Solid lipid nanoparticles reduce systemic toxicity of docetaxel: Performance and mechanism in animal

Abstract

Nanotechnology presents great potential for increasing efficacy of docetaxel while reducing side-effects and toxicity. However, in vivo toxicity of nano-formulation of docetaxel has not been systemically investigated yet. Herein, the new docetaxel-loaded solid lipid nanoparticles (DSNs) were prepared, and systemic toxicity of DSNs in different animals was comprehensively investigated. The experimental results showed that no allergenicity and vascular irritation were induced by DSNs at the highest drug concentration of clinical infusion. The maximum tolerated dose (MTD) of DSNs was as high as 400 mg/kg in mice while the medial lethal dose (LD₅₀) of Taxotere was 149.31 mg/kg. The long-term toxicity of DSNs compared with Taxotere in beagle dogs by intravenous infusion weekly for four weeks showed that the administration of Taxotere at 1 mg/kg brought about severe signs of toxicity such as skin flushing, vocalization and salivation. However, no abnormal reactions appeared on animals treated with DSNs at dose of 4 mg/kg. At the same dose level, DSNs induced more minor decreases in body weight gains, slighter hemotoxicity (changes in some clinical hematology and biochemistry parameters), cardiac toxicity, hepatotoxicity and myelosuppression than Taxotere. These results could provide an important reference for developing the novel delivery system of docetaxel.

Keywords::

• Nanotoxicity
• nanoparticles
• docetaxel
• nanomedicine
• toxicity

Declaration of interest: The National Basic Research Program of China (2010CB934000 and 2007CB935800), the National Natural Science Foundation of China (30925041 and 30901866), National Science & Technology Major Project “Key New Drug Creation and Manufacturing Program” (No. 2009ZX09501-024- and 2009ZX09301-001), and the Important Direction Program of CAS (KSCX2-YW-R-193) are gratefully acknowledged for financial support. The authors report no conflict of interest. The authors alone are responsible for the content and writing of the paper.