Publications by authors named "Sarpietro Maria Grazia"

56 Publications

Interaction of new sigma ligands with biomembrane models evaluated by differential scanning calorimetry and Langmuir-Blodgett studies.

Colloids Surf B Biointerfaces 2021 May 18;201:111643. Epub 2021 Feb 18.

Dipartimento di Scienze del Farmaco, Viale Andrea Doria 6, 95125, Catania, Italy. Electronic address:

The compound (+)-MR200 [(+)-methyl (1R,2S)-2-{[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]methyl}-1-phenylcyclopropanecarboxylate] is a selective sigma 1 (σ) 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 antagonist with an improved σ/σ selectivity respect to (+)-MR200, play a role in both central sensitization and pain hypersensitivity, suggesting a potential use of σ 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).
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http://dx.doi.org/10.1016/j.colsurfb.2021.111643DOI Listing
May 2021

Astaxanthin-Loaded Stealth Lipid Nanoparticles (AST-SSLN) as Potential Carriers for the Treatment of Alzheimer's Disease: Formulation Development and Optimization.

Nanomaterials (Basel) 2021 Feb 3;11(2). Epub 2021 Feb 3.

Department of Drug Science and Health, University of Catania, Viale Andrea Doria 6, 95125 Catania, Italy.

Alzheimer's disease (AD) is a neurodegenerative disorder associated with marked oxidative stress at the level of the brain. Recent studies indicate that increasing the antioxidant capacity could represent a very promising therapeutic strategy for AD treatment. Astaxanthin (AST), a powerful natural antioxidant, could be a good candidate for AD treatment, although its use in clinical practice is compromised by its high instability. In order to overcome this limit, our attention focused on the development of innovative AST-loaded stealth lipid nanoparticles (AST-SSLNs) able to improve AST bioavailability in the brain. AST-SSLNs prepared by solvent-diffusion technique showed technological parameters suitable for parenteral administration (<200 nm). Formulated nanosystems were characterized by calorimetric studies, while their toxicological profile was evaluated by the MTT assay on the stem cell line OECs (Olfactory Ensheathing Cells). Furthemore, the protective effect of the nanocarriers was assessed by a long-term stability study and a UV stability assay confirming that the lipid shell of the nanocarriers was able to preserve AST concentration in the formulation. SSLNs were also capable of preserving AST's antioxidant capacity as demonstrated in the oxygen radical absorbance capacity (ORAC) assay. In conclusion, these preliminary studies outline that SSLNs could be regarded as promising carriers for systemic administration of compounds such as AST aimed at AD treatment.
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http://dx.doi.org/10.3390/nano11020391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913486PMC
February 2021

Curcumin Containing PEGylated Solid Lipid Nanoparticles for Systemic Administration: A Preliminary Study.

Molecules 2020 Jun 30;25(13). Epub 2020 Jun 30.

Department of Drug Sciences, University of Catania, Viale Andrea Doria n°6, 95125 Catania, Italy.

Curcumin (CUR) has a wide range of pharmacological properties, including anti-inflammatory and antioxidant activities, and it can be considered a good candidate for the potential treatment of central nervous system (CNS) pathologies, although its use in clinical practice is compromised due to its high lipophilicity. Solid lipid nanoparticles (SLNs) are well-known nanocarriers representing a consolidated approach for the delivery of lipophilic compounds, but their systemic use is limited due their short half-life. The formulation of stealth SLNs (pSLNs) could be a valid strategy to overcome this limit. Curcumin-loaded-pSLNs were prepared by the solvent evaporation method. Formulation was characterized for their mean size, zeta potential, size distribution, and morphology. Drug antioxidant activity was evaluated by Oxygen Radical Absorbance Capacity (ORAC) assay. Finally, the obtained formulations were analyzed in terms of long-term stability. Curcumin-loaded-pSLNs showed good technological parameters with a mean particle size below 200 nm, as confirmed by TEM images, and a zeta potential value around -30 mV, predicting good long-term stability. Differential Scanning Calorimetry (DSC) analysis confirmed that PEG micelles interacted with the SLN surface; this suggests the location of the PEG on the pSLN surface. Therefore, these preliminary studies suggest that the produced formulation could be regarded as a promising carrier for the systemic administration.
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http://dx.doi.org/10.3390/molecules25132991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7411787PMC
June 2020

Differential Scanning Calorimetry Analyses of Idebenone-Loaded Solid Lipid Nanoparticles Interactions with a Model of Bio-Membrane: A Comparison with In Vitro Skin Permeation Data.

Pharmaceuticals (Basel) 2018 Dec 16;11(4). Epub 2018 Dec 16.

Department of Drug Sciences, University of Catania, V.le A. Doria 6, 95125 Catania, Italy.

Differential scanning calorimetry (DSC) has emerged as a helpful technique both to characterize drug delivery systems and to study their interactions with bio-membranes. In this work, we compared idebenone (IDE)-loaded solid lipid nanoparticle (SLN) interactions with bio-membranes assessed by DSC with previous in vitro skin penetration data to evaluate the feasibility of predicting IDE skin penetration using DSC analyses. In vitro interactions experiments were performed using multi-lamellar liposomes as a model of bio-membrane. Enthalpy changes (ΔH) and transition temperature (Tm) were assessed during nine repeated DSC scans to evaluate IDE-loaded SLN⁻bio-membrane interactions over time. Analyzing ΔH and Tm values for each scan, we observed that the difference of ΔH and Tm values between the first and the last scan seemed to be related to SLN ability to locate IDE in the epidermis and in the stratum corneum, respectively. Therefore, the results of this study suggest the possibility of qualitatively predicting in vitro IDE skin penetration from IDE-loaded SLN utilizing the calorimetric parameters obtained from interaction experiments between the carriers under investigation and a model of bio-membrane.
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http://dx.doi.org/10.3390/ph11040138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6316718PMC
December 2018

Anomalous interaction of tri-acyl ester derivatives of uridine nucleoside with a l-α-dimyristoylphosphatidylcholine biomembrane model: a differential scanning calorimetry study.

J Pharm Pharmacol 2019 Mar 20;71(3):329-337. Epub 2018 Nov 20.

Dipartimento di Scienze del Farmaco, Università degli Studi di Catania, Catania, Italia.

Objectives: Uridine was conjugated with fatty acids to improve the drug lipophilicity and the interaction with phospholipid bilayers.

Methods: The esterification reaction using carbodiimides compounds as coupling agents and a nucleophilic catalyst allowed us to synthesize tri-acyl ester derivatives of uridine with fatty acids. Analysis of molecular interactions between these tri-acyl ester derivatives and l-α-dimyristoylphosphatidylcholine (DMPC) multilamellar vesicles (MLV) - as a mammalian cell membrane model - have been performed by differential scanning calorimetry (DSC).

Key Findings: The DSC thermograms suggest that nucleoside and uridine triacetate softly interact with phospholipidic multilamellar vesicles which are predominantly located between the polar phase, whereas the tri-acyl ester derivatives with fatty acids (myristic and stearic acids) present a strongly interaction with the DMPC bilayer due to the nucleoside and aliphatic chains parts which are oriented towards the polar and lipophilic phases of the phospholipidic bilayer, respectively. However, the effects caused by the tri-myristoyl uridine and tri-stearoyl uridine are different.

Conclusions: We show how the structural changes of uridine modulate the calorimetric behaviour of DMPC shedding light on their affinity with the phospholipidic biomembrane model.
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http://dx.doi.org/10.1111/jphp.13038DOI Listing
March 2019

Synthesis and interaction of sterol-uridine conjugate with DMPC liposomes studied by differential scanning calorimetry.

Colloids Surf B Biointerfaces 2018 Jun 19;166:203-209. Epub 2018 Mar 19.

Dipartimento di Scienze del Farmaco, Università degli Studi di Catania, Viale Andrea Doria 6, 95125, Catania, Italy. Electronic address:

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.
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http://dx.doi.org/10.1016/j.colsurfb.2018.03.023DOI Listing
June 2018

Amphiphilic naproxen prodrugs: differential scanning calorimetry study on their interaction with phospholipid bilayers.

J Pharm Pharmacol 2017 Sep 16;69(9):1091-1098. Epub 2017 Jun 16.

Dipartimento di Scienze del Farmaco, Università degli Studi di Catania, Catania, Italy.

Objectives: Naproxen, a nonsteroid anti-inflammatory drug studied for Alzheimer's disease, was conjugated with lipoamino acids (LAA) directly or through a diethylamine (EDA) spacer to improve the drug lipophilicity and the interaction with phospholipid bilayers.

Methods: The interaction of naproxen and its prodrugs with biomembrane models consisting of dimyristoylphosphatidylcholine multilamellar vesicles was studied by differential scanning calorimetry. The transfer of prodrugs from a lipophilic carrier to a biomembrane model was also studied.

Key Findings: Naproxen conjugation to lipoamino acids improves its interaction with biomembrane models and affects the transfer from a lipophilic carrier to biomembrane model. LAA portion may localize between the phospholipid chains; the entity of the interaction depends not only on the presence of the spacer but also on the LAA chain length.

Conclusions: Variation of LAA portion can modulate the naproxen prodrugs affinity towards the biological membrane as well as towards the lipophilic carrier.
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http://dx.doi.org/10.1111/jphp.12754DOI Listing
September 2017

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

Colloids Surf B Biointerfaces 2017 Jul 13;155:266-275. Epub 2017 Apr 13.

Department of Pharmacy, University of Chieti - Pescara "G. d'Annunzio", Via dei Vestini 31, I - 66100 Chieti, Italy; Department of Nanomedicine, Houston Methodist Research Institute, 6670 Bertner Avenue, Houston, TX 77030, USA. Electronic address:

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-PEG that can be used to stabilize stealth liposomes, these were synthesized at different concentrations of DSPE-PEG 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-PEG suspension at different incubation times, and then analyzing the data using DSC and dynamic light scattering (DLS) techniques. The results demonstrated that DSPE-PEG was self-assembled in the phospholipid bilayers, thus forming stealth liposomes. The different amounts of DSPE-PEG in the bilayer triggered a de-PEGylation phenomenon, resulting in mixed nanoaggregates, which derived from the detergent-like properties of the PEGylated phospholipids.
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http://dx.doi.org/10.1016/j.colsurfb.2017.04.018DOI Listing
July 2017

Calorimetric evidence of interaction of brominated flame retardants with membrane model.

Environ Toxicol Pharmacol 2015 May 13;39(3):1154-60. Epub 2015 Apr 13.

Dipartimento di Scienze del Farmaco, Università degli Studi di Catania, Viale A. Doria 6, Catania 95125, Italy. Electronic address:

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.
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http://dx.doi.org/10.1016/j.etap.2015.04.002DOI Listing
May 2015

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

J Nat Prod 2015 May 20;78(5):1154-9. Epub 2015 Apr 20.

†Department of Drug Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy.

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.
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http://dx.doi.org/10.1021/acs.jnatprod.5b00152DOI Listing
May 2015

Lipid nanocarriers containing a levodopa prodrug with potential antiparkinsonian activity.

Mater Sci Eng C Mater Biol Appl 2015 Mar 10;48:294-300. Epub 2014 Dec 10.

Department of Life Sciences & Biotechnology, University of Ferrara, Ferrara, Italy. Electronic address:

This paper describes the production, characterization and in vivo activity of lipid nanocarriers (LN) containing a levodopa prodrug (LD-PD) with therapeutic potential in Parkinson's disease. LD is the mainstay of the pharmacotherapy of Parkinson's disease. However, after a good initial response, motor fluctuations, dyskinesia and loss of efficacy, develop over time, partly due to oscillations in plasma and brain levels of the drug. LD-PD was produced with the aim of prolonging the pharmacological activity of LD. To improve solubility, and simultaneously provide a long lasting release and therapeutic efficacy, the prodrug was formulated in tristearin/lecithin LN. The obtained formulation was homogeneous in particle size and remained stable for up to 2months from preparation. For the three different tested LD concentrations, namely 1.25, 2.5 and 5.0mg/ml, the morphological characterization revealed no substantial differences between unloaded and LD-PD loaded LN. The calorimetric test showed an interaction between the lipid phase and the loaded prodrug. In vitro studies using the dialysis method and enzymatic degradation procedure showed that the LD-PD loaded LN provided a controlled prodrug release. Finally, two behavioural tests specific to akinesia (bar test) or akinesia/bradykinesia (drag test) performed in 6-hydroxydopamine hemilesioned mice (a model of Parkinson's disease) demonstrated that the LD-PD loaded LN attenuated parkinsonian disabilities, showing a slightly reduced maximal efficacy but a longer lasting action (up to 24h) than an equal dose of LD. We conclude that LD-PD loaded LN may represent a future LD formulation useful in Parkinson's disease therapy.
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http://dx.doi.org/10.1016/j.msec.2014.12.014DOI Listing
March 2015

α-Hexylcinnamaldehyde inhibits the genotoxicity of environmental pollutants in the bacterial reverse mutation assay.

J Nat Prod 2014 Dec 10;77(12):2664-70. Epub 2014 Dec 10.

Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of Rome , P.le Aldo Moro 5, 00185 Rome, Italy.

The antimutagenicity of α-hexylcinnamaldehyde (1), a semisynthetic and more stable derivative of cinnamaldehyde, was evaluated against common environmental pollutants in the bacterial reverse mutation assay. The pre-, co-, and post-treatment protocols were applied to assess the involvement of desmutagenic and/or bioantimutagenic mechanisms. Compound 1 (9-900 μM) produced a strong antimutagenicity (>40% inhibition) in the Salmonella typhimurium TA98 strain against the nitroarenes 2-nitrofluorene and 1-nitropyrene in almost all experimental conditions. A strong inhibition was also reached against the nitroarene 1,8-dinitropyrene and the arylamine 2-aminoanthracene in the cotreatment at the highest concentrations tested. In order to evaluate if an inhibition of bacterial nitroreductase (NR) and O-acetyltransferase (OAT) could be involved in the antimutagenicity of 1 against nitroarenes, the substance was further tested against 1-nitropyrene (activated by both NR and OAT) in TA98NR and TA98 1,8-DNP strains (lacking the NR and OAT enzymes, respectively). Although both desmutagenic and bioantimutagenic mechanisms appear mostly involved in the antimutagenicity of 1, based on data obtained in the TA98NR strain, applying the pretreatment protocol, compound 1 seems to act as an inhibitor of the OAT-mediated mutagen bioactivation. These results provide justification for further studies on 1 as a possible chemopreventive agent.
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http://dx.doi.org/10.1021/np500567dDOI Listing
December 2014

Lipophilic prodrug of paclitaxel: interaction with a dimyristoylphosphatidylcholine monolayer.

Int J Pharm 2014 Nov 16;475(1-2):624-31. Epub 2014 Sep 16.

Dipartimento di Scienze del Farmaco, Università degli Studi di Catania, Viale A. Doria 6, 95125 Catania, Italy. Electronic address:

Interactions between paclitaxel and its squalenoyl prodrug with dimyristoylphosphatidylcholine (DMPC) monolayer at the air/water interface were studied. Paclitaxel is an antineoplastic drug, largely used as anti-cancer agents. Because its low aqueous solubility, Cremophor EL is used as excipient for its formulation. However, it has been shown that Cremophor causes serious side effects. Several attempts have been made to develop a safer formulation such as the synthesis of lipophilic prodrug. In particular we have synthesized a paclitaxel prodrug obtained by conjugation with 1,1,2-trisnorsqualenoic acid to improve the physico-chemical properties of this antineoplastic drug. The miscibility of these compounds with DMPC monolayer were studied analyzing thermodynamic properties as well as excess Gibbs free energies, compressibility modulus and mixed monolayer isotherms. The results allowed to evaluate the spatial organization of the compounds and suggested that the prodrug can efficiently be incorporated in the DMPC monolayer.
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http://dx.doi.org/10.1016/j.ijpharm.2014.09.022DOI Listing
November 2014

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

Int J Pharm 2014 Aug 17;471(1-2):69-74. Epub 2014 May 17.

Dipartimento di Scienze del Farmaco, Università degli Studi di Catania, Viale A. Doria 6, Catania95125, Italy. Electronic address:

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.
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http://dx.doi.org/10.1016/j.ijpharm.2014.05.019DOI Listing
August 2014

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

Int J Pharm 2014 Jul 23;469(1):88-93. Epub 2014 Apr 23.

Department of Drug Sciences, University of Catania, Viale A. Doria, 6, Catania 95125, Italy.

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.
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http://dx.doi.org/10.1016/j.ijpharm.2014.04.052DOI Listing
July 2014

Differential scanning calorimetry approach to investigate the transfer of the multitarget opioid analgesic LP1 to biomembrane model.

Eur J Med Chem 2014 Apr 25;77:84-90. Epub 2014 Feb 25.

Department of Drug Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy.

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.
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http://dx.doi.org/10.1016/j.ejmech.2014.02.056DOI Listing
April 2014

Effect of resveratrol-related stilbenoids on biomembrane models.

J Nat Prod 2013 Aug 29;76(8):1424-31. Epub 2013 Jul 29.

Dipartimento di Scienze del Farmaco, Università degli Studi di Catania, Viale A. Doria 6, 95125 Catania, Italy.

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.
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http://dx.doi.org/10.1021/np400188mDOI Listing
August 2013

Antimutagenic and antioxidant activities of some bioflavours from wine.

Food Chem Toxicol 2013 Oct 24;60:141-6. Epub 2013 Jul 24.

Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy. Electronic address:

Monoterpenes limonene and its metabolic derivatives, α-terpineol and 1,8-cineol, commonly found as aroma wine components, were studied for their antimutagenicity by the bacterial reverse mutation assay on different strains. Substances were also tested for their antioxidant activity, i.e. radical scavenger, chelation, reduction, and lipid peroxidation inhibition. Limonene and its metabolites, α-terpineol and 1,8-cineol, resulted able to inhibit the chemically-induced mutagenesis, although with a different specificity. The antimutagenicity of limonene has been generally retained by its metabolites and sometimes increased. In particular, α-terpineol exhibited the strongest inhibition, moreover it showed to be a remarkable ferrous ions chelating agent. Limonene and 1,8-cineol were devoid of antioxidant activity. Present results are a starting point in evaluating the potential of α-terpineol as a chemopreventive agent and suggest potential functional dietary benefits of wine.
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http://dx.doi.org/10.1016/j.fct.2013.07.042DOI Listing
October 2013

Sustained zero-order release of intact ultra-stable drug-loaded liposomes from an implantable nanochannel delivery system.

Adv Healthc Mater 2014 Feb 23;3(2):230-8. Epub 2013 Jul 23.

Department of Nanomedicine, The Methodist Hospital Research Institute, 6670 Bertner Ave. Houston, TX 77030, USA; Department of Health Sciences, University "Magna Graecia" of Catanzaro, V.le "S. Venuta" Germaneto-Catanzaro 88100, Italy.

Metronomic chemotherapy supports the idea that long-term, sustained, constant administration of chemotherapeutics, currently not achievable, could be effective against numerous cancers. Particularly appealing are liposomal formulations, used to solubilize hydrophobic therapeutics and minimize side effects, while extending drug circulation time and enabling passive targeting. As liposome alone cannot survive in circulation beyond 48 h, sustaining their constant plasma level for many days is a challenge. To address this, we develop, as a proof of concept, an implantable nanochannel delivery system and ultra-stable PEGylated lapatinib-loaded liposomes, and we demonstrate the release of intact vesicles for over 18 d. Further, we investigate intravasation kinetics of subcutaneously delivered liposomes and verify their biological activity post nanochannel release on BT474 breast cancer cells. The key innovation of this work is the combination of two nanotechnologies to exploit the synergistic effect of liposomes, demonstrated as passive-targeting vectors and nanofluidics to maintain therapeutic constant plasma levels. In principle, this approach could maximize efficacy of metronomic treatments.
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http://dx.doi.org/10.1002/adhm.201300188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3970317PMC
February 2014

Genotoxicity assessment of β-caryophyllene oxide.

Regul Toxicol Pharmacol 2013 Aug 7;66(3):264-8. Epub 2013 May 7.

Department of Physiology and Pharmacology, Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy.

β-caryophyllene oxide is a biciclic sesquiterpene, occurring naturally in essential oils from various medicinal and edible plants and used as a flavouring agent. Due to its potential hazardous chemical structure, the European Food Safety Authority reported to be pending a safety assessment for this compound. Here, this flavouring agent was tested for its mutagenic effect in the Ames test and micronucleus assay. Furthermore, considering that the penetration of a substance through phospholipid bilayers is determinant for its activity, the ability of β-caryophyllene oxide to be absorbed into cells was evaluated by differential scanning calorimetry (DSC) using multilamellar vesicles of dimyristoylphosphatidylcholine as a biomembrane model. β-caryophyllene oxide was found to be devoid of mutagenic effect, both at gene level (frameshift or base-substitution mutations), and on chromosome (clastogenicity and aneuploidogenicity). Results of DSC analysis highlighted that the substance was strongly absorbed through the membrane bilayer. Present results show that β-caryophyllene oxide, although absorbed through cell membranes and in spite of its potentially reactive chemical structure, is devoid of genotoxic effects, inducing neither point mutations nor chromosomal damages. These negative genotoxic findings will be critical to the safety assessment of β-caryophyllene oxide as used as a flavouring/fragrance ingredient.
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http://dx.doi.org/10.1016/j.yrtph.2013.04.006DOI Listing
August 2013

Differential scanning calorimetry as a tool to investigate the transfer of anticancer drugs to biomembrane model.

Curr Drug Targets 2013 Aug;14(9):1053-60

Department of Health Sciences, University "Magna Graecia" of Catanzaro, V.le "S. Venuta" 88100 Germaneto-Catanzaro, Italy.

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.
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http://dx.doi.org/10.2174/1389450111314090013DOI Listing
August 2013

Calorimetric evaluation of interaction and absorption of polychlorinated biphenyls by biomembrane models.

Chemosphere 2013 May 28;91(6):791-6. Epub 2013 Feb 28.

Dipartimento di Scienze Chimiche, Università degli Studi di Catania, Viale A. Doria 6, Catania, Italy.

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.
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http://dx.doi.org/10.1016/j.chemosphere.2013.01.091DOI Listing
May 2013

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

Mol Pharm 2012 Sep 15;9(9):2534-41. Epub 2012 Aug 15.

Department of Drug Sciences, University of Catania, V.le A. Doria 6, 95125 Catania, Italy.

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.
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http://dx.doi.org/10.1021/mp300149wDOI Listing
September 2012

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

Int J Pharm 2012 Oct 21;436(1-2):135-40. Epub 2012 Jun 21.

Dipartimento di Scienze del Farmaco, Università degli Studi di Catania, Viale A. Doria 6, 95125 Catania, Italy.

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.
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http://dx.doi.org/10.1016/j.ijpharm.2012.06.034DOI Listing
October 2012

Anticlastogenic effect in human lymphocytes by the sodium salt of 3,4-secoisopimar-4(18),7,15-trien-3-oic acid.

J Nat Prod 2012 Jul 14;75(7):1294-8. Epub 2012 Jun 14.

Department of Physiology and Pharmacology, "Sapienza" University , P.le Aldo Moro 5, 00185 Rome, Italy.

The ability of the sodium salt of 3,4-secoisopimar-4(18),7,15-trien-3-oic acid (1), a diterpenoid obtained from Salvia cinnabarina, to inhibit the genotoxic effect of ethyl methanesulfonate (a clastogenic agent) and colcemid (an aneugenic agent), was studied using a micronucleus assay on cultured human lymphocytes. Cells were treated with 1 before (pretreatment), during (co-treatment), and after (post-treatment) treatment with the mutagens, in order to investigate the type of antimutagenic activity (desmutagenic or bioantimutagenic) manifested. In the range of concentrations tested (0.3-330 μM) 1 reduced significantly the frequency of micronuclei induced by ethyl methanesulfonate, in both pre- and co-treatment protocols (up to 74% and 70% of reduction, respectively), showing an anticlastogenic activity. Conversely, 1 did not inhibit the effect of colcemid in all treatments. The nuclear division index value of lymphocytes was not affected by treatment with 1, thus demonstrating that the anticlastogenic effect of 1 was not due to a cytotoxic effect. On the basis of the results obtained, it can be hypothesized that 1 exerts its anticlastogenic activity against ethyl methanesulfonate by a desmutagenic mechanism, possibly by chemical inactivation of the mutagen.
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http://dx.doi.org/10.1021/np3001893DOI Listing
July 2012

Synthesis and biological evaluation of a new polymeric conjugate and nanocarrier with osteotropic properties.

J Funct Biomater 2012 Jan 19;3(1):79-99. Epub 2012 Jan 19.

Dipartimento di Scienze del Farmaco, Università degli Studi di Catania, viale A. Doria 6, Catania I-95125, Italy.

Bone-seeking (osteotropic) drug delivery systems (ODDS) represent an interesting solution for targeting different types of drugs to the bones. In particular, anticancer and antibacterial agents could take advantage of such therapeutic strategy. We have recently developed an innovative approach to this aim: a new osteotropic biomaterial was prepared, based on the conjugation of a poly(lactide-co-glycolide) (PLGA) with the bisphosphonate drug alendronate (PLGA-ALE); its hemo- and cytocompatibility were verified. Starting with this copolymer, an osteotropic nanoparticle system (NP) was produced for the targeted delivery of antineoplastic drugs to osteolytic bone metastases; in particular, doxorubicin was tested as a model drug. The in vitro and in vivo results of the new ODDS are validated in this article. All the experimental data confirmed that the drug retained its activity after loading in the PLGA-ALE NP; they can be thus considered a new promising strategy for active targeting of drugs to bone tissues in different pathological situations.
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http://dx.doi.org/10.3390/jfb3010079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4031017PMC
January 2012

The effect of poly(d,l-lactide-co-glycolide)-alendronate conjugate nanoparticles on human osteoclast precursors.

J Biomater Sci Polym Ed 2012 8;23(10):1285-300. Epub 2012 May 8.

a Laboratorio di Fisiopatologia Ortopedica e Medicina Rigenerativa, Istituto Ortopedico Rizzoli , via di Barbiano 1/10 , 40136 , Bologna , Italy.

Nanoparticles (NPs) formed from polymers conjugated with bisphosphonates (BPs) allow the bone targeting of loaded drugs, such as doxorubicin, for the treatment of skeletal tumours. The additional antiosteoclastic effect of the conjugated BP could contribute to the inhibition of tumour-associated bone degradation. With this aim, we have produced NPs made of poly(d,l-lactide-co-glycolide) (PLGA) conjugated with alendronate (ALE). To show if ALE retained the antiosteoclastic properties after the conjugation with PLGA and the production of NPs, we treated human osteoclasts, derived from circulating precursors, with PLGA-ALE NPs and compared the effects on actin ring generation, apoptosis and type-I collagen degradation with those of free ALE and with NPs made of pure PLGA. PLGA-ALE NPs disrupted actin ring, induced apoptosis and inhibited collagen degradation. Unexpectedly, also NPs made of pure PLGA showed similar effects. Therefore, we cannot exclude that in addition to the observed antiosteoclastic activity dependent on ALE in PLGA-ALE NPs, there was also an effect due to pure PLGA. Still, as PLGA-ALE NPs are intended for the loading with drugs for the treatment of osteolytic bone metastases, the additional antiosteoclastic effect of PLGA-ALE NPs, and even of PLGA, may contribute to the inhibition of the disease-associated bone degradation.
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http://dx.doi.org/10.1163/092050611X580373DOI Listing
May 2016

Interaction of naproxen amphiphilic derivatives with biomembrane models evaluated by differential scanning calorimetry and Langmuir-Blodgett studies.

J Colloid Interface Sci 2011 Aug 4;360(2):359-69. Epub 2011 May 4.

Dipartimento di Scienze del Farmaco, Viale Andrea Doria 6, 95125 Catania, Italy.

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.
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http://dx.doi.org/10.1016/j.jcis.2011.04.092DOI Listing
August 2011

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

Mol Pharm 2011 Jun 9;8(3):642-50. Epub 2011 May 9.

Dipartimento di Scienze del Farmaco, Università degli Studi di Catania , Viale A. Doria 6, 95125 Catania, Italy.

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,β-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.
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http://dx.doi.org/10.1021/mp100445kDOI Listing
June 2011

Transfer kinetics from colloidal drug carriers and liposomes to biomembrane models: DSC studies.

J Pharm Bioallied Sci 2011 Jan;3(1):77-88

Department of Chemical Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy.

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.
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http://dx.doi.org/10.4103/0975-7406.76472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3053524PMC
January 2011