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J Pharm Biomed Anal. 2016 Jan 5;117:532-43. doi: 10.1016/j.jpba.2015.05.023. Epub 2015 May 28.

Development of a validated LC-APCI-MS/MS method to study the plasma and tumor distribution of CHO-PTX intravenous lipid emulsion.

Author information

1
Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 1 Xiannongtan Street, Beijing, China; Beijing Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 1 Xiannongtan Street, Beijing, China.
2
Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 1 Xiannongtan Street, Beijing, China; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 1 Xiannongtan Street, Beijing, China.
3
Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 1 Xiannongtan Street, Beijing, China.
4
Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 1 Xiannongtan Street, Beijing, China; Beijing Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 1 Xiannongtan Street, Beijing, China; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 1 Xiannongtan Street, Beijing, China. Electronic address: ylliu@imm.ac.cn.

Abstract

Conjugation of a cholesterol moiety to active compounds for cancer treatment or diagnosis is an attractive approach for increasing lipophilicity and improving loading into lipid carriers. We developed a highly sensitive and specific liquid chromatography atmospheric-pressure chemical ionization tandem mass spectrometry (LC-APCI-MS/MS) analytical method to investigate the in vivo plasma and tumor distribution characteristic of a cholesterol-paclitaxel conjugate (CHO-PTX) in nude mice with MDA-MB-231 human breast cancer xenografts. The samples were analyzed in positive ion, multiple reaction monitoring mode. The plasma and tumor tissue samples were processed by liquid-liquid extraction with methyl tert-butyl ether (MTBE). Docetaxel was used as the internal standard (IS) for sample processing and analysis. MS/MS detection was carried out by monitoring the transitions of m/z 1266.7→369.4 and 330.3 for CHO-PTX, and m/z 808.7→226.4 and 509.1 for IS. The calibration curves were linear over 100-25,000 ng/mL in mouse plasma and tumor homogenate samples. The limit of quantitation of CHO-PTX was 100 ng/mL in both matrices. The intra-day and inter-day precisions were less than 15%, and the accuracy was between -8.0% and 8.6% for both matrices. The developed method was successfully applied to measure CHO-PTX levels in plasma and tumor tissues in nude mice. The mean tumor concentrations in mice tumor tissues after intravenous administration of CHO-PTX emulsion at a dose equivalent to 20 mg/kg paclitaxel were 2022±630 ng/mL ng/mL, 2516±982 ng/mL, 3056±1438 ng/mL, and 2367±1029 ng/mL at 0.25, 3, 24, and 120 h, respectively. The accumulation of CHO-PTX in the tumor suggests that cholesteryl drug conjugates are a promising approach for medical treatment of various human cancers.

KEYWORDS:

Bioanalytical method; Cholesterol-paclitaxel conjugate; Emulsion; LC–APCI-MS/MS; Tumor-bearing mouse

PMID:
26476881
DOI:
10.1016/j.jpba.2015.05.023
[Indexed for MEDLINE]

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