Publications by authors named "Gabriele Caviglioli"

13 Publications

  • Page 1 of 1

Exosomes and Extracellular Vesicles as Emerging Theranostic Platforms in Cancer Research.

Cells 2020 Dec 1;9(12). Epub 2020 Dec 1.

Department of Pharmacy, University of Genova, 16147 Genova, Italy.

Exosomes are endosome-derived nanovesicles produced by healthy as well as diseased cells. Their proteic, lipidic and nucleic acid composition is related to the cell of origin, and by vehiculating bioactive molecules they are involved in cell-to-cell signaling, both in healthy and pathologic conditions. Being nano-sized, non-toxic, biocompatible, scarcely immunogenic, and possessing targeting ability and organotropism, exosomes have been proposed as nanocarriers for their potential application in diagnosis and therapy. Among the different techniques exploited for exosome isolation, the sequential ultracentrifugation/ultrafiltration method seems to be the gold standard; alternatively, commercially available kits for exosome selective precipitation from cell culture media are frequently employed. To load a drug or a detectable agent into exosomes, endogenous or exogenous loading approaches have been developed, while surface engineering procedures, such as click chemistry, hydrophobic insertion and exosome display technology, allow for obtaining actively targeted exosomes. This review reports on diagnostic or theranostic platforms based on exosomes or exosome-mimetic vesicles, highlighting the diverse preparation, loading and surface modification methods applied, and the results achieved so far.
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http://dx.doi.org/10.3390/cells9122569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761021PMC
December 2020

Neuroinflammation in Aged Brain: Impact of the Oral Administration of Ellagic Acid Microdispersion.

Int J Mol Sci 2020 May 21;21(10). Epub 2020 May 21.

Department of Pharmacy (DiFar), Center of Excellence for Biomedical Research, 3Rs Center, University of Genoa, Viale Cembrano 4, 16148 Genoa, Italy.

The immune system and the central nervous system message each other to preserving central homeostasis. Both systems undergo changes during aging that determine central age-related defects. Ellagic acid (EA) is a natural product which is beneficial in both peripheral and central diseases, including aging. We analyzed the impact of the oral administration of a new oral ellagic acid micro-dispersion (EAm), that largely increased the EA solubility, in young and old mice. Oral EAm did not modify animal weight and behavioral skills in young and old mice, but significantly recovered changes in "ex-vivo, in vitro" parameters in old animals. Cortical noradrenaline exocytosis decreased in aged mice. EAm administration did not modify noradrenaline overflow in young animals, but recovered it in old mice. Furthermore, GFAP staining was increased in the cortex of aged mice, while IBA-1 and CD45 immunopositivities were unchanged when compared to young ones. EAm treatment significantly reduced CD45 signal in both young and old cortical lysates; it diminished GFAP immunopositivity in young mice, but failed to affect IBA-1 expression in both young and old animals. Finally, EAm treatment significantly reduced IL1beta expression in old mice. These results suggest that EAm is beneficial to aging and represents a nutraceutical ingredient for elders.
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http://dx.doi.org/10.3390/ijms21103631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279224PMC
May 2020

Author Correction: A new microdispersed albumin derivative potentially useful for radio-guided surgery of occult breast cancer lesions.

Sci Rep 2020 Mar 10;10(1):4633. Epub 2020 Mar 10.

Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, IRST-IRCCS, Meldola. via P. Maroncelli 40, Meldola, Italy.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-020-60471-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064564PMC
March 2020

A new microdispersed albumin derivative potentially useful for radio-guided surgery of occult breast cancer lesions.

Sci Rep 2019 04 4;9(1):5623. Epub 2019 Apr 4.

Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, IRST-IRCCS, Meldola. via P. Maroncelli 40, Meldola, Italy.

This paper describes a new nuclear imaging agent, 2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid of human albumin (HAC), potentially suitable for application in the Radio-guided Occult Lesion Localization (ROLL) of non-palpable mammalian cancerous lesions, as a tool to overtake the short radio-signal half-life of the technetium-99m based radiopharmaceutical currently used. This conjugate is a microsized powder aggregate, water-insoluble between pH 3 and 8.5, obtained by conjugating the protein with the macrocyclic chelating agent DOTA through a one-pot reaction in aqueous medium. The product has been fully characterized and is stable to the thermal conditions adopted for labeling; after radiolabeling with longer half-life radionuclides such as Lu or In, it has shown radiochemical purity (RCP) >90% and resulted stable when stored in saline or plasma for 6 days at 37 °C. A μPET/CT study, performed in vivo on adult female rats, showed that the radioactivity of HAC labeled with Cu remained located in the mammary glands for at least 40 h, without diffusion or drainage in healthy tissues or in the lymphatic circulation. This new imaging agent might make the ROLL procedure more accessible, safe and flexible, promoting a significant time and cost reduction of this intervention. Moreover, HAC might also be used in other radio-guided surgical procedures in oncology.
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http://dx.doi.org/10.1038/s41598-019-42014-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6449347PMC
April 2019

Development of an Injectable Slow-Release Metformin Formulation and Evaluation of Its Potential Antitumor Effects.

Sci Rep 2018 03 2;8(1):3929. Epub 2018 Mar 2.

Department of Internal Medicine (DiMI), University of Genova, 16132, Genova, Italy.

Metformin is an antidiabetic drug which possesses antiproliferative activity in cancer cells when administered at high doses, due to its unfavorable pharmacokinetics. The aim of this work was to develop a pharmacological tool for the release of metformin in proximity of the tumor, allowing high local concentrations, and to demonstrate the in vivo antitumor efficacy after a prolonged metformin exposition. A 1.2% w/w metformin thermoresponsive parenteral formulation based on poloxamers P407 and P124, injectable at room temperature and undergoing a sol-gel transition at body temperature, has been developed and optimized for rheological, thermal and release control properties; the formulation is easily scalable, and proved to be stable during a 1-month storage at 5 °C. Using NOD/SCID mice pseudo-orthotopically grafted with MDA-MB-231/luc human breast cancer cells, we report that multiple administrations of 100 mg of the optimized metformin formulation close to the tumor site cause tissue accumulation of the drug at levels significantly higher than those observed in plasma, and enough to exert antiproliferative and pro-apoptotic activities. Our results demonstrate that this formulation is endowed with good stability, tolerability, thermal and rheological properties, representing a novel tool to be pursued in further investigations for adjuvant cancer treatment.
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http://dx.doi.org/10.1038/s41598-018-22054-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834504PMC
March 2018

Development and characterization of a mucoadhesive sublingual formulation for pain control: extemporaneous oxycodone films in personalized therapy.

Drug Dev Ind Pharm 2017 Jun 31;43(6):917-924. Epub 2017 Jan 31.

a Department of Pharmacy , University of Genova , Genova , Italy.

Objective: The aim of this work was the development of mucoadhesive sublingual films, prepared using a casting method, for the administration of oxycodone.

Materials And Methods: A solvent casting method was employed to prepare the mucoadhesive films. A calibrated pipette was used to deposit single aliquots of different polymeric solutions on a polystyrene plate lid. Among the various tested polymers, hydroxypropylcellulose at low and medium molecular weight (HPC) and pectin at two different degrees of esterification (PC) were chosen for preparing solutions with good casting properties, capable of producing films suitable for mucosal application.

Results And Discussion: The obtained films showed excellent drug content uniformity and stability and rapid drug release, which, at 8 min, ranged from 60% to 80%. All films presented satisfactory mucoadhesive and mechanical properties, also confirmed by a test on healthy volunteers, who did not experience irritation or mucosa damages. Pectin films based on pectin at lower degrees of esterification have been further evaluated to study the influence of two different amounts of drug on the physicochemical properties of the formulation. A slight reduction in elasticity has been observed in films containing a higher drug dose; nevertheless, the formulation maintained satisfactory flexibility and resistance to elongation.

Conclusions: HPC and PC sublingual films, obtained by a simple casting method, could be proposed to realize personalized hospital pharmacy preparations on a small scale.
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http://dx.doi.org/10.1080/03639045.2017.1281290DOI Listing
June 2017

An innovative matrix controlling drug delivery produced by thermal treatment of DC tablets containing polycarbophil and ethylcellulose.

Int J Pharm 2013 Dec 18;458(1):74-82. Epub 2013 Oct 18.

Dipartimento di Farmacia, Università degli Studi di Genova, Via Brigata Salerno, 13, 16147 Genova, Italy. Electronic address:

An innovative matrix, produced by thermal treatment on direct compression (DC) tablets containing polycarbophil (POL) and ethylcellulose (EC), identified as matrix forming polymers, and able to control the release of diltiazem hydrochloride, was developed. At pH 7.2, 72 ± 1.2% (w/w) of drug loaded was released in 25 h, mostly at constant rate. This swellable and unerodible matrix controls drug release by an anomalous transport mechanism. The modifications induced by the thermal treatment are irreversible and can be used to control and characterize the matrix. A 3-component constrained mixture design allowed the investigation of the experimental domain in which the matrix forms and the computation of a mathematical model that can be used to optimize the formulation properties. The release rate can be modulated (0.032-0.064% drug released/min) through the choice of suitable treatment conditions and tablet composition. The maximum amount of diltiazem hydrochloride released by zero-order kinetics, at the lowest release rate, occurs for POL:EC ratio in the range of 1:1-2:3 with 20-30% of diluent. The tablets are able to load up to 50% (w/w) of diltiazem hydrochloride without losing their properties. A stability study performed on a selected formulation containing DTZ showed stability for at least 2.7 years at RT conditions.
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http://dx.doi.org/10.1016/j.ijpharm.2013.10.014DOI Listing
December 2013

A chitosan lactate/poloxamer 407-based matrix containing Eudragit RS microparticles for vaginal delivery of econazole: design and in vitro evaluation.

Drug Dev Ind Pharm 2013 Dec 8;39(12):1911-20. Epub 2012 Jun 8.

Dipartimento di Chimica e Tecnologie Farmaceutiche ed Alimentari , Genoa , Italy.

A matrix based on chitosan lactate and poloxamer 407 was evaluated as a delivery system for the vaginal administration of the antifungal drug econazole. The matrix was investigated both containing the pure drug and after introducing microparticles of Eudragit RS 100 containing econazole. Eudragit RS 100 microparticles were prepared using an emulsion-extraction method and dispersed in a solution containing chitosan lactate (2% w/w) and poloxamer 407 (1.7% w/w). The microparticles, obtained with a yield of 64% w/w and an encapsulation efficiency of 42% w/w, had a diameter of less than 2 μm and a drug loading of 13% w/w. The compressed matrices, characterized by DSC, swelling, erosion, release and mucoadhesion studies, had behaviours dependent on the relative amounts of the contained microparticles. The matrix without microparticles (MECN) showed zero-order release kinetics, with a maximum drug-release of 60% w/w, while those containing 50 or 75% w/w microparticles showed a diffusion controlled release up to 8 and 16 h, respectively, and a linear trend after those time intervals, caused by the erosion process, which allowed reaching a drug-release of approximately 100% w/w at 22 h. In in vitro experiments, the matrices were mucoadhesive and active in inhibiting the growth of Candida albicans 796.
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http://dx.doi.org/10.3109/03639045.2012.694589DOI Listing
December 2013

Preparation, characterisation and preliminary antitumour activity evaluation of a novel nanoparticulate system based on a cisplatin-hyaluronate complex and N-trimethyl chitosan.

Invest New Drugs 2011 Jun 29;29(3):443-55. Epub 2009 Dec 29.

Dipartimento di Chimica e Tecnologie Farmaceutiche ed Alimentari, Via Brigata Salerno 13, 16147, Genoa, Italy.

In this work, nanoparticles with a positive surface charge were prepared through the electrostatic interaction of a new cisplatin-hyaluronate complex with N-trimethyl chitosan (substitution degree of 85%). Mean particle diameter was approximately 195 nm. Drug loading of nanoparticles, which had a zeta potential of about 27 mV, was equal to 6% w/w. After 24 h, while the cisplatin-hyaluronate complex released approximately 60% w/w drug in phosphate buffered saline at pH 7.4, approximately 40% w/w of total cisplatin was released from nanoparticles. The same cumulative amounts of released drug were found after 48 h. These nanoparticles, as well as the starting cisplatin-hyaluronate complex, were active on all cell lines tested (P388, A2780, A549), with an antiproliferative activity similar to that of cisplatin. Apoptosis was markedly induced in A2780 cells by nanoparticles. In a preliminary in vivo experiment, the antitumour activity against a murine tumour (P388 cells) subcutaneously implanted in mice, resulted similar to that of cisplatin for nanoparticles whereas the starting complex showed a non-significant activity at the cisplatin dose tested. Body weight change of treated mice suggested a significantly better tolerance of the nanoparticles compared to cisplatin, after an initial brief period of acute toxicity higher than the parent drug. These results indicate that such a particulate system could be useful as a carrier for cisplatin delivery.
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http://dx.doi.org/10.1007/s10637-009-9373-yDOI Listing
June 2011

Study of retinoic acid polymorphism.

J Pharm Sci 2006 Oct;95(10):2207-21

Dipartimento di Chimica e Tecnologie Farmaceutiche ed Alimentari, Università degli Studi di Genova, via Brigata Salerno (Ponte), 16147 Genova, Italy.

Some authors recently hypothesized the existence of a new retinoic acid (RA) phase in addition to the two already known polymorphs. We investigated RA polymorphism and our results exclude the presence of new modifications and refine the properties of the known forms. By comparison of simulated and acquired X-Ray Powder Diffraction (XRPD) it was possible to identify only the known monoclinic (I) and the triclinic (II) modifications; the same were also characterized by DSC, IR, and Raman spectroscopy. A solubility study associated to DSC allowed establishing an enantiotropic relationship between the two forms, with form II being less stable (DeltaGII/I=0.71 kJ/mol at 37 degrees C) below the transition temperature (136.6 degrees C; DeltaH=3.2 kJ/mol). The intrinsic dissolution rate (IDR) (I=61 microg/cm2xmin-1; II=125 microg/cm2xmin-1) confirmed this energetic relationship. The kinetics of solid transition I-->II was examined and its activation energy estimated (356 kJ/mol). The attempts to produce new phases allowed the development of methods to obtain the two polymorphs with high chemical and polymorphic purity. A validated DSC method is presented that enables detection of the presence of form I at a level of 1% (w/w) when in mixture with form II.
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http://dx.doi.org/10.1002/jps.20699DOI Listing
October 2006

Transplacental passage of Pt after treatment with the new triamine complex cis-diaminechloro-[2-(diethylamino) ethyl 4-amino-benzoate, N4]-chloride platinum (II) monohydrochloride monohydrate.

Arch Toxicol 2004 Oct 19;78(10):584-8. Epub 2004 May 19.

Istituto Nazionale per la Ricerca sul Cancro, Servizio Modelli Animali, Lgo R. Benzi, 10, 16132, Genova, Italy.

Cis-diaminechloro-[2-(diethylamino) ethyl 4-amino-benzoate, N4]-chloride platinum (II) monohydrochloride monohydrate (DPR) is a monofunctional Pt triamine complex synthesized starting from cisplatin and procaine hydrochloride, characterized by a good antitumor activity coupled with low toxic effects and able to impair prenatal development of mice but at doses outside or just in the upper range of therapeutic doses. In the present paper the transplacental passage of DPR-derived Pt was investigated in CD1 mice on days 9, 13, 16 and 18 of pregnancy, 24 h after ip administration of 21 mg/kg DPR. For comparison, groups of mice were treated with an equivalent Pt-containing dose of cisplatin (10.7 mg/kg). Similarly to cisplatin, small amounts of Pt were detected in fetuses on day 9. From day 13 of gestation the concentration of DPR- and cisplatin-derived Pt increased up to the highest fetal concentrations detected on day 16. On day 18 the concentration of Pt decreased. Most importantly, on days 13-18 of pregnancy cisplatin-derived Pt was always significantly higher than that assayed after DPR administration. In addition, on day 13 of pregnancy Pt exposure of fetuses was significantly higher when dams were treated with cisplatin (AUC(0.5-24)= 3.40 vs. 4.95 microg.h/g). Finally, it is worth noting that serum decay of Pt after DPR or cisplatin administration in adult female mice was similar with AUC0.13-2h s of 7.5 and 6.6 microg.h/ml, respectively. When we determined the concentration of Pt into the main organs of fetuses from dams treated with either DPR or cisplatin on day 18 of gestation, we observed a different organ distribution. In fact, while the concentration of DPR-derived Pt was greater in the heart (1.08+/-0.30 vs. 0.78 +/- 0.35 microg/g, p <0.10), an opposite situation was found in the kidney (0.51+/-0.20 vs. 0.69 +/- 0.22 microg/g, p <0.05). In conclusion, our data show that DPR may pass through the placenta with an efficiency significantly lower than that of cisplatin. This finding may represent one of the possible causes of the lower embryotoxic/teratogenic effect of DPR as compared to cisplatin.
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http://dx.doi.org/10.1007/s00204-004-0576-xDOI Listing
October 2004

Identification of degradation products of ibuprofen arising from oxidative and thermal treatments.

J Pharm Biomed Anal 2002 Oct;30(3):499-509

Dipartimento di Chimica e Tecnologie Farmaceutiche e Alimentari, Università degli Studi di Genova, Via Brigata Salerno (ponte), 16147 Genova, Italy.

Ibuprofen is a widely utilised analgesic anti-inflammatory drug. It is sensitive to oxidation and photodegradation. In this work, the oxidative and thermal degradations were investigated. The treatments adopted allowed the detection of 13 degradation products, seven of which have never been reported: hydratropic acid, 4-ethylbenzaldehyde, 4-(1-carboxyethyl)benzoic acid, 1-(4-isobutylphenyl)-1-ethanol, 2-[4-(1-hydroxy-2-methylpropyl)phenyl]propanoic acid, 1-isobutyl-4-vinylbenzene, 4-isobutylphenol. For 1-(4-isobutylphenyl)-1-ethanol, the in vitro toxic effects have already been described in the literature. To detect all degradation products, two RP-HPLC methods and a GC-MS procedure were developed or modified from the official monographs. The identification was conducted by evaluating chromatographic and spectral data and the structural attributions were confirmed by simple and univocal synthesis. Moreover, the actual presence of these molecules in marketed medicinal products was investigated.
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http://dx.doi.org/10.1016/s0731-7085(02)00400-4DOI Listing
October 2002

Reduction of cisplatin hepatotoxicity by procainamide hydrochloride in rats.

Eur J Pharmacol 2002 May;442(3):265-72

Dipartimento di Medicina Sperimentale, Sezione di Anatomia Umana, Università di Genova, Via De Toni, 14, 16132 Genoa, Italy.

In preceding papers, we proposed that procainamide hydrochloride, a class I antiarrhythmic agent, was able to protect mice and rats from cisplatin-induced nephrotoxicity and that it could exert its action through accumulation in kidneys followed by coordination with cisplatin (or its hydrolysis metabolites) and formation of a less toxic platinum compound similar to the new platinum(II) triamine complex cis-diamminechloro-[2-(diethylamino)ethyl 4-amino-benzoate, N4]-chlorideplatinum(II) monohydrochloride monohydrate, obtained by the reaction of cisplatin with procaine hydrochloride. Hepatotoxicity is not considered as a dose-limiting toxicity for cisplatin, but liver toxicity can occur when the antineoplastic drug is administered at high doses. Here, we report that procainamide hydrochloride, at an i.p. dose of 100 mg/kg, reduces cisplatin-induced hepatotoxicity, as evidenced by the normalization of plasma activity of glutamic oxalacetic transaminase and gamma-glutamyl transpeptidase, as well as by histological examination of the liver tissue. Twenty-four hours after i.p. treatment with the combination of 7.5 mg/kg cisplatin and 100 mg/kg procainamide, a significant increase of procainamide (+56%, P<0.05), total platinum (+31%, P<0.05), platinum-DNA adducts (+31%, P<0.05) and percent DNA-DNA interstrand cross-links (+69%, P<0.02) was found in liver tissue, as compared to animals treated with cisplatin alone. Moreover, in accordance with these findings, we also observed a slightly lower concentration and cumulative excretion of platinum in the feces. Since mitochondrial injury is considered a central event in the early stages of the nephrotoxic effect of cisplatin, the distribution of platinum in these subcellular organelles obtained from hepatocytes was determined after treatment with cisplatin with or without procainamide hydrochloride, together with platinum concentration in their cytosolic fraction. Our data show that the coadministration of procainamide hydrochloride produced a rearrangement of subcellular platinum distribution in hepatocytes with a slight decrease in mitochondria (-15%, P<0.10) and a slight increase in the cytosolic fraction (+40%, P<0.10) of platinum content, compared to the treatment with cisplatin alone. In analogy with our previous results in the kidney, confirmed here by our data in vitro, we suggest that the hepatoprotective activity of procainamide hydrochloride is linked to the formation of a less toxic platinum complex, which leads to inactivation of cisplatin itself and/or its highly toxic hydrolysis metabolites and to a different subcellular distribution of platinum.
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http://dx.doi.org/10.1016/s0014-2999(02)01537-6DOI Listing
May 2002