Anticancer Efficacies of Cisplatin-Releasing pH-Responsive Nanoparticles

• Published in: Biomacromolecules 2006-03, Vol.7 (3), p.829-835
• Main Authors: Xu, Peisheng, Van Kirk, Edward A, Murdoch, William J, Zhan, Yihong, Isaak, Dale D, Radosz, Maciej, Shen, Youqing
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacology; Applied sciences; Biological and medical sciences; Cell Line, Tumor; Cisplatin - administration & dosage; Cisplatin - pharmacology; Drug Delivery Systems; Exact sciences and technology; Female; Forms of application and semi-finished materials; General pharmacology; Humans; Medical sciences; Methacrylates - chemistry; Mice; Miscellaneous; Nanostructures - chemistry; Neoplasm Transplantation; Neoplasms - drug therapy; Nylons - chemistry; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Polyesters - chemistry; Polyethylene Glycols - chemistry; Polymer industry, paints, wood; Technology of polymers
• ISSN: 1525-7797; 1526-4602
• DOI: 10.1021/bm050902y

The objective of these investigations was to test the hypothesis that a rapid cytoplasmic release profile from nanoparticles would potentiate the anticancer activity of cisplatin. Cisplatin-loaded nanoparticles with pH-responsive poly[2-(N,N-diethylamino)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(ε-caprolactone) (PCL) cores made from PCL-block-PEG (PCL−PEG) were used for comparison. Nanoparticle sizes, ζ 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 MTT assay. Intraperitoneal tumor responses to cisplatin and 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 was predicted that the PDEA nanoparticles would rapidly release cisplatin into cytoplasm upon integration into acidic lysosomes 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-releasing 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.