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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.

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.

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.

Polychlorinated biphenyls (PCBs) are organic pollutants with lipophilic properties, due to their persistence, they are present in environment at potentially dangerous concentrations for humans health. In this work we investigated the interaction and absorption of 2,4,4'-trichlorobiphenyl (PCB 28), 2,3,3',4,4'-pentachlorobiphenyl (PCB 105) and 2,3,3',4,4',5,5'-eptachlorobiphenyl (PCB 189) with dimyristoylphosphatidylcholine (DMPC) multilamellar vesicles (MLV), chosen as biomembrane models, by differential scanning calorimetry technique (DSC). The obtained results indicate that the tested compounds affected the thermotropic behaviour of MLV to different degree, modifying the phase transition peak and shifting it towards lower temperature. The effect of an aqueous or lipophilic medium on the absorption process of these compounds by the biomembrane models was also investigated revealing that the process is hindered by the aqueous medium but favoured by the lipophilic medium.

3,4-Secoisopimar-4(18),7,15-trien-3-oic acid is a diterpenoid contained in the aerial parts of Salvia cinnabarina M. Martens et Galeotti which has been proved to inhibit the effect of some known mutagens, in several bacterial strains, acting as a desmutagenic agent. In order to evaluate if 3,4-Secoisopimar-4(18),7,15-trien-3-oic inactivate the mutagen in intra- or extracellular compartment, present work investigated the interaction between the test substance and the biological membrane in a model of biomembrane, represented by multilamellar vesicles of dimyristoylphosphatidylcholine, using differential scanning calorimetry. The results obtained indicate a strong interaction of the examined diterpenoid with the model of biomembrane and that its absorption is quite improved by a lipophilic carrier.

The ability of the flavouring sesquiterpenes β-caryophyllene and β-caryophyllene oxide to be absorbed into the cell has been investigated by an in vitro biomembrane model of multilamellar vesicles. Dimyristoylphosphatidylcholine was used as a constituent of the biomembrane and permitted the experiments to be carried out at 37.0 °C, close to body temperature. Differential scanning calorimetry was applied for measuring the effect of the compounds on the thermotropic behaviour of the vesicles. Studies were also carried out in order to characterize the interference of an aqueous medium or a lipid carrier with the uptake of the substances by the biomembrane. The results showed that both sesquiterpenes influenced the behaviour of the multilamellar vesicles, with β-caryophyllene producing a larger effect than β-caryophyllene oxide. The aqueous medium hindered the absorption of the test substances, probably because of their low water solubility; on the contrary, the lipophilic medium strongly favoured their uptake. Present results provide preliminary information on the bioavailability of β-caryophyllene and β-caryophyllene oxide and allow us to expect their uptake through cell membranes. Moreover, these results could be of importance for future design of lipophilic delivery systems for these sesquiterpenes.

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.

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.

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.

An emerging approach in pain management is the use of multitarget opioid ligands, owing an improved analgesic effect coupled to a reduced incidence of side effects. With a mu opioid receptor agonist/delta opioid receptor antagonist profile, the benzomorphan-based compound LP1 belongs to multitarget ligands class. Previous in vivo investigations showed that LP1 – subcutaneously administered as oxalate salt – was an antinociceptive agent as potent as morphine with a low tolerance-inducing capability. Because the renal toxicity of oxalate is known, an alternative approach allowing the administration of LP1 freebase could be more biocompatible. In this study the interaction of LP1 freebase and LP1 oxalate salt with multilamellar vesicles, as membrane model, was evaluated using differential scanning calorimetry technique. Despite the good membrane interaction showed by LP1 freebase, it was not capable to diffuse in the aqueous medium and to be uptaken by multilamellar vesicles. On the other hand, LP1 freebase possessed a good transfer profile by a liposomal carrier to a biomembrane model. Considering our findings and the need of safe formulations, studies for the development of a suitable carrier for a systemic administration of LP1 freebase are in progress.

The interactions of the two resveratrol analogues 2-hydroxy-3,5,3',5'-tetramethoxystilbene (4) and 2-hydroxy-3,5,3',4'-tetramethoxystilbene (5) with model biomembranes were studied. The aim of this investigation was to highlight possible differences in the interactions with such biomembranes related to the minimal structural differences between these isomeric stilbenoids. In particular, different experiments on stilbenoid/biomembrane model systems using both differential scanning calorimetry (DSC) and Langmuir-Blodgett techniques were carried out to evaluate stilbenoid/multilamellar vesicle and stilbenoid/phospholipid monolayer interactions, respectively. Dimyristoylphosphatidylcholine was used as constituent of the biomembrane models and permitted the experiments to be carried out at 37 °C, close to body temperature. Kinetic studies were also run by DSC to evaluate the uptake of the resveratrol derivatives by the biomembrane model in an aqueous medium and when transported by a lipophilic carrier. The results indicated that both of the resveratrol analogues influenced the behavior of multilamellar vesicles and monolayers, biomembrane models, with 4 producing a larger effect than 5. These results are useful for better understanding the mechanism of action of these compounds. Moreover, the kinetic results could be of importance for future design of lipophilic delivery systems for these stilbenoids.