Effects of Solution Concentration on the Physicochemical Properties of a Polymeric Anticancer Therapeutic
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- 作者：Lili X. Peng ; Lei Yu ; Stephen B. Howell ; David A. Gough
- 刊名：Molecular Pharmaceutics
- 出版年：2012
- 出版时间：January 1, 2012
- 年：2012
- 卷：9
- 期：1
- 页码：37-47
- 全文大小：755K
- 年卷期：v.9,no.1(January 1, 2012)
- ISSN：1543-8392
文摘
Poly(纬-glutamyl-glutamate) paclitaxel (PGG鈥揚TX) is a series of eighteen semiflexible polymer鈥揹rug constructs varying in PTX loading fraction (fPTX of 0.18, 0.24, and 0.37) and spatial PTX arrangement (uniform, 鈥渆ven鈥?and 鈥渞andom鈥? clustered, 鈥渃lusters鈥?and 鈥渆nds鈥? concentrated, 鈥渆nds鈥?and 鈥渟ide鈥?. Structural properties of PGG鈥揚TX in dilute and concentrated conditions are determined from coarse-grained molecular dynamics (MD) simulations. Since PGG鈥揚TX does not have a specific conformation, MD simulations were run until minimal structural deviations persisted. Root-mean-square deviation (RMSD) clustering was then used to determine the significant, unique characteristic conformations. Results show that dilute PGG鈥揚TX undergoes a globule-to-filament transition with respect to increasingly denser PTX arrangements. While a similar transition is apparent in concentrated conditions, PGG鈥揚TX tends to be more filamentous on the whole. PGG鈥揚TX is also more rigid in concentrated conditions, and a higher PTX loading fraction leads to decreased flexibility. In general, the dilute 鈥渆nds鈥? 鈥渕iddle鈥? and 鈥渟ide鈥?PGG鈥揚TX molecules at fPTX = 0.18 and 0.24 prove to be the most efficaciously promising and are recommended for future biological testing. This study demonstrates the practicality of molecular modeling toward understanding structural behavior of an anticancer therapeutic in different solution concentrations.