Shenyang Pharmaceutical University, Department of Pharmaceutics Science, Wenhua Road 103 Shenyang 110016 Liaoning Province, People's Republic of China.
Expert Opin Drug Deliv. 2012 Dec;9(12):1449-62. doi: 10.1517/17425247.2012.724675. Epub 2012 Sep 13.
The aim of this study was to perform a systematic preclinical evaluation of norcantharidin (NCTD)-loaded intravenous lipid microspheres (NLM).
Pharmacokinetics, biodistribution, antitumor efficacy and drug safety assessment (including acute toxicity, subchronic toxicity, hemolysis testing, intravenous stimulation and injection anaphylaxis) of NLM were carried out in comparison with the commercial product disodium norcantharidate injection (NI).
The pharmacokinetics of NLM in rats was similar to that of NI, and a non-linear correlation was observed between AUC and dose. A comparable antitumor efficacy of NLM and NI was observed in mice inoculated with A549, BEL7402 and BCAP-37 cell lines. It was worth noting that the NLM produced a lower drug concentration in heart compared with NI, and significantly reduced the cardiac and renal toxicity. The LD(50) of NLM was twice higher than that of NI. In NLM, over 80% of NCTD was loaded in the lipid phase or bound with phospholipids. Thus, NCTD was sequestered by direct contacting with body fluids and largely avoided distribution into tissues, consequently leading to significantly reduced cardiac and renal toxicity.
These preclinical results suggested that NLM could be a useful potential carrier for parenteral administration of NCTD, while providing a superior safety profile.
本研究旨在对载入静脉用脂微球的去甲斑蝥素（NCTD）进行系统的临床前评价。
将 NCTD 载入静脉用脂微球（NLM）与市售的去甲斑蝥酸钠注射液（NI）进行比较，对其进行药代动力学、生物分布、抗肿瘤疗效和药物安全性评估（包括急性毒性、亚慢性毒性、溶血试验、静脉刺激和注射过敏）。
NLM 在大鼠体内的药代动力学与 NI 相似，AUC 与剂量呈非线性相关。NLM 和 NI 在接种 A549、BEL7402 和 BCAP-37 细胞系的小鼠中显示出相似的抗肿瘤疗效。值得注意的是，NLM 在心内的药物浓度较 NI 低，且显著降低了心脏和肾脏毒性。NLM 的 LD50 是 NI 的两倍。在 NLM 中，超过 80%的 NCTD 载入脂相或与磷脂结合。因此，NCTD 通过与体液直接接触而被隔离，并在很大程度上避免了向组织分布，从而显著降低了心脏和肾脏毒性。
这些临床前结果表明，NLM 可能是 NCTD 静脉给药的一种有用的潜在载体，同时提供了更好的安全性。
