Verteporfin-Loaded Anisotropic Poly(Beta-Amino Ester)-Based Micelles Demonstrate Brain Cancer-Selective Cytotoxicity and Enhanced Pharmacokinetics

James G Shamul,1,2,* Sagar R Shah,1–3,* Jayoung Kim,1,2 Paula Schiapparelli,3 Carla A Vazquez-Ramos,3 Ben J Lee,1,2 Kisha K Patel,1,2 Alyssa Shin,1,2 Alfredo Quinones-Hinojosa,3 Jordan J Green1,2,4–6 1Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimo...

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Autores principales:	Shamul JG, Shah SR, Kim J, Schiapparelli P, Vazquez-Ramos CA, Lee BJ, Patel KK, Shin A, Quinones-Hinojosa A, Green JJ
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2019
Materias:	gbm verteporfin micelle anisotropic poly(ethylene glycol) (peg) poly(beta-amino ester) (pbae) Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/2496eb01f1894d55b0f3730a936e4f48
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spelling	oai:doaj.org-article:2496eb01f1894d55b0f3730a936e4f482021-12-02T05:37:43ZVerteporfin-Loaded Anisotropic Poly(Beta-Amino Ester)-Based Micelles Demonstrate Brain Cancer-Selective Cytotoxicity and Enhanced Pharmacokinetics1178-2013https://doaj.org/article/2496eb01f1894d55b0f3730a936e4f482019-12-01T00:00:00Zhttps://www.dovepress.com/verteporfin-loaded-anisotropic-polybeta-amino-ester-based-micelles-dem-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013James G Shamul,1,2,* Sagar R Shah,1–3,* Jayoung Kim,1,2 Paula Schiapparelli,3 Carla A Vazquez-Ramos,3 Ben J Lee,1,2 Kisha K Patel,1,2 Alyssa Shin,1,2 Alfredo Quinones-Hinojosa,3 Jordan J Green1,2,4–6 1Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore, MD 21231, USA; 2Translational Tissue Engineering Center and Institute for NanoBioTechnology, Johns Hopkins School of Medicine, Baltimore, MD 21231, USA; 3Department of Neurosurgery, Mayo Clinic, Jacksonville, FL 32224, USA; 4Department of Neurosurgery, Johns Hopkins Hospital, Baltimore, MD 21231, USA; 5Department of Oncology, The Sidney Kimmel Comprehensive Cancer, and The Bloomberg&sim;Kimmel Institute for Cancer Immunotherapy, Johns Hopkins School of Medicine, Baltimore, MD 21231, USA; 6Department of Ophthalmology, Department of Materials Science and Engineering, and Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21231, USA*These authors contributed equally to this workCorrespondence: Alfredo Quinones-Hinojosa; Jordan J Green Email Quinones-Hinojosa.Alfredo@mayo.edu; green@jhu.eduBackground: Nanomedicine can improve traditional therapies by enhancing the controlled release of drugs at targeted tissues in the body. However, there still exists disease- and therapy-specific barriers that limit the efficacy of such treatments. A major challenge in developing effective therapies for one of the most aggressive brain tumors, glioblastoma (GBM), is affecting brain cancer cells while avoiding damage to the surrounding healthy brain parenchyma. Here, we developed poly(ethylene glycol) (PEG)-poly(beta-amino ester) (PBAE) (PEG-PBAE)-based micelles encapsulating verteporfin (VP) to increase tumor-specific targeting.Methods: Biodegradable, pH-sensitive micelles of different shapes were synthesized via nanoprecipitation using two different triblock PEG-PBAE-PEG copolymers varying in their relative hydrophobicity. The anti-tumor efficacy of verteporfin loaded in these anisotropic and spherical micelles was evaluated in vitro using patient-derived primary GBM cells.Results: For anisotropic micelles, uptake efficiency was &sim;100% in GBM cells (GBM1A and JHGBM612) while only 46% in normal human astrocytes (NHA) at 15.6 nM VP (p ≤ 0.0001). Cell killing of GBM1A and JHGBM612 vs NHA was 52% and 77% vs 29%, respectively, at 24 hrs post-treatment of 125 nM VP-encapsulated in anisotropic micelles (p ≤ 0.0001), demonstrating the tumor cell-specific selectivity of VP. Moreover, anisotropic micelles showed an approximately fivefold longer half-life in blood circulation than the analogous spherical micelles in a GBM xenograft model in mice. In this model, micelle accumulation to tumors was significantly greater for anisotropic micelle-treated mice compared to spherical micelle-treated mice at both 8 hrs (&sim;1.8-fold greater, p ≤ 0.001) and 24 hrs (&sim;2.1-fold greater, p ≤ 0.0001).Conclusion: Overall, this work highlights the promise of a biodegradable anisotropic micelle system to overcome multiple drug delivery challenges and enhance efficacy and safety for the treatment of brain cancer.Keywords: GBM, verteporfin, micelle, anisotropic, poly(ethylene glycol), PEG, poly(beta-amino ester), PBAEShamul JGShah SRKim JSchiapparelli PVazquez-Ramos CALee BJPatel KKShin AQuinones-Hinojosa AGreen JJDove Medical Pressarticlegbmverteporfinmicelleanisotropicpoly(ethylene glycol) (peg)poly(beta-amino ester) (pbae)Medicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 14, Pp 10047-10060 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	gbm verteporfin micelle anisotropic poly(ethylene glycol) (peg) poly(beta-amino ester) (pbae) Medicine (General) R5-920
spellingShingle	gbm verteporfin micelle anisotropic poly(ethylene glycol) (peg) poly(beta-amino ester) (pbae) Medicine (General) R5-920 Shamul JG Shah SR Kim J Schiapparelli P Vazquez-Ramos CA Lee BJ Patel KK Shin A Quinones-Hinojosa A Green JJ Verteporfin-Loaded Anisotropic Poly(Beta-Amino Ester)-Based Micelles Demonstrate Brain Cancer-Selective Cytotoxicity and Enhanced Pharmacokinetics
description	James G Shamul,1,2,* Sagar R Shah,1–3,* Jayoung Kim,1,2 Paula Schiapparelli,3 Carla A Vazquez-Ramos,3 Ben J Lee,1,2 Kisha K Patel,1,2 Alyssa Shin,1,2 Alfredo Quinones-Hinojosa,3 Jordan J Green1,2,4–6 1Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore, MD 21231, USA; 2Translational Tissue Engineering Center and Institute for NanoBioTechnology, Johns Hopkins School of Medicine, Baltimore, MD 21231, USA; 3Department of Neurosurgery, Mayo Clinic, Jacksonville, FL 32224, USA; 4Department of Neurosurgery, Johns Hopkins Hospital, Baltimore, MD 21231, USA; 5Department of Oncology, The Sidney Kimmel Comprehensive Cancer, and The Bloomberg&sim;Kimmel Institute for Cancer Immunotherapy, Johns Hopkins School of Medicine, Baltimore, MD 21231, USA; 6Department of Ophthalmology, Department of Materials Science and Engineering, and Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21231, USA*These authors contributed equally to this workCorrespondence: Alfredo Quinones-Hinojosa; Jordan J Green Email Quinones-Hinojosa.Alfredo@mayo.edu; green@jhu.eduBackground: Nanomedicine can improve traditional therapies by enhancing the controlled release of drugs at targeted tissues in the body. However, there still exists disease- and therapy-specific barriers that limit the efficacy of such treatments. A major challenge in developing effective therapies for one of the most aggressive brain tumors, glioblastoma (GBM), is affecting brain cancer cells while avoiding damage to the surrounding healthy brain parenchyma. Here, we developed poly(ethylene glycol) (PEG)-poly(beta-amino ester) (PBAE) (PEG-PBAE)-based micelles encapsulating verteporfin (VP) to increase tumor-specific targeting.Methods: Biodegradable, pH-sensitive micelles of different shapes were synthesized via nanoprecipitation using two different triblock PEG-PBAE-PEG copolymers varying in their relative hydrophobicity. The anti-tumor efficacy of verteporfin loaded in these anisotropic and spherical micelles was evaluated in vitro using patient-derived primary GBM cells.Results: For anisotropic micelles, uptake efficiency was &sim;100% in GBM cells (GBM1A and JHGBM612) while only 46% in normal human astrocytes (NHA) at 15.6 nM VP (p ≤ 0.0001). Cell killing of GBM1A and JHGBM612 vs NHA was 52% and 77% vs 29%, respectively, at 24 hrs post-treatment of 125 nM VP-encapsulated in anisotropic micelles (p ≤ 0.0001), demonstrating the tumor cell-specific selectivity of VP. Moreover, anisotropic micelles showed an approximately fivefold longer half-life in blood circulation than the analogous spherical micelles in a GBM xenograft model in mice. In this model, micelle accumulation to tumors was significantly greater for anisotropic micelle-treated mice compared to spherical micelle-treated mice at both 8 hrs (&sim;1.8-fold greater, p ≤ 0.001) and 24 hrs (&sim;2.1-fold greater, p ≤ 0.0001).Conclusion: Overall, this work highlights the promise of a biodegradable anisotropic micelle system to overcome multiple drug delivery challenges and enhance efficacy and safety for the treatment of brain cancer.Keywords: GBM, verteporfin, micelle, anisotropic, poly(ethylene glycol), PEG, poly(beta-amino ester), PBAE
format	article
author	Shamul JG Shah SR Kim J Schiapparelli P Vazquez-Ramos CA Lee BJ Patel KK Shin A Quinones-Hinojosa A Green JJ
author_facet	Shamul JG Shah SR Kim J Schiapparelli P Vazquez-Ramos CA Lee BJ Patel KK Shin A Quinones-Hinojosa A Green JJ
author_sort	Shamul JG
title	Verteporfin-Loaded Anisotropic Poly(Beta-Amino Ester)-Based Micelles Demonstrate Brain Cancer-Selective Cytotoxicity and Enhanced Pharmacokinetics
title_short	Verteporfin-Loaded Anisotropic Poly(Beta-Amino Ester)-Based Micelles Demonstrate Brain Cancer-Selective Cytotoxicity and Enhanced Pharmacokinetics
title_full	Verteporfin-Loaded Anisotropic Poly(Beta-Amino Ester)-Based Micelles Demonstrate Brain Cancer-Selective Cytotoxicity and Enhanced Pharmacokinetics
title_fullStr	Verteporfin-Loaded Anisotropic Poly(Beta-Amino Ester)-Based Micelles Demonstrate Brain Cancer-Selective Cytotoxicity and Enhanced Pharmacokinetics
title_full_unstemmed	Verteporfin-Loaded Anisotropic Poly(Beta-Amino Ester)-Based Micelles Demonstrate Brain Cancer-Selective Cytotoxicity and Enhanced Pharmacokinetics
title_sort	verteporfin-loaded anisotropic poly(beta-amino ester)-based micelles demonstrate brain cancer-selective cytotoxicity and enhanced pharmacokinetics
publisher	Dove Medical Press
publishDate	2019
url	https://doaj.org/article/2496eb01f1894d55b0f3730a936e4f48
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Verteporfin-Loaded Anisotropic Poly(Beta-Amino Ester)-Based Micelles Demonstrate Brain Cancer-Selective Cytotoxicity and Enhanced Pharmacokinetics

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