Preclinical evaluations of norcantharidin-loaded intravenous lipid microspheres with low toxicity

Abstract

Objectives: The aim of this study was to perform a systematic preclinical evaluation of norcantharidin (NCTD)-loaded intravenous lipid microspheres (NLM).

Research design and methods: 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).

Results: 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 LD₅₀ 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.

Conclusions: These preclinical results suggested that NLM could be a useful potential carrier for parenteral administration of NCTD, while providing a superior safety profile.

Keywords::

• antitumor efficacy
• biodistribution
• norcantharidin-loaded lipid microsphere
• pharmacokinetics
• reduced toxicity

Acknowledgement

Professor Hui Zheng (Department of Pharmacology, China National Institute for Radiological Protection) and Professor Wei Yang (Department of Pharmacology, Guangzhou General Pharmaceutical Research Institute) are kindly acknowledged for the assistance in the antitumor activity and safety test. Dr. David B Jack is gratefully thanked for correcting English of the manuscript.