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Colorectal cancer is one of the most diffused tumoral diseases. Since most medicaments employed for its treatment are debilitating, the use of naturally derived products, which can be effective against the mutated cells and, in addition, can reduce most inflammatory-related effects, could be extremely beneficial for the continued treatment of this disease. In this research, ethyl protocatechuate (PCAEE), a protocatechuic acid prodrug, was encapsulated in solid lipid nanoparticles (SLN) (prepared without and with Tween 80), which were characterized in terms of size, polydispersity index (PDI), zeta potential and thermotropic behavior. Encapsulation efficiency, release profile and interaction with a model of biomembrane were also assessed. The nanoparticles were tested in vitro on both healthy cells and on a model of tumoral cells. SLN prepared with Tween 80 was promising in terms of physicochemical properties (z-average of 190 nm, PDI 0.150 and zeta potential around −20 mV) and encapsulation efficiency (56%); they showed a desirable release profile, demonstrated an ability to penetrate and release the encapsulated PCAEE into a biomembrane model and were nontoxic on healthy cells. In addition, they caused a greater dose-dependent decrease in the viability of CaCo-2 cells than PCAEE alone. In conclusion, the formulation could be proposed for further studies to assess its suitability for the treatment of colorectal cancer. [ABSTRACT FROM AUTHOR]

Skin is the first human barrier that is daily exposed to a broad spectrum of physical and chemical agents, which can increase reactive oxygen species (ROS) and lead to the formation of topical disorders. Antioxidant molecules, such as benzo[k,l]xanthene lignans (BXL), are ideal candidates to eliminate or minimize the effects of ROS. Herein, we aimed to formulate BXL-loaded solid lipid nanoparticles (SLN-BXL) to improve the bioavailability and interaction with the skin, and also to investigate the protective impact against intracellular ROS generation in HFF-1 in comparison with the drug-free situation. SLN-BXL were formulated using the PIT/ultrasonication method, and then were subjected to physicochemical characterizations, i.e., average size, zeta potential (ZP), polydispersity index (PDI), encapsulation efficiency (%EE), thermotropic behavior, and interaction with a biomembrane model. The results show a mean size around 200 nm, PDI of 0.2, and zeta potential of about −28 mV, with values almost unchanged over a period of three months, while the EE% is ≈70%. Moreover, SLN-BXL are able to deeply interact with the biomembrane model, and to achieve a double-action release in mildly hydrophobic matrices; the results of the in vitro experiments confirm that SLN-BXL are cell-safe and capable of attenuating the IL-2-induced high ROS levels. In conclusion, based on our findings, the formulation can be proposed as a candidate for a preventive remedy against skin disorders induced by increased levels of ROS. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]

Abstract: 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. [Copyright &y& Elsevier]

Differential Scanning Calorimetry was used to study the interaction of new resveratrol derivatives using dimyristoylphosphatidylcholine (DMPC) multilamellar vesicles (MLV) as biomembrane models. MLV prepared in the presence of increasing molar fractions of the following compounds: (A) 3,5,3′,5′-tetramethoxystilbene, (B) 3,5,3′,4′-tetramethoxystilbene, (C) 3,4,5,4′-tetramethoxystilbene, (D) 3,4,5,3′,5′-pentamethoxystilbene and (E) 3,4,2′,4′,5′-pentamethoxystilbene were analyzed to study the effects exerted by the number and position of the substituents on the variations of thermotropic properties of the biomembrane model. The results showed that the number and the position of the substituent strongly affected the interaction between the compounds and the MLV based on DMPC. Kinetic experiments demonstrated that, the absorption of compounds A to E is limited in an aqueous medium. The presence of a lipophilic medium improves the absorption of the compounds by the biomembrane model. [ABSTRACT FROM AUTHOR]

Abstract: Cytarabine (1-β-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. [Copyright &y& Elsevier]

The release of bioactive molecules by different delivery systems has been studied. We have proposed a protocol that takes into account a system that is able to carry out the uptake of a bioactive molecule released during the time, resembling an in vivo-like system, and for this reason we have used biomembrane models represented by multi-lamellar and unilamellar vesicles. The bioactive molecule loaded delivery system has been put in contact with the biomembrane model and the release has been evaluated, to consider the effect of the bioactive molecule on the biomembrane model thermotropic behavior, and to compare the results with those obtained when a pure drug interacts with the biomembrane model. The differential scanning calorimetry technique has been employed. Depending on the delivery system used, our research permits to evaluate the effect of different parameters on the bioactive molecule release, such as pH, drug loading degree, delivery system swelling, crosslinking agent, degree of cross-linking, and delivery system side chains. [ABSTRACT FROM AUTHOR]

Insight into the forces governing a system is essential for understanding its behavior and function. Thermodynamic investigations provide a wealth of information that is not, or is hardly, available from other methods. This article reviews thermodynamic approaches and assays to measure collective properties such as heat adsorption / emission and volume variations. These methods can be successfully applied to the study of lipid vesicles (liposomes) and biological membranes. With respect to instrumentation, differential scanning calorimetry, pressure perturbation calorimetry, isothermal titration calorimetry, dilatometry, and acoustic techniques aimed at measuring the isothermal and adiabatic processes, two- and three-dimensional compressibilities are considered. Applications of these techniques to lipid systems include the measurement of different thermodynamic parameters and a detailed characterization of thermotropic, barotropic, and lyotropic phase behavior. The membrane binding and / or partitioning of solutes (proteins, peptides, drugs, surfactants, ions, etc.) can also be quantified and modeled. Many thermodynamic assays are available for studying the effect of proteins and other additives on membranes, characterizing non-ideal mixing, domain formation, bilayer stability, curvature strain, permeability, solubilization, and fusion. Studies of membrane proteins in lipid environments elucidate lipid-protein interactions in membranes. Finally, a plethora of relaxation phenomena toward equilibrium thermodynamic structures can be also investigated. The systems are described in terms of enthalpic and entropic forces, equilibrium constants, heat capacities, partial volume changes, volume and area compressibility, and so on, also shedding light on the stability of the structures and the molecular origin and mechanism of the structural changes. [ABSTRACT FROM AUTHOR]

Abstract: Differential scanning calorimetry was used to study the interaction of acyclovir and its prodrug squalenoyl–acyclovir (obtained by conjugation of 1,1′,2-tris-nor-squalene acid (squaleneCOOH) with acyclovir) with biomembrane models made of DMPC multilamellar vesicles with the aim to verify whether a stronger interaction of the prodrug with respect to the free drug can be obtained. Multilamellar vesicles were prepared in the presence of increasing molar fractions of acyclovir, squaleneCOOH or prodrug and the effect of the compounds on the thermotropic behavior of vesicles was researched, revealing no effect of acyclovir but a strong effect of squaleneCOOH and prodrug. To evaluate if acyclovir, squaleneCOOH and prodrug can be absorbed by the biomembrane model, an experiment was carried out in which the considered compounds were left in contact with the biomembrane model and their eventual uptake was evaluated analyzing the effect on the thermotropic behavior of the biomembrane model. A very small uptake was revealed for all the compounds. To check the potential use of liposomes as a delivery system for the prodrug, the biomembrane models were incubated with liposomes loaded with the compounds and the compounds transferring from the loaded liposomes to the unloaded biomembrane model was followed. The results suggest that liposomes could be used to deliver the squalenoyl–acyclovir to the biomembrane model. [Copyright &y& Elsevier]

• Interaction and absorption of limonene, terpineol and 1,8-cineol by biomembrane model were studied. • Differential scanning calorimetry was used. • The compounds have a different localization within the biomembrane model. • The absorption of the compounds by the biomembrane model is limonene < terpineol<1,8-cineol. • Liposomes formulations could be used for therapeutic application of these substances. The interaction of limonene, terpineol, and 1,8 cineol with a model of biological membrane and the absorption of the three compounds by the same model of biological membrane were studied. In addition, the possibility to use a lipophilic carrier for the transport and delivery of the compounds to the biomembrane was investigated. Differential scanning calorimetry technique was used. The obtained results reveal that all the compounds interact and are absorbed by the model of biomembrane with different extent depending on their characteristics. Moreover, the lipophilic carrier could be used as a suitable system for the transport and delivery of such compounds to biomembranes. [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]

A comparative study between the release of Ibuprofen (IBU) from Eudragit RS100® (RS) and RL100® (RL) nanosuspensions as well as the free drug to a biological model membrane, consisting of dimyristoylphosphatidylcholine (DMPC) multilamellar vesicles (MLV), was carried out by DSC technique. The aim was to assess the suitability of such calorimetric technique to determine the kinetics of drug release from a polymer system, compared with a classical release test by dialysis method. Nanosuspensions were prepared by a modification of the quasi-emulsion solvent diffusion technique (QESD), a particular approach to the general solvent-change method. This kind of system was planned for the ophthalmic release of non-steroidal anti-inflammatory drugs in ocular diseases associated with inflammatory processes (i.e. post-cataract surgery or uveitis). The drug release was monitored by differential scanning calorimetry (DSC), following the effects exerted by IBU on the thermotropic behaviour of DMPC multilamellar vesicles. IBU affects the main transition temperature (Tm) of phospholipid vesicles, causing a shift towards lower values, driven by the drug fraction entering the lipid bilayer. The obtained values have been used as a calibration curve. DSC was performed on suspensions of blank liposomes added to fixed amounts of unloaded and IBU-loaded Eudragit RS100® and RL100® nanosuspensions as well as to powdered free drug. The Tm shifts caused by the drug released from the polymer system or by the free drug, during incubation cycles at 37 °C, were compared to the calibration curve in order to obtain the fraction of drug released. The results were also compared with in vitro dialysis release experiments. The suitability of the two different techniques to follow the drug release as well as the differences between the RL and RS polymer systems was compared, confirming the efficacy of DSC for studying the release from polymer nanoparticulate systems. Explanation of the different rate of kinetic release could be due to void liposomes, which represent a better up-taking system than the aqueous solution phase in the dialysis experiments. [Copyright &y& Elsevier]

Differential scanning calorimetry (DSC) is a thermoanalytical technique which provides information on the interaction between drugs and models of cell membranes. Studies on the calorimetric behavior of hydrated phospholipids within liposomes are employed to shed light on the changes in the physico-chemical properties when interacting with drugs. In this report, new potential anti-cancer drugs such as uridine and uridine derivatives (acetonide and its succinate), 3β-5α,8α-endoperoxide-cholestan-6-en-3-ol (5,8-epidioxicholesterol) and conjugate (uridine acetonide-epidioxicholesterol succinate) have been synthesized. Steglich esterification method using coupling agents allowed to obtain the uridine acetonide-sterol conjugate. The study on the interaction between the drugs and dimiristoyl-phophatidilcholine (DMPC) liposomes has been conducted by the use of DSC. The analysis of the DSC curves indicated that the uridine and derivatives (acetonide and its succinate) present a very soft interaction with the DMPC liposomes, whereas the 5,8-epidioxicholesterol and the conjugate showed a strong effect on the thermotropic behavior. Our results suggested that the lipophilic character of uridine acetonide-sterol conjugate improves the affinity with the DMPC liposomes. [ABSTRACT FROM AUTHOR]

Abstract: Anti-inflammatory drugs represent a potential new strategy for the treatment of Alzheimer’s disease (AD). The ability to cross the blood–brain barrier and to reach brain tissues is a critical point for these drugs and is strictly related to their lipophilicity. Naproxen (NAP) is a non-steroidal anti-inflammatory drug (NSAIDs) under active investigation for AD. To improve its lipophilic character, NAP was conjugated through a diethylamine spacer (EDA) to lipoamino acids (LAA), α-amino acids containing a long alkyl side chain, to obtain the NAP–EDA–LAA10 and NAP–EDA–LAA14 prodrugs. The interaction of NAP and prodrugs with dimyristoylphosphatidylcholine phospholipids, forming either multilamellar vesicles or monolayers (at the air/water interface) and used as biomembrane models, was studied by differential scanning calorimetry and Langmuir–Blodgett techniques. Experimental data showed that NAP conjugation with LAA residues was able to enhance the drug interaction with such biomembrane models. [Copyright &y& Elsevier]

[Display omitted] • (-)-MRV3 and (+)-MR200, new sigma ligands, interact with biomembrane models. • (-)-MRV3 affected the biomembrane models more than (+)-MR200. • Liposomal carrier could be used for the release of (-)-MRV3 and (+)-MR200. The compound (+)-MR200 [(+)-methyl (1R,2S)-2-{[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]methyl}-1-phenylcyclopropanecarboxylate] is a selective sigma 1 (σ 1) antagonist with antinociceptive effect, able to increase selective opioid receptor agonist-mediated analgesia. The parent compound (−)-MRV3 [(−)-methyl (1S,2R)-2-[(4-hydroxy-4-phenylpiperidin-1-yl)-methyl]-1-phenylcyclopropanecarboxylate], a σ 1 antagonist with an improved σ 1 /σ 2 selectivity respect to (+)-MR200, play a role in both central sensitization and pain hypersensitivity, suggesting a potential use of σ 1 antagonists for the treatment of persistent pain conditions. With the intention to assessing the membrane absorption of compounds and their ability to cross it, the interaction of (+)-MR200 and (−)-MRV3 with dimyristoylphosphatidylcholine phospholipids (DMPC), used as biomembrane models was studied by Differential Scanning Calorimetry (DSC) and Langmuir-Blodgett (LB). [ABSTRACT FROM AUTHOR]