Effects of tumbling and lateral diffusion on phosphatidylcholine model membrane 31P-NMR lineshapes

Burnell, E. Elliott; Cullis, Pieter R.; Kruijff, Ben de

doi:10.1016/0005-2736(80)90391-0

Cited by 191 publications

(102 citation statements)

References 17 publications

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“…Since up till now, there is no experimental evidence that membrane lipid head group conformations give rise to such spectra, the origin of this line shape is most likely of a motional nature. This line shape is characteristic for lipid structures in which lipid molecules can orient themselves very rapidly (T, < 10 ps), such as in (inverted) micelles, cubic phases and small vesicles [61]. In view of the reversibility of the spectral change and because in the related dioleoylglycerophosphoethanolamine-deoxycorticosterone system (data not shown), freeze-fracturing did not reveal the presence of small vesicles, we consider this latter possibility unlikely.…”

Section: Discussionmentioning

confidence: 72%

Corticosteroids as effectors of lipid polymorphism of dielaidoylglycerophosphoethanolamine

Gallay

Kruijff²

1984

European Journal of Biochemistry

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The influence of corticosteroids on the lipid polymorphism of dielaidoylglycerophosphoethanolamine was studied by 31P NMR spectroscopy and differential scanning calorimetry. Both techniques evidenced two transitions in the pure lipid samples. The first one corresponded to the gel+liquid crystalline phase transition. It occurred at a temperature of 38.9 "C, as measured by differential scanning calorimetry and at 35 -40 "C as detected by 31P NMR. The second transition corresponded to the bilayer-thexagonal HI, phase transition. It occurred at 64.2 "C as measured by differential scanning calorimetry and at 60 "C as detected by NMR. Addition of corticosteroids led to different specific effects on the bilayer+hexagonal HI, phase transition, according to their chemical structure. These effects appear to be the result of low amounts of incorporated steroids, according to binding studies (partition coefficient values range between 5 and 54). The presence of a conjugated 3-keto group in the steroid molecule (progesterone) promoted a downward shift in the bilayer + hexagonal H,,.phase transition temperature by about 6 -7 "C as compared to the 38-OH-bearing compound (pregnenolone), which did not exhibit any appreciable effect. No change in the AH of transition could be measured. The presence of the 21-OH group (like in deoxycorticosterone) induced the formation of a structure, characterized by an isotropic lineshape of the 31P NMR spectrum at temperatures where the 'hexagonal' type of lineshape is present, without steroid. The transition from the bilayer to this other structure occurred at a slightly higher temperature than the bilayer+hexagonal HI, phase transition. It corresponded to a peak in differential scanning calorimetry scans with a AH of 2.1 kJ .rnol-'. The presence of the 17j-OH group as present in 17j-OH-progesterone and 1 I-deoxycortisol suppressed the two former effects. These compounds had no influence on the bilayer-thexagonal H!,phase transition. The additional presence of the 118-OH group like in corticosterone and cortisol, evoked a stabilization of the bilayer organization as the bilayer-thexagonal HI, phase transition temperature is shifted upward by about 10 "C. This was accompanied by a decrease of the AH to 0.8 kJ 'mo1-l. Besides this, the corticosteroids did not affect to a large extent the gel-+liquid crystalline phase transition : a general slight downward shift of the transition temperature and a small broadening of the transition were observed without significant change in the AH. The effects of corticosteroids on the bilayer -+hexagonal HI, phase transition are qualitatively correlated with their influence on biological membranes. Steroid-membrane interactions are also involved in steroid hormone uptake by target cells. Though it is generally assumed that steroid hormones enter their target cells by passive diffusion [17], it has been reported that steroid hormone uptake by intact tissues [IS] or by tumour cell lines [19,20], involves a temperature-dependent mechanism of transport through the...

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Section: Discussionmentioning

confidence: 72%

Corticosteroids as effectors of lipid polymorphism of dielaidoylglycerophosphoethanolamine

Gallay

Kruijff²

1984

European Journal of Biochemistry

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“…As vesicle size decreases, motion increases, and it has been shown that for 7, < 14 ms, spectra from phosphatidylcholine vesicles lose their bilayer lineshape and exhibit instead a single isotropic peak (18). However, this explanation must be ruled out as small vesicles alone would not experience offresonance saturation effects ( ( 14, 1 6 ) , unpublished results).…”

Section: Discussionmentioning

confidence: 86%

Phospholipid bilayer contribution to ³¹P NMR spectra in vivo

Murphy

Rajagopalan

Brindle

et al. 1989

Magnetic Resonance in Med

138

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“…The presence of a bilayer coat was supported by 31 P nuclear magnetic resonance (NMR) spectroscopy (Fig. 2e), which showed a bilayer-type of spectrum typical for membranous particles of this shape and size 14 , as well as by freezefracture analysis (data not shown). An occasional cross-fracture through a nanocapsule revealed a multi-layered structure for the enclosed cisplatin, suggesting a quasi-crystalline organization.…”

Section: New Technologymentioning

confidence: 89%

Nanocapsules: lipid-coated aggregates of cisplatin with high cytotoxicity

Burger

Staffhorst

Vijlder

et al. 2002

Nat Med

173

160

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Cisplatin is one of the most widely used agents in the treatment of solid tumors, but its clinical utility is limited by toxicity. The development of less toxic, liposomal formulations of cisplatin has been hampered by the low water solubility and low lipophilicity of cisplatin, resulting in very low encapsulation efficiencies. We describe a novel method allowing the efficient encapsulation of cisplatin in a lipid formulation; it is based on repeated freezing and thawing of a concentrated solution of cisplatin in the presence of negatively charged phospholipids. The method is unique in that it generates nanocapsules, which are small aggregates of cisplatin covered by a single lipid bilayer. The nanocapsules have an unprecedented drug-to-lipid ratio and an in vitro cytotoxicity up to 1000-fold higher than the free drug. Analysis of the mechanism of nanocapsule formation suggests that the method may be generalized to other drugs showing low water solubility and lipophilicity.The clinical use of cis-diamminedichloroplatinum(II) (cisplatin) and many of its analogs faces three major problems: 1) serious dose-limiting toxicities in particular nephrotoxicity and neurotoxicity; 2) rapid inactivation of the drug as a result of complexation to plasma and tissue proteins; and 3) the frequent occurrence of platinum resistance [1][2][3][4][5] . In general, these problems can be reduced by shielding of a drug from the extracellular environment by means of a lipid coating. However, in many cases this approach fails because of inefficient encapsulation of the drug in lipid formulations resulting in low drug uptake by the tumor 6 . This is particularly true for cisplatin: the low water solubility and low lipophilicity of cisplatin result in lipid formulations with a very low drug-to-lipid ratio 7-9 . One approach is to synthesize lipophilic derivatives of cisplatin that can be efficiently encapsulated in large multilamellar liposomes 10 . Here, we describe a new method to efficiently encapsulate native, non-derivitized cisplatin in a lipid formulation. Nanocapsules of cisplatinOur method involves hydration of a dry lipid film composed of equimolar amounts of dioleoyl-phosphatidylserine (PS) and dioleoyl-phosphatidylcholine (PC), with a buffered solution (pH 7.4) of 5 mM cisplatin followed by 10 freeze-thaw (FT) cycles, and removal of free (extravesicular) cisplatin by centrifugation. The cisplatincontaining lipid suspension (cisPt-PS/PC) was extremely cytotoxic (Fig. 1a) with a typical IC 50 (the drug concentration at which cell growth is inhibited by 50%) of approximately 2 nM as compared with 0.5 µM for the free drug (conventional cisplatin). A lipid suspension not loaded with cisplatin (blank) was not cytotoxic, and mixing conventional cisplatin with the blank lipid suspension did not increase the cytotoxicity of cisplatin.Omitting the freeze-thaw step, or leaving out the negatively charged PS in the lipid mixture, resulted in a dramatic decrease in cytotoxicity (Fig. 1b). This decrease in cytotoxicity was paralleled by a sim...

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Effects of tumbling and lateral diffusion on phosphatidylcholine model membrane 31P-NMR lineshapes

Cited by 191 publications

References 17 publications

Corticosteroids as effectors of lipid polymorphism of dielaidoylglycerophosphoethanolamine

Corticosteroids as effectors of lipid polymorphism of dielaidoylglycerophosphoethanolamine

Phospholipid bilayer contribution to ³¹P NMR spectra in vivo

Nanocapsules: lipid-coated aggregates of cisplatin with high cytotoxicity

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Effects of tumbling and lateral diffusion on phosphatidylcholine model membrane 31P-NMR lineshapes

Cited by 191 publications

References 17 publications

Corticosteroids as effectors of lipid polymorphism of dielaidoylglycerophosphoethanolamine

Corticosteroids as effectors of lipid polymorphism of dielaidoylglycerophosphoethanolamine

Phospholipid bilayer contribution to 31P NMR spectra in vivo

Nanocapsules: lipid-coated aggregates of cisplatin with high cytotoxicity

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Product

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Phospholipid bilayer contribution to ³¹P NMR spectra in vivo