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3. A Correlative Imaging Study of in vivo and ex vivo Biodistribution of Solid Lipid Nanoparticles

Author

Mannucci S, Boschi F, Cisterna B, Esposito E, Cortesi R, Nastruzzi C, Cappellozza E, Bernardi P, Sbarbati A, Malatesta M, and Calderan L

Subjects
lipid-based nanoparticles, systemic biodistribution, optical imaging, light microscopy, transmission electron microscopy, tissue accumulation., Medicine (General), R5-920
Abstract

Silvia Mannucci,1 Federico Boschi,2,* Barbara Cisterna,1,* Elisabetta Esposito,3 Rita Cortesi,3 Claudio Nastruzzi,3 Enrica Cappellozza,1 Paolo Bernardi,1 Andrea Sbarbati,1 Manuela Malatesta,1 Laura Calderan1 1Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona I-37134, Italy; 2Department of Computer Science, University of Verona, Verona I-37134, Italy; 3Department of Chemical and Pharmaceutical Sciences, University of Ferrara, Ferrara I-44121, Italy*These authors contributed equally to this workCorrespondence: Manuela MalatestaDepartment of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Strada Le Grazie 8, Verona I-37134, ItalyTel +39 045 8027569Email manuela.malatesta@univr.itPurpose: Solid lipid nanoparticles are largely used in biomedical research and are characterized by high stability and biocompatibility and are also able to improve the stability of various loaded molecules. In vitro studies demonstrated that these nanoparticles are low cytotoxic, while in vivo studies proved their efficiency as nanocarriers for molecules characterized by a low bioavailability. However, to our knowledge, no data on the systemic biodistribution and organ accumulation of solid lipid nanoparticles in itself are presently available.Methods: In this view, we investigated the solid lipid nanoparticles biodistribution by a multimodal imaging approach correlating in vivo and ex vivo analyses. We loaded solid lipid nanoparticles with two different fluorophores (cardiogreen and rhodamine) to observe them with an optical imager in the whole organism and in the excised organs, and with fluorescence microscopy in tissue sections. Light and transmission electron microscopy analyses were also performed to evaluate possible structural modification or damage due to nanoparticle administration.Results: Solid lipid nanoparticles loaded with the two fluorochromes showed good optic characteristics and stable polydispersity. After in vivo administration, they were clearly detectable in the organism. Four hours after the injection, the fluorescent signal occurred in anatomical districts corresponding to the liver and this was confirmed by the ex vivo acquisitions of excised organs. Brightfield, fluorescence and transmission electron microscopy confirmed solid lipid nanoparticles accumulation in hepatocytes without structural damage.Conclusion: Our results support the systemic biocompatibility of solid lipid nanoparticles and demonstrate their detailed biodistribution from the whole organism to organs until the cells.Keywords: lipid-based nanoparticles, systemic biodistribution, optical imaging, light microscopy, transmission electron microscopy, tissue accumulation

Published
2020

5. Colloidal polymer-coated Zn-doped iron oxide nanoparticles with high relaxivity and specific absorption rate for efficient magnetic resonance imaging and magnetic hyperthermia

Author

Das, P, Salvioni, L, Malatesta, M, Vurro, F, Mannucci, S, Gerosa, M, Antonietta Rizzuto, M, Tullio, C, Degrassi, A, Colombo, M, Ferretti, A, Ponti, A, Calderan, L, Prosperi, D, Das P., Salvioni L., Malatesta M., Vurro F., Mannucci S., Gerosa M., Antonietta Rizzuto M. A., Tullio C., Degrassi A., Colombo M., Ferretti A. M., Ponti A., Calderan L., Prosperi D., Das, P, Salvioni, L, Malatesta, M, Vurro, F, Mannucci, S, Gerosa, M, Antonietta Rizzuto, M, Tullio, C, Degrassi, A, Colombo, M, Ferretti, A, Ponti, A, Calderan, L, Prosperi, D, Das P., Salvioni L., Malatesta M., Vurro F., Mannucci S., Gerosa M., Antonietta Rizzuto M. A., Tullio C., Degrassi A., Colombo M., Ferretti A. M., Ponti A., Calderan L., and Prosperi D.

Abstract

Colloidally stable nanoparticles-based magnetic agents endowed with very high relaxivity and specific absorption rate are extremely desirable for efficient magnetic resonance imaging and magnetic hyperthermia, respectively. Here, we report a water dispersible magnetic agent consisting of zinc-doped superparamagnetic iron oxide nanoparticles (i.e., Zn-SPIONs) of 15 nm size with high saturation magnetization coated with an amphiphilic polymer for effective magnetic resonance imaging and magnetic hyperthermia of glioblastoma cells. These biocompatible polymer-coated Zn-SPIONs had 24 nm hydrodynamic diameter and exhibited high colloidal stability in various aqueous media, very high transverse relaxivity of 471 mM−1 s−1, and specific absorption rate up to 743.8 W g−1, which perform better than most iron oxide nanoparticles reported in the literature, including commercially available agents. Therefore, using these polymer-coated Zn-SPIONs even at low concentrations, T2-weighted magnetic resonance imaging and moderate magnetic hyperthermia of glioblastoma cells under clinically relevant magnetic field were successfully implemented. In addition, the results of this in vitro study suggest the superior potential of Zn-SPIONs as a theranostic nanosystem for brain cancer treatment, simultaneously acting as a contrast agent for magnetic resonance imaging and a heat mediator for localized magnetic hyperthermia.

Published
2020

7. Imatinib-loaded gold nanoparticles inhibit proliferation of fibroblasts and macrophages from systemic sclerosis patients and ameliorate experimental bleomycin-induced lung fibrosis

Author

Codullo, V, Cova, E, Pandolfi, L, Breda, S, Morosini, M, Frangipane, V, Malatesta, M, Calderan, L, Cagnone, M, Pacini, C, Cavagna, L, Recalde, H, Distler, J, Giustra, M, Prosperi, D, Colombo, M, Meloni, F, Montecucco, C, Codullo V., Cova E., Pandolfi L., Breda S., Morosini M., Frangipane V., Malatesta M., Calderan L., Cagnone M., Pacini C., Cavagna L., Recalde H., Distler J. H. W., Giustra M., Prosperi D., Colombo M., Meloni F., Montecucco C., Codullo, V, Cova, E, Pandolfi, L, Breda, S, Morosini, M, Frangipane, V, Malatesta, M, Calderan, L, Cagnone, M, Pacini, C, Cavagna, L, Recalde, H, Distler, J, Giustra, M, Prosperi, D, Colombo, M, Meloni, F, Montecucco, C, Codullo V., Cova E., Pandolfi L., Breda S., Morosini M., Frangipane V., Malatesta M., Calderan L., Cagnone M., Pacini C., Cavagna L., Recalde H., Distler J. H. W., Giustra M., Prosperi D., Colombo M., Meloni F., and Montecucco C.

Abstract

Interstitial lung involvement in Systemic Sclerosis (SSc-ILD) is a complication with high morbidity and mortality. Specifically, engineered gold nanoparticles (GNPs) are proposed as targeted delivery system increasing efficacy of drugs with antifibrotic effect, such as tyrosine kinases. We aimed to test in vitro and in vivo the activity of targeted Imatinib (Im)-loaded GNP on SSc-ILD patients derived cells and in experimental model of lung fibrosis. GNPs functionalized with anti-CD44 and loaded with Im (GNP-HCIm) were synthesized. Lung fibroblasts (LFs) and alveolar macrophages from bronchoalveolar lavage fluids of SSc-ILD patients were cultured in presence of nanoparticles. GNP-HCIm significantly inhibited proliferation and viability inducing apoptosis of LFs and effectively reduced IL-8 release, viability and M2 polarization in alveolar macrophages. Anti-fibrotic effect of tracheal instilled GNP-HCIm was evaluated on bleomycin lung fibrosis mouse model comparing effect with common route of Im administration. GNP-HCIm were able to reduce significantly lung fibrotic changes and collagen deposition. Finally, electron microscopy revealed the presence of GNPs inside alveolar macrophages. These data support the use of GNPs locally administered in the development of new therapeutic approaches to SSc-ILD.

Published
2019

12. Nanocarriers for neuromuscular diseases

Author

Costanzo, M., Carton, F., Guglielmi, V., Calderan, L., Repellin, M., Lollo, G., Andreana, I., Arpicco, S., Stella, B., and Malatesta, M.

Subjects
myotonic dystrophy, nanoparticles, myotonic dystrophy, nanoparticles
Published
2019

13. Hyperthermic nanoparticles to trigger lipolysis

Author

Calderan, L., Vurro, F., Mannucci, S., Boschi, F., Tambalo, S., Lievens, P., Prosperi, D., and Malatesta, M.

Subjects
nanoparticles, hyperthermia, hyperthermia, nanoparticles
Published
2019

14. Nano-structures with hyperthermic properties for biomedical applications

Author

Vurro, F., Mannucci, S., Prosperi, D., Perduca, M., Jiménez Lopez, C., Busato, A., Gerosa, M., Tambalo, S., Marinozzi, M. R., Boschi, F., Malatesta, M., and Calderan, L.

Subjects
lipolysis, cancer, hyperthermic nanoparticles, cancer, lipolysis, hyperthermic nanoparticles
Published
2019

15. Anatomia umana

Author

Seeley, Vanputte, Regan, Russo, Amenta, F., Brunetti, A., Calderan, L., Castaldo, C., Castorina, S., De Luca, A., Di Meglio, F., Fabene, P. F., Ferrandino, I., Guerra, G., Grimaldi, M. C., Macchi, V., Macchiarelli, G., Montagnani, S., Nottola, S. A., Nurzynska, D., Papa, M., Raspanti, M., Rende, M., and Tafuri, D.

Published
2018

16. Biodistribution of different nanocarriers in murine myoblasts

Author

Vurro, Federica, Costanzo, M., Cisterna, B., Boschi, F., Marengo, A., Arpicco, S., Stella, B., Berlier, G., Calderan, L., and Malatesta, M.

Subjects
murine myoblasts, transmission electron microscopy, nanoparticles,murine myoblasts, biodistribution, confocal microscopy, transmission electron microscopy, nanoparticles, confocal microscopy, biodistribution
Published
2017

17. Innovative approach to safely induce controlled lipolysis by superparamagnetic iron oxide nanoparticles-mediated hyperthermic treatment

Author

Marinozzi, M, Pandolfi, L, Malatesta, M, Colombo, M, Collico, V, Lievens, P, Tambalo, S, Lasconi, C, Vurro, F, Boschi, F, Mannucci, S, Sbarbati, A, Prosperi, D, Calderan, L, Marinozzi, Maria Rosaria, Pandolfi, Laura, Malatesta, Manuela, Colombo, Miriam, Collico, Veronica, Lievens, Patricia Marie-Jeanne, Tambalo, Stefano, Lasconi, Chiara, Vurro, Federica, Boschi, Federico, Mannucci, Silvia, Sbarbati, Andrea, Prosperi, Davide, Calderan, Laura, Marinozzi, M, Pandolfi, L, Malatesta, M, Colombo, M, Collico, V, Lievens, P, Tambalo, S, Lasconi, C, Vurro, F, Boschi, F, Mannucci, S, Sbarbati, A, Prosperi, D, Calderan, L, Marinozzi, Maria Rosaria, Pandolfi, Laura, Malatesta, Manuela, Colombo, Miriam, Collico, Veronica, Lievens, Patricia Marie-Jeanne, Tambalo, Stefano, Lasconi, Chiara, Vurro, Federica, Boschi, Federico, Mannucci, Silvia, Sbarbati, Andrea, Prosperi, Davide, and Calderan, Laura

Abstract

During last years, evidence has been provided on the involvement of overweight and obesity in the pathogenesis and aggravation of several life-threatening diseases. Here, we demonstrate that, under appropriate administration conditions, polyhedral iron oxide nanoparticles are efficiently and safely taken up by 3T3 cell line-derived adipocytes (3T3 adipocytes) in vitro. Since these nanoparticles proved to effectively produce heat when subjected to alternating magnetic field, 3T3 adipocytes were submitted to superparamagnetic iron oxide nanoparticles-mediated hyperthermia treatment (SMHT), with the aim of modulating their lipid content. Notably, the treatment resulted in a significant delipidation persisting for at least 24 h, and in the absence of cell death, damage or dedifferentiation. Interestingly, transcript expression of adipose triglyceride lipase (ATGL), a key gene involved in canonical lipolysis, was not modulated upon SMHT, suggesting the involvement of a novel/alternative mechanism in the effective lipolysis observed. By applying the same experimental conditions successfully used for 3T3 adipocytes, SMHT was able to induce delipidation also in primary cultures of human adipose-derived adult stem cells. The success of this pioneering approach in vitro opens promising perspectives for the application of SMHT in vivo as an innovative safe and physiologically mild strategy against obesity, potentially useful in association with balanced diet and healthy lifestyle.

Published
2017

19. A novel orally active water-soluble inhibitor of human glutathione transferase exerts a potent and selective antitumor activity against human melanoma xenografts

Author

De Luca, A, Rotili, D, Carpanese, D, Lenoci, A, Calderan, L, Scimeca, M, Mai, A, Bonanno, E, Rosato, A, Geroni, C, Quintieri, L, Caccuri, Am, and DE LUCA, A

Subjects
Oral, Administration, Oral, Apoptosis, Human Melanoma Xenografts, Pharmacology, Settore MED/08 - Anatomia Patologica, Cell Line, chemistry.chemical_compound, Mice, Random Allocation, c-Jun N-terminal Kinase, Animals, Cell Line, Tumor, Cell Proliferation, Enzyme Inhibitors, Female, Glutathione S-Transferase pi, Humans, Melanoma, Oxadiazoles, Xenograft Model Antitumor Assays, In vivo, Settore BIO/10, Glutathione Transferase P1-1, 6-((7-nitrobenzo[c][1,2,5]oxadiazoles, Tumor, Chemistry, Cell growth, Glutathione, In vitro, Oncology, Cell culture, Settore CHIM/09 - Farmaceutico Tecnologico Applicativo, Administration, Target protein, Research Paper
Abstract

We designed and synthesized two novel nitrobenzoxadiazole (NBD) analogues of the anticancer agent 6-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)thio)hexan-1-ol (NBDHEX). The new compounds, namely MC3165 and MC3181, bear one and two oxygen atoms within the hydroxy-containing alkyl chain at the C4 position of the NBD scaffold, respectively. This insertion did not alter the chemical reactivity with reduced glutathione, while it conferred a remarkable increase in water solubility. MC3181 was more selective than NBDHEX towards the target protein, glutathione transferase P1-1, and highly effective in vitro against a panel of human melanoma cell lines, with IC50 in the submicromolar-low micromolar range. Interestingly, the cellular response to MC3181 was cell-type-specific; the compound triggered a JNK-dependent apoptosis in the BRAF-V600E-mutated A375 cells, while it induced morphological changes together with an increase in melanogenesis in BRAF wild-type SK23-MEL cells. MC3181 exhibited a remarkable therapeutic activity against BRAF-V600E-mutant xenografts, both after intravenous and oral administration. Outstandingly, no treatment-related signs of toxicity were observed both in healthy and tumor-bearing mice after single and repeated administrations. Taken together, these results indicate that MC3181 may represent a potential novel therapeutic opportunity for BRAF-mutated human melanoma, while being safe and water-soluble and thus overcoming all the critical aspects of NBDHEX in vivo.

Published
2015

22. Surrene

Author

BERTOLOTTO, MICHELE, CALDERAN L, TOM P, CALLIADA F, RESCINITO G, POZZI MUCELLI R., BUSILACCHI P, RAPACCINI GL, Bertolotto, Michele, Calderan, L, Tom, P, Calliada, F, Rescinito, G, and POZZI MUCELLI, R.

Published
2006

25. Principi fisici dei mezzi di contrasto in ecografia

Author

BERTOLOTTO, MICHELE, CALLIADA F, VERCELLI A, PASSAMONTI M, CALDERAN L, POZZI MUCELLI R., BUSILACCHI P, RAPACCINI GL, Bertolotto, Michele, Calliada, F, Vercelli, A, Passamonti, M, Calderan, L, and POZZI MUCELLI, R.

Published
2006

28. Apporto della colnagio-rmn nella diagnostica delle vie biliari

Author

Calderan, L., Rossi, A., Bortul, Marina, Stacul, F., Gava, S., Cova, MARIA ASSUNTA, Calderan, L., Rossi, A., Bortul, Marina, Stacul, F., Gava, S., and Cova, MARIA ASSUNTA

Subjects
patologia biliopancreatica, colangiopancreatografia con risonanza magnetica
Abstract

Abbiamo valutato il ruolo della colangio-RM nella diagnosi delle patologie delle vie biIiari e dei dotti pancreatici in relazione anche ai dati emersi dalla letteratura. Da febbraio2OO2 a luglio 2004 sono stati sottoposti a risonanza magnetica (RM) per lo studio delle vie biliari 252 pazienti consecutivi, con sospetto clinico o strumentale di patologia biliare. La diagnosi deflnitiva di patologia è stata ottenuta mediante intervento chirurgico e/o colangiopancreatografia retrograda perendoscopica (ERCp) nei pazienti con clinica o evidenza diagnostica di malattia, mediante follow-up nei restanti casi. La colangiopancreato-RM (CPRM), associata alla sequenza FSE T2 pesata sul piano assiale, è risultata positiva in 191/252 (75.79yo) pazienti, in 75/191 dei quali (39.26%) si è reso indispensabile il ricorso a ERCP (n = SS) o è stato necessario l,intervento chirurgico b = qZ). CPRM e reperto chirurgico non concordavano tn 3/42 (7.14yo) casi operati; CPRM e ERCP sono risultate dlscordanti in 11/33 (33.38%) casi sottoposti a ERCP Fatta eccezione per i limiti associati alla difficoltà dl acquisire informazioni dinamiche relative a patologie funzionali dello sfintere di Oddi, per le quali peraltro si sta registrando un progressivo aggiornamento tecnologico, la CpRM rappresenta la metodica diagnostica di riferimento nella patologia biliopancreatica, riservando all'esame endoscopico valenza terapeutica.

Published
2006

31. L’eco-color Doppler penieno: stato dell’arte

Author

BERTOLOTTO, MICHELE, COVA, MARIA ASSUNTA, GASPARINI C, CALDERAN L, LISSIANI A, Bertolotto, Michele, Gasparini, C, Calderan, L, Lissiani, A, and Cova, MARIA ASSUNTA

Published
2005

43. Corpora cavernosa divisa: una patologia sottostimata?

Author

Bucci S., Calderan L., Gasparini C., Scieri F., Salamè L., BERTOLOTTO, MICHELE, LIGUORI, GIOVANNI, TROMBETTA, CARLO, BELGRANO, Emanuele, Bucci, S., Bertolotto, Michele, Liguori, Giovanni, Calderan, L., Gasparini, C., Scieri, F., Salamè, L., Trombetta, Carlo, and Belgrano, Emanuele

Subjects
pene, varianti anatomiche pene, ecografia
Published
2004

50. US characterization of focal hepatic lesions with intermittent high acoustic power mode and contrast material

Author

Quaia, Emilio, Bertolotto, Michele, Calderan, L, Mosconi, E, Pozzi Mucelli, R., Quaia, Emilio, Bertolotto, Michele, Calderan, L, Mosconi, E, and Pozzi Mucelli, R.

Subjects
ultrasound (US), Liver neoplasms, diagnosis, liver neoplasms, US, microbubbles, ultrasound (US), contrast media, US, liver neoplasms, diagnosis, diagnosis, liver neoplasm, Liver neoplasm, microbubbles
Abstract

Rationale and Objectives. This study was performed to determine whether ultrasound (US) performed with SonoVue, a contrast agent that contains microbubbles filled with sulfur hexafluoride vapor, depicts differential patterns of contrast enhancement in focal hepatic lesions. Materials and Methods. Forty focal hepatic lesions (15 hepatocellular carcinomas [HCCs], 10 metastases, 11 hemangiomas, and four focal nodular hyperplasias) in 39 patients were evaluated by means of US, color Doppler US, and contrastenhanced US performed by using intermittent high-acoustic-power mode. Contrast-enhanced helical computed tomography (11 patients) and US-guided fine needle aspiration (28 patients) were used as reference procedures. Contrast enhancement patterns were defined by means of both subjective and objective analysis, and baseline and contrast-enhanced US scans were reviewed offline. Results. Thirteen of 15 HCCs, eight of 10 metastases, and all four hemangiomas with an atypical pattern at baseline US were correctly characterized after SonoVue injection. Two of 15 HCCs and two of 10 metastases remained indeterminate, with no characteristic baseline or contrast-enhanced patterns identified. Baseline US was essential in characterizing all hemangiomas with a typical pattern (n 7), and color Doppler US with spectral analysis of tumoral vessels was essential in characterizing focal nodular hyperplasia. The percentage of diagnostic agreement with reference procedures was significantly increased (P .001) for contrast-enhanced US compared with baseline US. Conclusion. Characteristic patterns of US contrast enhancement with SonoVue help in characterizing and differentiating focal hepatic lesions.

Published
2003

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