title: Insights into accelerated liposomal release of topotecan in plasma monitored by a non-invasive fluorescence spectroscopic method.
abstract: A non-invasive fluorescence method was developed to monitor liposomal release kinetics of the anticancer agent topotecan (TPT) in physiological fluids and subsequently used to explore the cause of accelerated release in plasma. Analyses of fluorescence excitation spectra confirmed that unencapsulated TPT exhibits a red shift in its spectrum as pH is increased. This property was used to monitor TPT release from actively loaded liposomal formulations having a low intravesicular pH. Mathematical release models were developed to extract reliable rate constants for TPT release in aqueous solutions monitored by fluorescence and release kinetics obtained by HPLC. Using the fluorescence method, accelerated TPT release was observed in plasma as previously reported in the literature. Simulations to estimate the intravesicular pH were conducted to demonstrate that accelerated release correlated with alterations in the low intravesicular pH. This was attributed to the presence of ammonia in plasma samples rather than proteins and other plasma components generally believed to alter release kinetics in physiological samples. These findings shed light on the critical role that ammonia may play in contributing to the preclinical/clinical variability and performance seen with actively-loaded liposomal formulations of TPT and other weakly-basic anticancer agents.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Kyle D
authors.initials: KD
authors.lastname: Fugit
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Amar
authors.initials: A
authors.lastname: Jyoti
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Upreti
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA. Electronic address: bande2@email.uky.edu.
authors.forename: Bradley D
authors.initials: BD
authors.lastname: Anderson
mesh_terms: D000641:Ammonia / Q000737:chemistry; D006801:Humans; D008081:Liposomes; D008962:Models, Theoretical; D015203:Reproducibility of Results; D013050:Spectrometry, Fluorescence / Q000379:methods; D059004:Topoisomerase I Inhibitors / Q000097:blood* / Q000737:chemistry; D019772:Topotecan / Q000097:blood* / Q000737:chemistry
chemical_list: D008081:Liposomes; D059004:Topoisomerase I Inhibitors; D000641:Ammonia; D019772:Topotecan
keywords: Fluorescence spectroscopy; Liposomes; Nanotechnology; Release kinetics; Topotecan