Anticancer efficacies of cisplatin-releasing pH-responsive nanoparticles.
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(epsilon-caprolactone) (PCL) cores made from PCL-block-PEG (PCL-PEG) were used for comparison. Nanoparticle sizes, zeta 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.
Xu
Peisheng
P
Soft Materials Laboratory and Department of Chemical and Petroleum Engineering, University of Wyoming, Laramie, 82071, USA.
Van Kirk
Edward A
EA
Murdoch
William J
WJ
Zhan
Yihong
Y
Isaak
Dale D
DD
Radosz
Maciej
M
Shen
Youqing
Y
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology*; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D008689:Methacrylates / Q000737:chemistry; D051379:Mice; D049329:Nanostructures / Q000737:chemistry*; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy*; D009757:Nylons / Q000737:chemistry; D011091:Polyesters / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry
D000970:Antineoplastic Agents; D008689:Methacrylates; D009757:Nylons; D011091:Polyesters; C109846:poly(2-(diethylamino)ethyl methacrylate); C016240:polycaprolactone; D011092:Polyethylene Glycols; D002945:Cisplatin