation of docetaxel liposomes in plasma samples. Extraction recovery of this method was higher than that of SPE method. As shown in electron microscopy, the liposomes adsorbed on TiO2 microspheres were intact and there was no drug leakage. The study proposed pseudo-first and the pseudo-second order equations to facilitate the adsorption of liposomal drugs with TiO2 microspheres. The proposed strategy supports the pharmacokinetic study of docetaxel liposomes in rats.Conclusion: TiO2 extraction method was stable, reproducible, and reliable for quantitation of encapsulated docetaxel. Because of versatility of lipids, it is expected to a universal bioanalysis method for the pharmacokinetic study of liposomes.Graphical Abstract: Keywords: liposomal-encapsulated drug, docetaxel liposomes, TiO2 microspheres, coordinate binding, bioanalysis