Malugin A, Kopecková P, Kopecek J
Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, Utah 84112, USA.
J Control Release. 2007 Dec 4;124(1-2):6-10. doi: 10.1016/j.jconrel.2007.08.016. Epub 2007 Aug 23.
Despite intensive study, the molecular mechanism for cell toxicity of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-bound doxorubicin remains unclear. Moreover, the ability of the released drug to accumulate in the nucleus has also been questioned. We have hypothesized that the pattern of cell cycle progression is a useful indicator for the presence of free doxorubicin in the nucleus and its interaction with nuclear DNA. The effects of HPMA copolymer-bound doxorubicin on cell cycle progression were evaluated in this study in cultured human ovarian cancer A2780 cells. We determined that P-GFLG-DOX, but not P-GG-DOX, initiates cell cycle arrest and nuclear fragmentation in the same manner as free DOX, but with a time-delay. Our data indicate that drug release from the conjugate is required for the apoptotic activity associated with the conjugate.
尽管进行了深入研究，但N-（2-羟丙基）甲基丙烯酰胺（HPMA）共聚物结合阿霉素的细胞毒性分子机制仍不清楚。此外，释放的药物在细胞核中积累的能力也受到了质疑。我们推测细胞周期进程模式是细胞核中游离阿霉素存在及其与核DNA相互作用的有用指标。本研究在培养的人卵巢癌A2780细胞中评估了HPMA共聚物结合阿霉素对细胞周期进程的影响。我们确定P-GFLG-DOX而非P-GG-DOX会以与游离DOX相同的方式引发细胞周期停滞和核碎片化，但存在时间延迟。我们的数据表明，与缀合物相关的凋亡活性需要药物从缀合物中释放。
