Maria Lorena Accolla

Idebenone loaded solid lipid nanoparticles: calorimetric studies on surfactant and drug loading effects.

In this study we prepared solid lipid nanoparticles (SLN), by the phase inversion temperature (PIT) method, using cetyl palmitate as solid lipid and three different non-ionic emulsifiers of the polyoxyethylene ethers family (ceteth-20, isoceteth-20, oleth-20). These SLN were loaded with different amount of idebenone (IDE), an antioxidant drug useful in the treatment of neurodegenerative diseases and skin oxidative damages. The differential scanning calorimetry (DSC) was employed to evaluate the effects of the different emulsifiers and the different amounts of drug loaded on the thermotropic behavior of SLN and to investigate how the drug was arranged into these nanoparticles. The IDE seemed to be located into different regions of the SLN depending on its concentration and on the surfactant used. The results of this study suggest that the calorimetric studies performed on SLN could provide valuable information to optimize SLN design and drug release from these carriers.

Differential Scanning Calorimetry as a Tool to Investigate the Transfer of Anticancer Drugs to Biomembrane Model

Different anticancer drugs clinically approved by international regulatory organizations present poor water solubility and low stability after systemic injection. Their administration requires suitable carriers capable of maximizing therapeutic efficacy. Lipid and polymeric nanotherapeutics, particularly liposomes, are widely used to deliver chemotherapeutics in the clinic. The interaction between chemotherapeutics and biocompatible lipids and polymers can affect their efficacy and play a pivotal role in chemotherapy. Phospholipids are the main components of liposomes and their interactions with therapeutic agents are widely investigated in the pharmaceutical field using differential scanning calorimetry (DSC). In this work, DSC was exploited to investigate the interaction between hydrophobic chemotherapeutics, i.e. docetaxel, tamoxifen and lapatinib, with lipid vesicles. Lipid carriers are prepared using dimyristoylphosphatidylcholine (DMPC), a phosphatidylcholine derivative, showing the same physicochemical features of the main lipids in the biological membranes. DMPC was used as a biological membrane model to evaluate interaction, passage, diffusion, and adsorption of chemotherapeutics. These processes were evaluated through the variation of thermotropic parameters of the biological membrane model. DSC studies were carried out in heating and cooling mode. Results demonstrated a modification of calorimetric curves and this effect is strictly related to the molar fraction and physicochemical features of chemotherapeutics. Furthermore, the interaction between chemotherapeutics and biological membranes affects their internalization and distribution inside tumors and this process depends on gel-liquid crystal transition of phospholipids. DSC results provide suitable information about this effect and can be used as tool to predict further interaction between chemotherapeutics and biological membranes.

Interaction between PEG lipid and DSPE/DSPC phospholipids: An insight of PEGylation degree and kinetics of de-PEGylation

The degree to which liposomes are PEGylated is the feature, which most influences the length of the presence of stealth liposomes in the bloodstream. In order to thoroughly investigate the maximum amount of DSPE-PEG2000 that can be used to stabilize stealth liposomes, these were synthesized at different concentrations of DSPE-PEG2000 and their physicochemical properties were investigated by using differential scanning calorimetry (DSC). The kinetics of PEGylation and de-PEGylation were performed by incubating non-stealth liposomes in a DSPE-PEG2000 suspension at different incubation times, and then analyzing the data using DSC and dynamic light scattering (DLS) techniques. The results demonstrated that DSPE-PEG2000 was self-assembled in the phospholipid bilayers, thus forming stealth liposomes. The different amounts of DSPE-PEG2000 in the bilayer triggered a de-PEGylation phenomenon, resulting in mixed nanoaggregates, which derived from the detergent-like properties of the PEGylated phospholipids.

Calorimetric evidence of interaction of brominated flame retardants with membrane model

The presence of polybrominated flame retardants in the environment seems to be increasing in the past decade. Considering the toxic effects of these pollutants, it is important evaluating the potential interaction with biological membranes for a risk assessment. In this study low and high brominated biphenyls and biphenyl ethers were used to investigate their interaction with biological membrane models constituted by liposomes, using differential scanning calorimetry (DSC) technique. The medium influence on membrane absorption was also assessed. The findings indicate that membrane interaction is controlled by compound structural characteristics. The membrane absorption is allowed by lipophilic medium; instead hydrophilic medium prevents membrane permeation.

Calorimetry and Langmuir-Blodgett studies on the interaction of a lipophilic prodrug of LHRH with biomembrane models

The interaction between an amphiphilic luteinizing hormone-releasing hormone (LHRH) prodrug that incorporated a lipoamino acid moiety (C12-LAA) with biological membrane models that consisted of multilamellar liposomes (MLVs) and phospholipid monolayers, was studied using Differential Scanning Calorimetry (DSC) and Langmuir-Blodgett film techniques. The effect of the prodrug C12[Q1]LHRH on the lipid layers was compared with the results obtained with the pure precursors, LHRH and C12-LAA. Conjugation of LHRH with a LAA promoiety showed to improve the peptide interaction with biomembrane models. Basing on the calorimetric findings, the LAA moiety aided the transfer of the prodrug from an aqueous solution to the biomembrane model.

DSC investigation of the effect of the new sigma ligand PPCC on DMPC lipid membrane

The new sigma ligand cis-(±)-methyl (1R,2S/1S,2R)-2-[(4-hydroxy-4-phenylpiperidin-1-yl) methyl]-1-(4-methylphenyl) cyclopropanecarboxylate [(±)-PPCC] is a promising tool for the treatment of various diseases. With the aim to investigate the absorption of (±)-PPCC by the cell membranes, in this study we evaluated the influence on thermotropic behavior of membrane model exerted by PPCC both as free base or as oxalic salt. To fulfill this purpose differential scanning calorimetry was used. The findings highlight that PPCC affects the thermodynamic parameters of phospholipids in different manner depending on whether it is in the salt or base form as well as function of the amount of drugs dispersed in the lipid matrix. The salt form of PPCC was uptaken by the membrane model faster than the free base. In addition, preliminary information on the use of a lipophilic carrier for PPCC was obtained.

Interaction of α-Hexylcinnamaldehyde with a Biomembrane Model: A Possible MDR Reversal Mechanism

The ability of the naturally derived compound α-hexylcinnamaldehyde (1) to interact with biomembranes and to modulate their permeability has been investigated as a strategy to reverse multidrug resistance (MDR) in cancer cells. Dimyristoylphosphatidylcholine (DMPC) multilamellar vesicles (MLVs) were used as biomembrane models, and differential scanning calorimetry was applied to measure the effect of 1 on the thermotropic behavior of DMPC MLVs. The effect of an aqueous medium or a lipid carrier on the uptake of 1 by the biomembrane was also characterized. Furthermore, taking into account that MDR is strictly regulated by redox signaling, the pro-oxidant and/or antioxidant effects of 1 were evaluated by the crocin-bleaching assay, in both hydrophilic and lipophilic environments. Compound 1 was uniformly distributed in the phospholipid bilayers and deeply interacted with DMPC MLVs, intercalating among the phospholipid acyl chains and thus decreasing their cooperativity. The lipophilic medium allowed the absorption of 1 into the phospholipid membrane. In the crocin-bleaching assay, the substance produced no pro-oxidant effects in both hydrophilic and lipophilic environments; conversely, a significant inhibition of AAPH-induced oxidation was exerted in hydrophilic medium. These results suggest a possible role of 1 as a chemopreventive and chemosensitizing agent for fighting cancer.