Investigation of antitumor activities of trastuzumab delivered by PLGA nanoparticles

Barbara Colzani,1,* Laura Pandolfi,1,* Ada Hoti,1 Pietro Alessandro Iovene,1 Antonino Natalello,1 Svetlana Avvakumova,1 Miriam Colombo,1 Davide Prosperi1,2 1Department of Biotechnology and Biosciences, University of Milano Bicocca, Milano, Italy; 2Nanomedicine Laboratory, ICS Maugeri S. p. A. SB, P...

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Autores principales:	Colzani B, Pandolfi L, Hoti A, Iovene PA, Natalello A, Avvakumova S, Colombo M, Prosperi D
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2018
Materias:	biocompatible nanoparticles ADCC HER2-positive breast cancer immunotherapy chemotherapy. Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/7841875efdfd460e843d809544d49318
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spelling	oai:doaj.org-article:7841875efdfd460e843d809544d493182021-12-02T07:33:30ZInvestigation of antitumor activities of trastuzumab delivered by PLGA nanoparticles1178-2013https://doaj.org/article/7841875efdfd460e843d809544d493182018-02-01T00:00:00Zhttps://www.dovepress.com/investigation-of-antitumor-activities-of-trastuzumab-delivered-by-plga-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Barbara Colzani,1,* Laura Pandolfi,1,* Ada Hoti,1 Pietro Alessandro Iovene,1 Antonino Natalello,1 Svetlana Avvakumova,1 Miriam Colombo,1 Davide Prosperi1,2 1Department of Biotechnology and Biosciences, University of Milano Bicocca, Milano, Italy; 2Nanomedicine Laboratory, ICS Maugeri S. p. A. SB, Pavia, Italy *These authors contributed equally to this work Background: We report the development of an efficient antibody delivery system for the incorporation of trastuzumab (TZ) into poly(lactic-co-glycolic) acid nanoparticles (PLGA NPs). The aim of the work was to overcome the current limitations in the clinical use of therapeutic antibodies, including immunogenicity, poor pharmacokinetics, low tumor penetration and safety issues.Materials and methods: Trastuzumab-loaded PLGA NPs (PLGA-TZ) were synthesized according to a double emulsion method. The same protocol was used to produce control batches of nonspecific IgG-loaded NPs and empty PLGA NPs. After release of TZ from PLGA NPs, the effects on the main biological activities of the antibody were evaluated on SKBR3 (human epidermal growth factor receptor 2 [HER2]-positive breast cancer cell line), including specific binding to HER2, phosphorylation of HER2 (Y1248), degradation of HER2 protein and antibody-dependent cell-mediated cytotoxicity (ADCC) mechanism. In addition, an MTT assay was performed for treating SKBR3 cells with PLGA NPs loaded with TZ and doxorubicin to evaluate the cytotoxic activity of the combined treatment.Results and discussion: TZ was gradually released in a prolonged way over 30 days. The physical characterization performed with circular dichroism, Fourier transform infrared and fluorescence spectroscopy of TZ after release demonstrated that no structural alterations occurred compared to the native antibody. In vitro experiments using SKBR3 cells showed that TZ released from PLGA NPs maintained the same biological activity of native TZ. PLGA NPs allowed a good co-encapsulation efficiency of TZ and doxorubicin resulting in improved therapy.Conclusion: With the TZ case study, we demonstrate that the distinctive features of therapeutic monoclonal antibodies, including molecular targeting efficiency, capability to inhibit or properly affect the regulatory signaling pathways of cancer cells and stimulation of the ADCC, are fully preserved after loading into and release from PLGA NPs. In addition, PLGA NPs are shown to allow for the simultaneous incorporation of TZ and conventional chemotherapeutics, resulting in a potent antitumor nanodrug well suited for in situ combination and neoadjuvant therapy. Keywords: biocompatible nanoparticles, ADCC, HER2-positive breast cancer, immunotherapy, chemotherapy, nanodrugColzani BPandolfi LHoti AIovene PANatalello AAvvakumova SColombo MProsperi DDove Medical Pressarticlebiocompatible nanoparticlesADCCHER2-positive breast cancerimmunotherapychemotherapy.Medicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 13, Pp 957-973 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	biocompatible nanoparticles ADCC HER2-positive breast cancer immunotherapy chemotherapy. Medicine (General) R5-920
spellingShingle	biocompatible nanoparticles ADCC HER2-positive breast cancer immunotherapy chemotherapy. Medicine (General) R5-920 Colzani B Pandolfi L Hoti A Iovene PA Natalello A Avvakumova S Colombo M Prosperi D Investigation of antitumor activities of trastuzumab delivered by PLGA nanoparticles
description	Barbara Colzani,1,* Laura Pandolfi,1,* Ada Hoti,1 Pietro Alessandro Iovene,1 Antonino Natalello,1 Svetlana Avvakumova,1 Miriam Colombo,1 Davide Prosperi1,2 1Department of Biotechnology and Biosciences, University of Milano Bicocca, Milano, Italy; 2Nanomedicine Laboratory, ICS Maugeri S. p. A. SB, Pavia, Italy *These authors contributed equally to this work Background: We report the development of an efficient antibody delivery system for the incorporation of trastuzumab (TZ) into poly(lactic-co-glycolic) acid nanoparticles (PLGA NPs). The aim of the work was to overcome the current limitations in the clinical use of therapeutic antibodies, including immunogenicity, poor pharmacokinetics, low tumor penetration and safety issues.Materials and methods: Trastuzumab-loaded PLGA NPs (PLGA-TZ) were synthesized according to a double emulsion method. The same protocol was used to produce control batches of nonspecific IgG-loaded NPs and empty PLGA NPs. After release of TZ from PLGA NPs, the effects on the main biological activities of the antibody were evaluated on SKBR3 (human epidermal growth factor receptor 2 [HER2]-positive breast cancer cell line), including specific binding to HER2, phosphorylation of HER2 (Y1248), degradation of HER2 protein and antibody-dependent cell-mediated cytotoxicity (ADCC) mechanism. In addition, an MTT assay was performed for treating SKBR3 cells with PLGA NPs loaded with TZ and doxorubicin to evaluate the cytotoxic activity of the combined treatment.Results and discussion: TZ was gradually released in a prolonged way over 30 days. The physical characterization performed with circular dichroism, Fourier transform infrared and fluorescence spectroscopy of TZ after release demonstrated that no structural alterations occurred compared to the native antibody. In vitro experiments using SKBR3 cells showed that TZ released from PLGA NPs maintained the same biological activity of native TZ. PLGA NPs allowed a good co-encapsulation efficiency of TZ and doxorubicin resulting in improved therapy.Conclusion: With the TZ case study, we demonstrate that the distinctive features of therapeutic monoclonal antibodies, including molecular targeting efficiency, capability to inhibit or properly affect the regulatory signaling pathways of cancer cells and stimulation of the ADCC, are fully preserved after loading into and release from PLGA NPs. In addition, PLGA NPs are shown to allow for the simultaneous incorporation of TZ and conventional chemotherapeutics, resulting in a potent antitumor nanodrug well suited for in situ combination and neoadjuvant therapy. Keywords: biocompatible nanoparticles, ADCC, HER2-positive breast cancer, immunotherapy, chemotherapy, nanodrug
format	article
author	Colzani B Pandolfi L Hoti A Iovene PA Natalello A Avvakumova S Colombo M Prosperi D
author_facet	Colzani B Pandolfi L Hoti A Iovene PA Natalello A Avvakumova S Colombo M Prosperi D
author_sort	Colzani B
title	Investigation of antitumor activities of trastuzumab delivered by PLGA nanoparticles
title_short	Investigation of antitumor activities of trastuzumab delivered by PLGA nanoparticles
title_full	Investigation of antitumor activities of trastuzumab delivered by PLGA nanoparticles
title_fullStr	Investigation of antitumor activities of trastuzumab delivered by PLGA nanoparticles
title_full_unstemmed	Investigation of antitumor activities of trastuzumab delivered by PLGA nanoparticles
title_sort	investigation of antitumor activities of trastuzumab delivered by plga nanoparticles
publisher	Dove Medical Press
publishDate	2018
url	https://doaj.org/article/7841875efdfd460e843d809544d49318
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Investigation of antitumor activities of trastuzumab delivered by PLGA nanoparticles

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