Idebenone loaded solid lipid nanoparticles interact with biomembrane models: calorimetric evidence.

The knowledge of the interactions between solid lipid nanoparticles (SLN) and cell membranes is important to develop effective carrier systems for drug delivery applications. Loading idebenone (IDE), an antioxidant drug useful in the treatment of neurodegenerative diseases, into SLN improves IDE antioxidant activity in in vitro biological studies, but the mechanism by which IDE permeation through the blood-brain barrier (BBB) occurs are still unclear. Therefore, in this research, unloaded and IDE loaded SLN interaction with biomembrane models, consisting of dimyristoylphosphatidylcholine multilamellar vesicles (MLV), were studied by differential scanning calorimetry (DSC). In the experiments performed, unloaded and IDE loaded SLN where incubated with the biomembrane models and their interactions were evaluated through the variations in their calorimetric curves. The results of our DSC studies indicated that the SLN under investigation were able to go inside the phospholipid bilayers with a likely localization in the outer bilayers of the MLV from where they moved toward the inner layers by increasing the contact time between SLN and MLV. Furthermore, IDE loaded SLN were able to release IDE into the biomembrane model, thus facilitating IDE penetration into the bilayers while free IDE showed only a low ability to interact with this model of biomembranes. Our results suggest that these SLN could be regarded as a promising drug delivery system to improve IDE bioavailability and antioxidant activity.

Squalenoyl prodrug of paclitaxel: synthesis and evaluation of its incorporation in phospholipid bilayers.

1,1',2-Trisnorsqualenoic acid was conjugated to paclitaxel to obtain the squalenoyl-paclitaxel prodrug with the aim to improve the incorporation in phospholipid bilayers. Differential scanning calorimetry technique was employed to compare the interaction of squalenoyl-paclitaxel prodrug and free paclitaxel with phospholipid bilayers. The possibility of using lipid vesicles as carrier for the prodrug was also evaluated. An increased encapsulation into phospholipid bilayers of squalenoyl-paclitaxel with respect to the free drug was observed. The ability of lipid vesicles to retain the loaded prodrug was also observed which make this system to be considered as carrier for the prodrug.

Interaction between drug loaded polyaspartamide-polylactide-polysorbate based micelles and cell membrane models: a calorimetric study.

Amphiphilic biodegradable copolymers, for their ability to self-assemble into micelle-like aggregates, with a suitable loading capacity, are of emerging interest for the delivery of water-insoluble drugs. α,ß-Poly[(N-hydroxyethyl)-dl-aspartamide] (PHEA) is suitable to obtain amphiphilic graft copolymers. These copolymers can be obtained starting from PHEA-ethylenediamine (PHEA-EDA) which is functionalized with polysorbate 80 (PS80, like targeting residues to the brain) and polylactide (PLA, like hydrophobic chains) in order to obtain polymeric micelles of PHEA-EDA-PS80-PLA potentially useful to release drugs to the central nervous system. In this paper, the interaction and absorption of PHEA-EDA-PS80-PLA micelles loaded with (R)-flurbiprofen with biomembrane models, represented by multilamellar or unilamellar vesicles made of dimyristoylphosphatidylcholine, are investigated by means of differential scanning calorimetry technique. (R)-Flurbiprofen is the single enantiomer of the racemate flurbiprofen; the capacity of this nonsteroidal anti-inflammatory drug to reduce risk of Alzheimer's disease has been recently reported. Drug release from the micelles to the lipid vesicles has been investigated in simulated physiological fluid, and it resulted to be affected by the biomembrane model.

Evaluation of the interaction of coumarins with biomembrane models studied by differential scanning calorimetry and Langmuir-Blodgett techniques.

Three coumarins, scopoletin (1), esculetin (2), and esculin (3), were investigated by differential scanning calorimetry and Langmuir-Blodgett techniques to gain information about the interaction of these compounds with cellular membranes. Phospholipids assembled as multilamellar vesicles or monolayers (at the air-water interface) were used as biomembrane models. Differential scanning calorimetry was employed to study the interaction of these coumarins with multilamellar vesicles and to evaluate their absorption by multilamellar vesicles. These experiments indicated that 1-3 interact in this manner to different extents. The Langmuir-Blodgett technique was used to study the effect of these coumarins on the organization of phospholipids assembled as a monolayer. The data obtained were in agreement with those obtained in the calorimetric experiments.

Synthesis of n-squalenoyl cytarabine and evaluation of its affinity with phospholipid bilayers and monolayers.

Cytarabine (1-ß-D-arabinofuranosylcytosine, Ara-C), a pyrimidine nucleoside analogue, is an attractive therapeutic agent for the treatment of both acute and chronic myeloblastic leukemias. 1,1',2-tris-nor-Squalene acid (squaleneCOOH) has been conjugated to cytarabine with the formation of the squalenoyl-cytarabine prodrug, in order to improve the drug lipophilicity and, consequently, the affinity towards the environment of biological membranes, as well as of lipophilic carriers. The interaction of cytarabine and its prodrug with dimyristoylphosphatidylcholine (DMPC) multilamellar vesicles and monolayers has been studied by the differential scanning calorimetry and the Langmuir-Blodgett techniques. The interaction has been evaluated considering the effect of the compounds on the DMPC MLV and monolayers behaviour. The aim was to have information on the interaction of the drug and the prodrug with the biological membranes and on the possibility to use liposomes as carriers for the prodrug. The results showed an improved affinity of the prodrug with MLV and monolayers with respect to the free drug.

Interaction of acyclovir and its squalenoyl-acyclovir prodrug with DMPC in monolayers at the air/water interface.

Acyclovir has been conjugated to the acyclic isoprenoid chain of squalene to form the squalenoyl-acyclovir prodrug. Its interaction with biomembrane models constituted by dimyristoylphosphatidylcholine (DMPC) monolayers has been studied by employing the Langmuir-Blodgett technique. The aim of the work was to gain information on the interaction of these compounds with phospholipid membranes. DMPC/acyclovir or squalenoyl-acyclovir prodrug mixed monolayers have been prepared at increasing molar fractions of the compound and the isotherm mean molecular area/surface pressure has been registered at 10 and 37 degrees C. Results reveal that the squalenoyl moiety enhances the affinity of acyclovir for the biomembrane model.

beta-Cyclodextrins influence on E-3,5,4'-trimethoxystilbene absorption across biological membrane model: a differential scanning calorimetry evidence.

E-3,5,4'-trimethoxystilbene (TMS) is a naturally occurring analog of resveratrol. The anti-neoplastic, antiallergic and anti-angiogenic activities of TMS have been recently reported. From the viewpoint of metabolism, TMS may be more favourable than resveratrol because all of its hydroxyl groups, which are subjected to extensive glucuronide or sulphate conjugation in the metabolic pathways of resveratrol, are protected by methylation. Moreover, methylation increases lipophilicity and may enhance cell membrane permeability, but it decreases its solubility in aqueous media. A way to increase TMS solubility can be represented by complexation with beta-cyclodextrins. In the present paper, the differential scanning calorimetry technique has been used to study the interaction of TMS with a biomembrane model constituted by dimyristoylphosphatidylcholine multilamellar vesicles. Furthermore, kinetic experiments have been carried out to follow the uptake of TMS by biomembranes in the presence of beta-cyclodextrins to gain information on the effect of beta-cyclodextrins on the uptake process. Our results indicate that opportune concentrations of beta-cyclodextrins greatly improve the uptake of TMS by biomembrane models.

Absorption of nitro-polycyclic aromatic hydrocarbons by biomembrane models: effect of the medium lipophilicity.

To demonstrate the relationship between the structure of nitro-polycyclic aromatic hydrocarbons and their effect on biomembranes, we have investigated the influence of three structurally different nitro-polycyclic aromatic hydrocarbons, 2-nitrofluorene, 2,7-dinitrofluorene and 3-nitrofluoranthene, on the thermotropic behavior of dimyristoylphosphatidylcholine multilamellar vesicles, used as biomembrane models, by means of differential scanning calorimetry. The obtained results indicate that the studied nitro-polycyclic aromatic hydrocarbons affected the thermotropic behavior of multilamellar vesicles to various extents, modifying the pretransition and the main phase transition peaks and shifting them to lower temperatures. The effect of the aqueous and lipophilic medium on the absorption process of these compounds by the biomembrane models has been also investigated revealing that the process is hindered by the aqueous medium but strongly allowed by the lipophilic medium.

Differential scanning calorimetry study on drug release from an inulin-based hydrogel and its interaction with a biomembrane model: pH and loading effect.

Inulin has been derivatized with methacrylic anhydride (MA) and succinic anhydride (SA) to obtain a methacrylated/succinilated derivative (INU-MA-SA) able to produce a pH sensitive hydrogel after UV irradiation. The hydrogel was characterized and loaded with diflunisal (10.4, 17 and 24%, w/w) chosen as a model drug. The drug release from INU-MA-SA-based hydrogel to a biomembrane model made by unilamellar vesicles of dimyristoylphosphatidylcholine (DMPC) was investigated at pH 4.0 and 7.4 by differential scanning calorimetry (DSC) that appears to be a suitable technique to follow the transfer kinetics of a drug from a controlled release system to a biomembrane model. The drug release from the hydrogel was compared with the dissolution of drug solid form by examining the effects exerted on the thermotropic behaviour of the DMPC unilamellar vesicles. The transferred drug and the release rate were affected by the drug loading as well as by the pH of the external medium. In particular the release was not linearly related to the drug loading but an intermediate loading allowed a better release at both investigated pHs, with a faster and more complete release observed at pH 7.4.