title: Preclinical evaluations of norcantharidin-loaded intravenous lipid microspheres with low toxicity.
abstract: OBJECTIVE
  The aim of this study was to perform a systematic preclinical evaluation of norcantharidin (NCTD)-loaded intravenous lipid microspheres (NLM).
  
  
  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 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.
  
  
  CONCLUSIONS
  These preclinical results suggested that NLM could be a useful potential carrier for parenteral administration of NCTD, while providing a superior safety profile.
authors.affiliation: Shenyang Pharmaceutical University, Department of Pharmaceutics Science, Wenhua Road 103 Shenyang 110016 Liaoning Province, People's Republic of China.
authors.forename: Xia
authors.initials: X
authors.lastname: Lin
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.forename: Keru
authors.initials: K
authors.lastname: Zhang
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Juan
authors.initials: J
authors.lastname: Wang
authors.forename: Na
authors.initials: N
authors.lastname: Qi
authors.forename: Shenshen
authors.initials: S
authors.lastname: Yang
authors.forename: Haibing
authors.initials: H
authors.lastname: He
authors.forename: Xing
authors.initials: X
authors.lastname: Tang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000633:toxicity*; D001191:Arylamine N-Acetyltransferase / Q000037:antagonists & inhibitors; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000493:pharmacokinetics* / Q000633:toxicity*; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D004337:Drug Carriers; D004353:Drug Evaluation, Preclinical; D005217:Fat Emulsions, Intravenous; D005260:Female; D006168:Guinea Pigs; D006461:Hemolysis; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008863:Microspheres; D010316:Particle Size; D010323:Passive Cutaneous Anaphylaxis; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D053719:Tandem Mass Spectrometry; D014018:Tissue Distribution; D018366:Vasculitis, Leukocytoclastic, Cutaneous / Q000139:chemically induced; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004337:Drug Carriers; D005217:Fat Emulsions, Intravenous; C069741:norcantharidin; D001191:Arylamine N-Acetyltransferase