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Fibrin Gels Entrapment of a Poly-Cyclodextrin Nanocarrier as a Doxorubicin Delivery System in an Orthotopic Model of Neuroblastoma: Evaluation of In Vitro Activity and In Vivo Toxicity

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Abstract

Purpose

Fibrin gels (FBGs) are potential delivery vehicles for many drugs, and can be easily prepared from purified components. We previously demonstrated their applicability for the release of different doxorubicin (Dox) nanoparticles used clinically or in an experimental stage, such as its inclusion complex with the amino β-cyclodextrin polymer (oCD-NH2/Dox). Here we extend these studies by in vitro and in vivo evaluations.

Methods

An in vitro cytotoxicity model consisting of an overlay of a neuroblastoma (NB) cell-containing agar layer above a drug-loaded FBG layer was used. Local toxicity in vivo (histology and blood analysis) was studied in a mouse orthotopic NB model (SHSY5YLuc+ cells implanted into the left adrenal gland).

Results

In vitro data show that FBGs loaded with oCD-NH2/Dox have a slightly lower cytotoxicity against NB cell lines than those loaded with Dox. Fibrinogen (FG), and Ca2+ concentrations may modify this activity. In vivo data support a lower general and local toxicity for FBGs loaded with oCD-NH2/Dox than those loaded with Dox.

Conclusion

Our results suggest a possible increase of the therapeutic index of Dox when locally administered through FBGs loaded with oCD-NH2/Dox, opening the possibility of using these releasing systems for the treatment of neuroblastoma.

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Abbreviations

ALT:

Alanine transaminase

AST:

Aspartate transaminase

CD:

Cyclodextrin

CRE:

Creatinine

DDP:

Cisplatin

Dox:

Doxorubicin

FBG:

Fibrin gel

FG:

Fibrinogen

NB:

Neuroblastoma

oCD-NH2 :

Cyclodextrin oligomer

oCD-NH2/Dox:

Cyclodextrin oligomer loaded with Dox

PUN:

Plasma urea nitrogen

ROI:

Region of interest

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Acknowledgments and Disclosures

Financial support of this study was mainly provided by the Compagnia di San Paolo (Turin, Italy) under Grant 2012.1020. The authors are grateful for additional support from Università degli Studi di Catania (Piano della Ricerca di Ateneo 2016–2018). We thank Dr. E. Brookes, University of Montana, Missoula, MT, USA, for carefully checking our manuscript for English usage. There is no conflict of interest about this article. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

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Authors and Affiliations

  1. UOC Bioterapie, IRCCS Ospedale Policlinico San Martino, Largo R. Benzi 10, 16132, Genoa, Italy

    Maurizio Viale, Massimiliano Monticone & Irena Maric

  2. Dipartimento di Scienze Chimiche, Università di Catania, Viale A. Doria 6, 95125, Catania, Italy

    Graziella Vecchio & Valentina Giglio

  3. Lab. Anatomia Comparata e Citologia, Dipartimento Biologia e Biotecnologie, Università di Pavia “L. Spallanzani”, Via Ferrata 9, 27100, Pavia, Italy

    Vittorio Bertone

  4. UOS Animal Facility, IRCCS Ospedale Policlinico San Martino, Largo R. Benzi 10, 16132, Genoa, Italy

    Michele Cilli & Laura Emionite

  5. Segreteria Comitato Etico Regione Liguria, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132, Genoa, Italy

    Vittorio Bocchini

  6. UOS Biopolimeri e Proteomica, IRCCS Ospedale Policlinico San Martino, Largo R. Benzi 10, 16132, Genoa, Italy

    Aldo Profumo & Mattia Rocco

  7. Laboratorio di Terapie Sperimentali in Oncologia, Istituto G. Gaslini, Via G. Gaslini 5, 16147, Genoa, Italy

    Mirco Ponzoni

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  1. Maurizio Viale
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Correspondence to Maurizio Viale.

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Viale, M., Vecchio, G., Monticone, M. et al. Fibrin Gels Entrapment of a Poly-Cyclodextrin Nanocarrier as a Doxorubicin Delivery System in an Orthotopic Model of Neuroblastoma: Evaluation of In Vitro Activity and In Vivo Toxicity. Pharm Res 36, 115 (2019). https://doi.org/10.1007/s11095-019-2636-1

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