Quantitative structure - property relationship modeling of remote liposome loading of drugs

JOURNAL OF CONTROLLED RELEASE

卷:160

Article

Cern, Ahuva^1,2  Golbraikh, Alexander³  Sedykh, Aleck³  Tropsha, Alexander³  Barenholz, Yechezkel¹  Goldblum, Amiram² 

[1] Hebrew Univ Jerusalem, Hadassah Med Sch Jerusalem, IMRIC, Dept Biochem, IL-91905 Jerusalem, Israel

[2] Hebrew Univ Jerusalem, Inst Drug Res, Mol Modeling & Drug Design Lab, IL-91905 Jerusalem, Israel

[3] Univ N Carolina, UNC Eshelman Sch Pharm, Lab Mol Modeling, Chapel Hill, NC USA

关键词: Chemical descriptors;    Liposome;    Loading conditions;    Loading efficiency;    QSPR;    Remote loading;   

DOI  :  10.1016/j.jconrel.2011.11.029

来源: Elsevier

【 摘 要 】

Remote loading of liposomes by trans-membrane gradients is used to achieve therapeutically efficacious intra-liposome concentrations of drugs. We have developed Quantitative Structure Property Relationship (QSPR) models of remote liposome loading for a data set including 60 drugs studied in 366 loading experiments internally or elsewhere. Both experimental conditions and computed chemical descriptors were employed as independent variables to predict the initial drug/lipid ratio (D/L) required to achieve high loading efficiency. Both binary (to distinguish high vs. low initial D/L) and continuous (to predict real D/L values) models were generated using advanced machine learning approaches and 5-fold external validation. The external prediction accuracy for binarymodels was as high as 91-96%; for continuous models the mean coefficient R-2 for regression between predicted versus observed values was 0.76-0.79. We conclude that QSPR models can be used to identify candidate drugs expected to have high remote loading capacity while simultaneously optimizing the design of formulation experiments. (C) 2011 Elsevier B. V. All rights reserved.

【 授权许可】

Free