Sterol-Modified Phospholipids: Cholesterol and Phospholipid Chimeras with Improved Biomembrane Properties

Abstract

We synthesized a family of sterol-modified glycerophospholipids (SML) in which the sn-1 or sn-2 position is covalently attached to cholesterol and the alternative position contains an aliphatic chain. The SML were used to explore how anchoring cholesterol to a phospholipid affects cholesterol behavior in a bilayer. Notably, cholesterol in the SML retains the membrane condensing properties of free cholesterol regardless of the chemistry or position of its attachment to the glycerol moiety of the phospholipid. SMLs by themselves formed liposomes upon hydration and in mixtures between an SML and diacylglycerophospholipids (C14 to C18 chain length) the thermotropic phase transition is eliminated at the SML equivalent of about 30 mole percent free cholesterol. Osmotic-induced contents leakage from SML (C14-C18) liposomes depends upon the linkage and position of cholesterol but in general is similar to that observed in diacylphosphatidylcholine/ cholesterol: 3/2 (mole ratio) liposomes. SML liposomes are exceptionally resistant to contents release in the presence of serum at 37 °C. This is probably due to fact that SML exchange between bilayers is more than 100 fold less than the exchange rate of free cholesterol in the same conditions. Importantly SML liposomes containing doxorubicin are as effective in treating the murine C26 colon carcinoma, as Doxil™ a commercial liposome doxorubicin formulation. SMLs stabilize bilayers but do not exchange hence provide a new tool for biophysical studies on membranes and they may improve liposomal drug delivery in organs predisposed to the extraction of free cholesterol from bilayers, such as; the skin, lung or blood.

Biodistribution and In Vivo Antileishmanial Activity of 1,2-Distigmasterylhemisuccinoyl- sn -Glycero-3-Phosphocholine Liposome-Intercalated Amphotericin B

“…Our hemolytic studies showed that DSHemsPC-AMBLip was slightly less hemolytic than AmBisome in this model (Table 1), which suggests the higher affinity of AMB for DSHemsPC-Lip than AmBisome. This may be due to the stabilizing effect of SML liposomes, which retain their contents more efficiently, since serum proteins play a major role in extracting cholesterol from the liposome bilayer, and action that results in content leakage (29).…”

Tat peptide and hexadecylphosphocholine introduction into pegylated liposomal doxorubicin: An in vitro and in vivo study on drug cellular delivery, release, biodistribution and antitumor activity

“…Twelve days after tumor inoculation, when the C26 tumors were approximately 5 mm in diameter, mice (3 per group) were injected intravenously ( Dox concentration prepared in the tissue and sera extracts of the control mice (Huang et al, 2009;Huang and Szoka Jr, 2008).…”

Investigation of Hexadecylphosphocholine (miltefosine) usage in Pegylated liposomal doxorubicin as a synergistic ingredient: In vitro and in vivo evaluation in mice bearing C26 colon carcinoma and B16F0 melanoma

“…Then, all samples were stored at 4 o C overnight for Dox extraction. After centrifugation, the supernatant was assayed for Dox concentration spectrofluorimetrically (Ex: 470 nm, Em: 590 nm), using Dox calibration curves, which were prepared in the tissue and sera extracts of the control mice (Huang et al, 2009;Huang and Szoka, 2008).…”