Intravenous lipid microspheres loaded with alkylated norcantharidin derivative norcantharimide: Improved stability and prolonged half‐life

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 (−1.06), pH = 7.4). After optimization of the lipid microsphere formulation, the particle size distribution, zeta‐potential and entrapment efficacy were determined to be 189.2 ± 49.8 nm, −26.78 ± 1.03 mV, and 98.4 ± 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 Vss 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.Significantly enhanced stability and prolonged half‐life were obtained for N‐14NCTDA LMs compared with NCDT LMs.