期刊
BIOMACROMOLECULES
卷 7, 期 3, 页码 829-835出版社
AMER CHEMICAL SOC
DOI: 10.1021/bm050902y
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资金
- NCRR NIH HHS [P20 RR016474-077207, RR-016474, P20 RR016474, P20 RR016474-067003] Funding Source: Medline
The objective of these investigations was to test the hypothesis that a rapid cytoplasmic release profile from narroparticles would potentiate the anticancer activity of cisplatin. Cisplatin-loaded nanoparticles with pH-responsive poly[2-(N,N-diethylammo)ethyl methacrylate] (PDEA) cores were synthesized from PDEA-block-poly(ethylene Glycol) (PDEA-PEG) copolymer by using a solvent-displacement (acetone-water) method. Nanoparticles with pH-nonresponsive poly(epsilon-caprolactone) (PCL) cores made from PCL-block-PEG (PCL-PEG) were used for comparison. Nanoparticle sizes, xi 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-3 epithelial ovarian cancer cells were estimated by using the NITT assay. Tntraperitoneal tumor responses to cisplatin and cisplatin/PDEA-PEG were evaluated in athymic mice at 4-6 weeks postinoculation of SKOV-3 cells. PDEAPEG nanoparticles dissolved at pH < 6 and rapidly internalized and transferred to lysosomes; it therefore was predicted that the PDEA narroparticles would rapidly release cisplatin into cytoplasm upon integration into acidic lysosornes and thereby overwhelm the chemoresistant properties of SKOV-3 cells. Indeed, relative proportions of viable cells were diminished to a greater extent by exposure in vitro to fast-releasing nanoparticles compared to slow-releasin-nanoparticles or an equivalent dose of free cisplatin. Incidences of cellular pyknosis (a morphological indicator of apoptosis) were most evident within intestinal/mesentery tumors of mice treated with cisplatin/PDEA-PEG; tumor burdens were correspondingly reduced.
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