Anticancer Efficacies of Cisplatin-Releasing pH-Responsive Nanoparticles

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• 作者：Peisheng Xu ; Edward A. Van Kirk ; William J. Murdoch ; Yihong Zhan ; Dale D. Isaak ; Maciej Radosz ; and Youqing Shen
• 刊名：Biomacromolecules
• 出版年：2006
• 出版时间：March 2006
• 年：2006
• 卷：7
• 期：3
• 页码：829 - 835
• 全文大小：372K
• 年卷期：v.7,no.3(March 2006)
• ISSN：1526-4602

文摘

The objective of these investigations was to test the hypothesis that a rapid cytoplasmic release profile fromnanoparticles would potentiate the anticancer activity of cisplatin. Cisplatin-loaded nanoparticles with pH-responsivepoly[2-(N,N-diethylamino)ethyl methacrylate] (PDEA) cores were synthesized from PDEA-block-poly(ethyleneglycol) (PDEA-PEG) copolymer by using a solvent-displacement (acetone-water) method. Nanoparticles withpH-nonresponsive poly(-caprolactone) (PCL) cores made from PCL-block-PEG (PCL-PEG) were used forcomparison. Nanoparticle sizes, potentials, drug-loading capacities, and pH responsiveness were characterized.The cellular uptakes and localization in lysosomes were visualized by using confocal fluorescence microscopy.Cytostatic effects of free and encapsulated cis-diammineplatinum(II) dichloride (cisplatin) toward human SKOV-3epithelial ovarian cancer cells were estimated by using the MTT assay. Intraperitoneal tumor responses to cisplatinand cisplatin/PDEA-PEG were evaluated in athymic mice at 4-6 weeks postinoculation of SKOV-3 cells. PDEA-PEG nanoparticles dissolved at pH < 6 and rapidly internalized and transferred to lysosomes; it therefore waspredicted that the PDEA nanoparticles would rapidly release cisplatin into cytoplasm upon integration into acidiclysosomes and thereby overwhelm the chemoresistant properties of SKOV-3 cells. Indeed, relative proportions ofviable cells were diminished to a greater extent by exposure in vitro to fast-releasing nanoparticles compared toslow-releasing nanoparticles or an equivalent dose of free cisplatin. Incidences of cellular pyknosis (a morphologicalindicator of apoptosis) were most evident within intestinal/mesentery tumors of mice treated with cisplatin/PDEA-PEG; tumor burdens were correspondingly reduced.