The Pyrazolo[3,4-<i>d</i>]Pyrimidine Derivative Si306 Encapsulated into Anti-GD2-Immunoliposomes as Therapeutic Treatment of Neuroblastoma
Si306, a pyrazolo[3,4-<i>d</i>]pyrimidine derivative recently identified as promising anticancer agent, has shown favorable in vitro and in vivo activity profile against neuroblastoma (NB) models by acting as a competitive inhibitor of c-Src tyrosine kinase. Nevertheless, Si306 antitumor...
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| Language: | English |
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MDPI AG
2022-03-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/10/3/659 |
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| author | Enrico Rango Fabio Pastorino Chiara Brignole Arianna Mancini Federica Poggialini Salvatore Di Maria Claudio Zamperini Giulia Iovenitti Anna Lucia Fallacara Samantha Sabetta Letizia Clementi Massimo Valoti Silvia Schenone Adriano Angelucci Mirco Ponzoni Elena Dreassi Maurizio Botta |
| author_facet | Enrico Rango Fabio Pastorino Chiara Brignole Arianna Mancini Federica Poggialini Salvatore Di Maria Claudio Zamperini Giulia Iovenitti Anna Lucia Fallacara Samantha Sabetta Letizia Clementi Massimo Valoti Silvia Schenone Adriano Angelucci Mirco Ponzoni Elena Dreassi Maurizio Botta |
| author_sort | Enrico Rango |
| collection | DOAJ |
| description | Si306, a pyrazolo[3,4-<i>d</i>]pyrimidine derivative recently identified as promising anticancer agent, has shown favorable in vitro and in vivo activity profile against neuroblastoma (NB) models by acting as a competitive inhibitor of c-Src tyrosine kinase. Nevertheless, Si306 antitumor activity is associated with sub-optimal aqueous solubility, which might hinder its further development. Drug delivery systems were here developed with the aim to overcome this limitation, obtaining suitable formulations for more efficacious in vivo use. Si306 was encapsulated in pegylated stealth liposomes, undecorated or decorated with a monoclonal antibody able to specifically recognize and bind to the disialoganglioside GD2 expressed by NB cells (LP[Si306] and GD2-LP[Si306], respectively). Both liposomes possessed excellent morphological and physio-chemical properties, maintained over a period of two weeks. Compared to LP[Si306], GD2-LP[Si306] showed in vitro specific cellular targeting and increased cytotoxic activity against NB cell lines. After intravenous injection in healthy mice, pharmacokinetic profiles showed increased plasma exposure of Si306 when delivered by both liposomal formulations, compared to that obtained when Si306 was administered as free form. In vivo tumor homing and cytotoxic effectiveness of both liposomal formulations were finally tested in an orthotopic animal model of NB. Si306 tumor uptake resulted significantly higher when encapsulated in GD2-LP, compared to Si306, either free or encapsulated into untargeted LP. This, in turn, led to a significant increase in survival of mice treated with GD2-LP[Si306]. These results demonstrate a promising antitumor efficacy of Si306 encapsulated into GD2-targeted liposomes, supporting further therapeutic developments in pre-clinical trials and in the clinic for NB. |
| first_indexed | 2024-03-09T13:49:09Z |
| format | Article |
| id | doaj.art-76fcd042be33447e9734d22a84d6e765 |
| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-09T13:49:09Z |
| publishDate | 2022-03-01 |
| publisher | MDPI AG |
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| series | Biomedicines |
| spelling | doaj.art-76fcd042be33447e9734d22a84d6e7652023-11-30T20:52:42ZengMDPI AGBiomedicines2227-90592022-03-0110365910.3390/biomedicines10030659The Pyrazolo[3,4-<i>d</i>]Pyrimidine Derivative Si306 Encapsulated into Anti-GD2-Immunoliposomes as Therapeutic Treatment of NeuroblastomaEnrico Rango0Fabio Pastorino1Chiara Brignole2Arianna Mancini3Federica Poggialini4Salvatore Di Maria5Claudio Zamperini6Giulia Iovenitti7Anna Lucia Fallacara8Samantha Sabetta9Letizia Clementi10Massimo Valoti11Silvia Schenone12Adriano Angelucci13Mirco Ponzoni14Elena Dreassi15Maurizio Botta16Dipartimento Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, 53100 Siena, ItalyLaboratory of Experimental Therapies in Oncology, IRCCS Istituto G. Gaslini, 16148 Genoa, ItalyLaboratory of Experimental Therapies in Oncology, IRCCS Istituto G. Gaslini, 16148 Genoa, ItalyDipartimento Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, 53100 Siena, ItalyDipartimento Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, 53100 Siena, ItalyDipartimento Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, 53100 Siena, ItalyLead Discovery Siena S.r.l., Via Vittorio Alfieri 31, 53019 Castelnuovo Berardenga, ItalyDipartimento Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, 53100 Siena, ItalyDipartimento Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, 53100 Siena, ItalyDipartimento Scienze Cliniche Applicate e Biotecnologiche, Università dell’Aquila, Via Vetoio, 67100 Coppito, ItalyDipartimento Scienze Cliniche Applicate e Biotecnologiche, Università dell’Aquila, Via Vetoio, 67100 Coppito, ItalyDipartimento Scienze della Vita, Università degli Studi di Siena, Via Aldo Moro 2, 53100 Siena, ItalyDipartimento di Farmacia, Università degli Studi di Genova, Viale Benedetto XV 3, 16132 Genoa, ItalyDipartimento Scienze Cliniche Applicate e Biotecnologiche, Università dell’Aquila, Via Vetoio, 67100 Coppito, ItalyLaboratory of Experimental Therapies in Oncology, IRCCS Istituto G. Gaslini, 16148 Genoa, ItalyDipartimento Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, 53100 Siena, ItalyDipartimento Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, 53100 Siena, ItalySi306, a pyrazolo[3,4-<i>d</i>]pyrimidine derivative recently identified as promising anticancer agent, has shown favorable in vitro and in vivo activity profile against neuroblastoma (NB) models by acting as a competitive inhibitor of c-Src tyrosine kinase. Nevertheless, Si306 antitumor activity is associated with sub-optimal aqueous solubility, which might hinder its further development. Drug delivery systems were here developed with the aim to overcome this limitation, obtaining suitable formulations for more efficacious in vivo use. Si306 was encapsulated in pegylated stealth liposomes, undecorated or decorated with a monoclonal antibody able to specifically recognize and bind to the disialoganglioside GD2 expressed by NB cells (LP[Si306] and GD2-LP[Si306], respectively). Both liposomes possessed excellent morphological and physio-chemical properties, maintained over a period of two weeks. Compared to LP[Si306], GD2-LP[Si306] showed in vitro specific cellular targeting and increased cytotoxic activity against NB cell lines. After intravenous injection in healthy mice, pharmacokinetic profiles showed increased plasma exposure of Si306 when delivered by both liposomal formulations, compared to that obtained when Si306 was administered as free form. In vivo tumor homing and cytotoxic effectiveness of both liposomal formulations were finally tested in an orthotopic animal model of NB. Si306 tumor uptake resulted significantly higher when encapsulated in GD2-LP, compared to Si306, either free or encapsulated into untargeted LP. This, in turn, led to a significant increase in survival of mice treated with GD2-LP[Si306]. These results demonstrate a promising antitumor efficacy of Si306 encapsulated into GD2-targeted liposomes, supporting further therapeutic developments in pre-clinical trials and in the clinic for NB.https://www.mdpi.com/2227-9059/10/3/659neuroblastomac-Src inhibitorliposomesanti-GD2 monoclonal antibodyimmunoliposomes |
| spellingShingle | Enrico Rango Fabio Pastorino Chiara Brignole Arianna Mancini Federica Poggialini Salvatore Di Maria Claudio Zamperini Giulia Iovenitti Anna Lucia Fallacara Samantha Sabetta Letizia Clementi Massimo Valoti Silvia Schenone Adriano Angelucci Mirco Ponzoni Elena Dreassi Maurizio Botta The Pyrazolo[3,4-<i>d</i>]Pyrimidine Derivative Si306 Encapsulated into Anti-GD2-Immunoliposomes as Therapeutic Treatment of Neuroblastoma Biomedicines neuroblastoma c-Src inhibitor liposomes anti-GD2 monoclonal antibody immunoliposomes |
| title | The Pyrazolo[3,4-<i>d</i>]Pyrimidine Derivative Si306 Encapsulated into Anti-GD2-Immunoliposomes as Therapeutic Treatment of Neuroblastoma |
| title_full | The Pyrazolo[3,4-<i>d</i>]Pyrimidine Derivative Si306 Encapsulated into Anti-GD2-Immunoliposomes as Therapeutic Treatment of Neuroblastoma |
| title_fullStr | The Pyrazolo[3,4-<i>d</i>]Pyrimidine Derivative Si306 Encapsulated into Anti-GD2-Immunoliposomes as Therapeutic Treatment of Neuroblastoma |
| title_full_unstemmed | The Pyrazolo[3,4-<i>d</i>]Pyrimidine Derivative Si306 Encapsulated into Anti-GD2-Immunoliposomes as Therapeutic Treatment of Neuroblastoma |
| title_short | The Pyrazolo[3,4-<i>d</i>]Pyrimidine Derivative Si306 Encapsulated into Anti-GD2-Immunoliposomes as Therapeutic Treatment of Neuroblastoma |
| title_sort | pyrazolo 3 4 i d i pyrimidine derivative si306 encapsulated into anti gd2 immunoliposomes as therapeutic treatment of neuroblastoma |
| topic | neuroblastoma c-Src inhibitor liposomes anti-GD2 monoclonal antibody immunoliposomes |
| url | https://www.mdpi.com/2227-9059/10/3/659 |
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