No abstract

To facilitate the preparation of lipid microspheres, norcantharimide, a C14 alkyl chain derivative of norcantharidin, was synthesized and its physicochemical properties were investigated. The N-14NCTDA loaded lipid microspheres (N-14NCTDA LMs) were prepared by a high-pressure homogenization method and characterized in terms of size, zeta-potential, encapsulation efficiency and stability. The apparent oil-water partition coefficient of N-14NCTDA (Log P > 2) was considerably enhanced in comparison to NCTD (Log P (À1.06), pH ¼ 7.4). After optimization of the lipid microsphere formulation, the particle size distribution, zeta-potential and entrapment efficacy were determined to be 189.2 AE 49.8 nm, À26.78 AE 1.03 mV, and 98.4 AE 0.38%, respectively. High physical and chemical stability was demonstrated in accelerated stability test. A pharmacokinetic study was carried out in rats after intravenous administration of N-14NCTDA LMs and N-14NCTDA solution. Their pharmacokinetic profiles were similar with no significant differences in main parameters. Nevertheless, it was noteworthy that a greatly prolonged half-life and higher V ss was obtained for N-14NCTDA LMs compared with NCTD loaded lipid microspheres (NCTD LMs). Therefore, the N-14NCTDA LMs with high encapsulation efficiency and high stability are superior for the treatment of cancer, not only due to reduced venous irritation, but also due to prolonged half-life.Practical applications: Norcantharidin (NCTD) has been shown to be effective against cancer, especially against primary hepatic carcinoma, but its application is limited by severe renal toxicity and short half-life. Compared to common injection preparations, lipid microspheres loaded with NCTD lead to greatly reduced venous irritation but problems with low encapsulation efficiency, short half-life and high kidney toxicity have not been solved. N-14NCTDA is a new synthetic chemotherapeutic agent, which displayed good broad spectrum cytotoxicity compared with NCTD. In this preformulation study we show that N-14NCTDA is a promising alternative to NCTD.