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The characterization of the phase behavior of mixtures formed by palmitic acid (PA), cholesterol (Chol), and sodium cholesteryl sulfate (Schol) is presented.

Gemcitabine, an anticancer agent which acts against a wide range of solid tumors, is known to be rapidly deaminated in blood to the inactive metabolite 2',2'-difluorodeoxyuridine and to be rapidly excreted by the urine. Moreover, many cancers develop resistance against this drug, such as loss of transporters and kinases responsible for the first phosphorylation step. To increase its therapeutic levels, gemcitabine is administered at high doses (1000 mg/m(2)) causing side effects (neutropenia, nausea, and so forth). To improve its metabolic stability and cytotoxic activity and to limit the phenomena of resistance many alternatives have emerged, such as the synthesis of prodrugs. Modifying an anticancer agent is not new; paclitaxel or ara-C has been subjected to such changes. This review summarizes the various chemical modifications that can be found in the 4-(N)- and 5'-positions of gemcitabine. They can provide (i) a protection against deamination, (ii) a better storage and (iii) a prolonged release in the cell, (iv) a possible use in the case of deoxycytidine kinase deficiency, and (v) transporter deficiency. These new gemcitabine-based sysems have the potential to improve the clinical outcome of a chemotherapy strategy.

Systems composed of a monoalkylated amphiphile and a sterol have been shown to form stable liquid-ordered (lo) lamellar phases; these include negatively charged mixtures of unprotonated palmitic acid/cholesterol (Chol) or cholesterol sulfate (Schol) and mixtures of positively charged cetylpyridinium chloride/Schol. Large unilamellar vesicles (LUVs) could be formed by these systems, using conventional extrusion methods. The passive permeability of these LUVs was drastically limited, a phenomenon associated with the high sterol content. In the present paper, we showed that octadecyl methyl sulfoxide (OMSO), a neutral monoalkylated amphiphile, can form, in the presence of cholesterol, LUVs that are stable at room temperature. Differential scanning calorimetry, infrared spectroscopy, and nuclear magnetic resonance spectroscopy of deuterium were used to characterize the phase behavior of OMSO/Chol mixtures. A temperature-composition diagram summarizing the behavior of the OMSO/Chol system is proposed; it includes a eutectic with an OMSO/Chol molar ratio of 5/5. It is found that the fluid phase observed at temperature higher than 43 degrees C is metastable at room temperature, and this situation allows extruding these mixtures to form stable LUVs at room temperature. This distinct behavior is associated with the strong H-bond capability of the sulfoxide group. The properties associated with this neutral formulation expand the potential of these non-phospholipid liposomes for applications in several areas such as drug delivery.

We present a novel formulation of non-phospholipid liposomes formed from cholesterol and palmitic acid. Despite the fact that these two lipidic species do not form individually fluid bilayers, we show that once mixed together, fluid bilayers can be obtained and, moreover, these can be extruded using classical extrusion processes to form liposomes. The chemical analysis indicates that these liposomes contain 70 mol % cholesterol, a content that is considerably higher that the saturation limit generally reported for phospholipid bilayers. These cholesterol-rich liposomes, formed with molecules that have low toxicity in vivo, display an improved impermeability relative to that of traditional phospholipid liposomes. In addition, because of the presence of palmitic acid, the stability of the liposomes is pH-dependent, and it is possible to trigger the release of encapsulated materials by pH stimuli.

Sodium dodecyl sulfate (SDS)-poly(propylene oxide) methacrylate (PPOMA) (of molecular weight M(w) = 434 g x mol(-1)) mixtures have been studied using conductimetry, static light scattering, fluorescence spectroscopy, and 1H NMR. It has been shown that SDS and PPOMA form mixed micelles, and SDS and PPOMA aggregation numbers, N(ag SDS) and N(ag PPOMA), have been determined. Total aggregation numbers of the micelles (N(ag SDS) + N(ag PPOMA)) and those of SDS decrease upon increasing the weight ratio R = PPOMA/SDS. Localization of PPOMA inside the mixed micelles is considered (i) using 1H NMR to localize the methacrylate function at the hydrophobic core-water interface and (ii) by studying the SDS-PPO micellar system (whose M(w) = 400 g x mol(-1)). Both methods have indicated that the PPO chain of the macromonomer is localized at the SDS micelle surface. Models based on the theorical prediction of the critical micellar concentration of mixed micelles and structural model of swollen micelles are used to confirm the particular structure proposed for the SDS-PPOMA system, i.e., the micelle hydrophobic core is primarily composed of the C12 chains of the sodium dodecyl sulfate, the hydrophobic core-water interface is made up of the SDS polar heads as well as methacrylate functions of the PPOMA, the PPO chains of the macromonomer are adsorbed preferentially on the surface, i.e., on the polar heads of the SDS.