title: 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.
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Gao
authors.forename: Rongfu
authors.initials: R
authors.lastname: Yang
authors.forename: Zhiwen
authors.initials: Z
authors.lastname: Zhang
authors.forename: Lingli
authors.initials: L
authors.lastname: Chen
authors.forename: Zuyue
authors.initials: Z
authors.lastname: Sun
authors.forename: Yaping
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D016009:Chi-Square Distribution; D000077143:Docetaxel; D004285:Dogs; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity; D004562:Electrocardiography / Q000187:drug effects; D006168:Guinea Pigs; D006651:Histocytochemistry; D007928:Lethal Dose 50; D008055:Lipids / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D008099:Liver / Q000187:drug effects; D008297:Male; D020714:Maximum Tolerated Dose; D051379:Mice; D008813:Mice, Inbred ICR; D050997:Nanomedicine; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D011817:Rabbits; D043823:Taxoids / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D013950:Thymus Gland / Q000187:drug effects; D018675:Toxicity Tests
chemical_list: D004337:Drug Carriers; D008055:Lipids; D043823:Taxoids; D000077143:Docetaxel