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

Abstract

Cisplatin nanocapsules represent a lipid formulation of the anticancer drug cis-diamminedichloroplatinum(II) (cisplatin) characterized by an unprecedented cisplatin-to-lipid ratio and exhibiting strongly improved 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 an equimolar dispersion of phosphatidylserine (PS) and phosphatidylcholine (PC) in a concentrated aqueous solution of cisplatin. Here, the molecular architecture of these novel nanostructures was elucidated by solid-state NMR techniques. 15 N NMR and 2 H NMR spectra of nanocapsules containing 15 N-and 2 H-labeled cisplatin, respectively, demonstrated that the core of the nanocapsules consists of solid cisplatin devoid of free water. Magic-angle spinning 15 N NMR showed that ∼90% of the cisplatin in the core is present as the dichloro species. The remaining 10% was accounted for by a newly discovered dinuclear Pt compound that was identified as the positively charged chloride-bridged dimer of cisplatin. NMR techniques sensitive to lipid organization, 31 P NMR and 2 H NMR, revealed that the cisplatin core is coated by phospholipids in a bilayer configuration and that the interaction between solid core and bilayer coat exerts a strong ordering effect on the phospholipid molecules. Compared to phospholipids in liposomal membranes, the motion of the phospholipid headgroups is restricted and the ordering of the acyl chains is increased, particularly in PS. The implications of these findings for the structural organization, the mechanism of formation, and the mode of action of cisplatin nanocapsules are discussed.

Nanocapsules: A Novel Formulation Technology For Platinum-Based Anticancer Drugs

“…Ramachandran et al [55] used atomic force microscopy (AFM) to characterize cisplatin nanoliposomes that were prepared according to a procedure that is very similar to the protocol for preparing nanocapsules. AFM force curves revealed that the nanoliposomes containing cisplatin are stiffer than vesicles not containing cisplatin, which was attributed to the presence of cisplatin clusters inside the liposomes [55], in agreement with previous data [52,54].…”

“…Using 15 N-labeled cisplatin, Chupin et al [54] elucidated the molecular architecture of cisplatin nanocapsules by nuclear magnetic resonance (NMR) methods. Cisplatin nanocapsules were found to consist of a core of solid cisplatin virtually devoid of free water, coated by a phospholipid bilayer [54].…”

“…Cisplatin nanocapsules were found to consist of a core of solid cisplatin virtually devoid of free water, coated by a phospholipid bilayer [54]. Ramachandran et al [55] used atomic force microscopy (AFM) to characterize cisplatin nanoliposomes that were prepared according to a procedure that is very similar to the protocol for preparing nanocapsules.…”

“…(2007) 2(4) future science group future science group Magic angle spinning NMR complemented by mass spectrometry revealed the chemical composition of the nanocapsules' solid core, which was found to consist mainly of the dichloro species of cisplatin with a minor contribution of a newly identified positively charged chloride-bridged dimer [54]. Most likely the chloride-bridged dimer is formed as a result of the increasing concentrations of the dichloro and mono-aqua species in the remaining fluid during the freezing of water, which facilitates the reaction between these species [54]. The chloride-bridged dimer is not stable in the presence of water.…”

“…The chloride-bridged dimer is not stable in the presence of water. Upon disrupting the lipid coat, cisplatin in the core returns to the initial equilibrium of dichloro and aqua species [54].…”