Preparation and Characterization of Water-Soluble Prodrug, Liposomes and Micelles of Paclitaxel

Anand   Babu   Dhanikula; Ramesh      Panchagnula

Abstract

Alternative formulations of paclitaxel were developed in order to improve its aqueous solubility, and characterized in vitro. A methacrylic acid based nanoconjugate of paclitaxel was synthesized by a simple esterification reaction with molecular weight of 1657 Da. The in vitro hydrolysis study on the prodrug of paclitaxel in presence of rat plasma has shown that the ester bond was quite stable (less than 1% of paclitaxel was liberated from prodrug in 24 h). This water-soluble prodrug was encapsulated into polyethylene glycol coated liposomes optimized with saturated lipids, to overcome the physical instability associated with paclitaxel. Under in vitro testing, prodrug liposomes seem very impressive with release of only 45% of payload in 180 h. Further, chemical as well as physical stability studies have shown that liposomes were stable without any signs of crystallization of paclitaxel. In addition, paclitaxel was covalently coupled to poloxamer via methacrylic acid linker to obtain a micelle forming conjugate. Evidence for self-assembly of this conjugate into micelles was provided by fluorescence spectroscopy, light scattering and differential scanning calorimetry techniques. Micellization of the conjugate was thermodynamically favored and the core of resulting micelles exhibited higher microviscosities (than poloxamer micelles). Release studies using dialysis technique along with high performance liquid chromatography revealed that paclitaxel is liberated from micelle in the form of methacrylic acid oligomer based prodrug in a gradual manner. These preliminary studies provided indication on the performance and feasibility of testing these carrier systems as a safer alternative to the Cremophor EL based paclitaxel formulation.

Keywords: paclitaxel, prodrug, liposomes, micelles, stability

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