Molecular Architecture of Nanocapsules, Bilayer-Enclosed Solid Particles of Cisplatin

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• 作者：Vladimir Chupin ; Anton I. P. M. de Kroon ; and Ben de Kruijff
• 刊名：Journal of the American Chemical Society
• 出版年：2004
• 出版时间：October 27, 2004
• 年：2004
• 卷：126
• 期：42
• 页码：13816 - 13821
• 全文大小：107K
• 年卷期：v.126,no.42(October 27, 2004)
• ISSN：1520-5126

文摘

Cisplatin nanocapsules represent a lipid formulation of the anticancer drug cis-diamminedichloroplatinum(II) (cisplatin) characterized by an unprecedented cisplatin-to-lipid ratio and exhibiting stronglyimproved cytotoxicity against tumor cells in vitro as compared to the free drug (Burger, K. N. J., et al. Nat.Med. 2002, 8, 81-84). Cisplatin nanocapsules are prepared by the repeated freezing and thawing of anequimolar dispersion of phosphatidylserine (PS) and phosphatidylcholine (PC) in a concentrated aqueoussolution of cisplatin. Here, the molecular architecture of these novel nanostructures was elucidated bysolid-state NMR techniques. ¹⁵N NMR and ²H NMR spectra of nanocapsules containing ¹⁵N- and ²H-labeledcisplatin, respectively, demonstrated that the core of the nanocapsules consists of solid cisplatin devoid offree water. Magic-angle spinning ¹⁵N NMR showed that ~90% of the cisplatin in the core is present as thedichloro species. The remaining 10% was accounted for by a newly discovered dinuclear Pt compoundthat was identified as the positively charged chloride-bridged dimer of cisplatin. NMR techniques sensitiveto lipid organization, ³¹P NMR and ²H NMR, revealed that the cisplatin core is coated by phospholipids ina bilayer configuration and that the interaction between solid core and bilayer coat exerts a strong orderingeffect on the phospholipid molecules. Compared to phospholipids in liposomal membranes, the motion ofthe phospholipid headgroups is restricted and the ordering of the acyl chains is increased, particularly inPS. The implications of these findings for the structural organization, the mechanism of formation, and themode of action of cisplatin nanocapsules are discussed.