Remarkable Boron Delivery Of iRGD-Modified Polymeric Nanoparticles For Boron Neutron Capture Therapy

Jiejian Chen,1,2 Qiyao Yang,1,2 Minchen Liu,3 Mengting Lin,2 Tiantian Wang,2 Zhentao Zhang,2 Xincheng Zhong,2 Ningning Guo,2 Yiying Lu,2 Jing Xu,1 Changsheng Wang,4 Min Han,2 Qichun Wei1 1Department of Radiation Oncology, Ministry of Education Key Laboratory of Cancer Prevention and Intervention, Th...

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Autores principales:	Chen J, Yang Q, Liu M, Lin M, Wang T, Zhang Z, Zhong X, Guo N, Lu Y, Xu J, Wang C, Han M, Wei Q
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2019
Materias:	BNCT drug delivery Polymer-drug conjugate BSH Doxorubicin Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/50037a8e28514f2e9f6333f4c08d0a47
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id	oai:doaj.org-article:50037a8e28514f2e9f6333f4c08d0a47
record_format	dspace
institution	DOAJ
collection	DOAJ
language	EN
topic	BNCT drug delivery Polymer-drug conjugate BSH Doxorubicin Medicine (General) R5-920
spellingShingle	BNCT drug delivery Polymer-drug conjugate BSH Doxorubicin Medicine (General) R5-920 Chen J Yang Q Liu M Lin M Wang T Zhang Z Zhong X Guo N Lu Y Xu J Wang C Han M Wei Q Remarkable Boron Delivery Of iRGD-Modified Polymeric Nanoparticles For Boron Neutron Capture Therapy
description	Jiejian Chen,1,2 Qiyao Yang,1,2 Minchen Liu,3 Mengting Lin,2 Tiantian Wang,2 Zhentao Zhang,2 Xincheng Zhong,2 Ningning Guo,2 Yiying Lu,2 Jing Xu,1 Changsheng Wang,4 Min Han,2 Qichun Wei1 1Department of Radiation Oncology, Ministry of Education Key Laboratory of Cancer Prevention and Intervention, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310009, People’s Republic of China; 2Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, People’s Republic of China; 3Engineering Research Center of Modern Preparation Technology of TCM, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, People’s Republic of China; 4Department of Spinal Surgery, The First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, People’s Republic of ChinaCorrespondence: Qichun WeiDepartment of Radiation Oncology, Ministry of Education Key Laboratory of Cancer Prevention and Intervention, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310009, People’s Republic of ChinaTel +86 571 8778 3521Fax +86 571 8721 4404Email qichun_wei@zju.edu.cnChangsheng WangDepartment of Spinal Surgery, The First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, People’s Republic of ChinaEmail wangcs15@163.comPurpose: Boron neutron capture therapy (BNCT) is an emerging binary radiotherapy, which is limited for application due to the challenge of targeted delivery into tumor nowadays. Here, we propose the use of iRGD-modified polymeric nanoparticles for active targeted delivery of boron and doxorubicin (DOX) in BNCT.Methods: 10B-enriched BSH was covalently grafted to PEG-PCCL to prepare 10B-polymer, then surface-modified with iRGD. And, DOX was physically incorporated into polymers afterwards. Characterization of prepared polymers and in vitro release profile of DOX from polymers were determined by several methods. Cellular uptake of DOX was observed by confocal microscope. Accumulation of boron in cells and tissues was analyzed by ICP-MS. Biodistribution of DOX was studied by ex vivo fluorescence imaging and quantitative measurement. Tumor vascular normalization of Endostar for promoting delivery efficiency of boron on refractory B16F10 tumor was also studied.Results: The polymers were monodisperse and spheroidal in water with an average diameter of 24.97 nm, which were relatively stable at physiological pH and showed a sustained release of DOX, especially at endolysosomal pH. Enhanced cellular delivery of DOX was found in iRGD-modified polymer group. Cellular boron uptake of iRGD-modified polymers in A549 cells was remarkably raised fivefold (209.83 ng 10B/106 cells) compared with BSH. The polymers represented prolonged blood circulation, enhanced tumor accumulation of 10B against BSH, and favorable tumor:normal tissue boron concentration ratios (tumor:blood = 14.11, tumor:muscle = 19.49) in A549 tumor-bearing mice 24 hrs after injection. Both fluorescence imaging and quantitative measurement showed the highest tumor accumulation of DOX at 24 hrs after injecting of iRGD-modified polymers. Improvement of vascular integrity and reduction of vascular mimicries were found after Endostar injection, and raised tumor accumulation of boron as well.Conclusion: The developed nanoparticle is an inspiring candidate for the safe clinical application for BNCT.Keywords: BNCT, drug delivery, polymer–drug conjugate, BSH, doxorubicin
format	article
author	Chen J Yang Q Liu M Lin M Wang T Zhang Z Zhong X Guo N Lu Y Xu J Wang C Han M Wei Q
author_facet	Chen J Yang Q Liu M Lin M Wang T Zhang Z Zhong X Guo N Lu Y Xu J Wang C Han M Wei Q
author_sort	Chen J
title	Remarkable Boron Delivery Of iRGD-Modified Polymeric Nanoparticles For Boron Neutron Capture Therapy
title_short	Remarkable Boron Delivery Of iRGD-Modified Polymeric Nanoparticles For Boron Neutron Capture Therapy
title_full	Remarkable Boron Delivery Of iRGD-Modified Polymeric Nanoparticles For Boron Neutron Capture Therapy
title_fullStr	Remarkable Boron Delivery Of iRGD-Modified Polymeric Nanoparticles For Boron Neutron Capture Therapy
title_full_unstemmed	Remarkable Boron Delivery Of iRGD-Modified Polymeric Nanoparticles For Boron Neutron Capture Therapy
title_sort	remarkable boron delivery of irgd-modified polymeric nanoparticles for boron neutron capture therapy
publisher	Dove Medical Press
publishDate	2019
url	https://doaj.org/article/50037a8e28514f2e9f6333f4c08d0a47
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spelling	oai:doaj.org-article:50037a8e28514f2e9f6333f4c08d0a472021-12-02T08:53:46ZRemarkable Boron Delivery Of iRGD-Modified Polymeric Nanoparticles For Boron Neutron Capture Therapy1178-2013https://doaj.org/article/50037a8e28514f2e9f6333f4c08d0a472019-10-01T00:00:00Zhttps://www.dovepress.com/remarkable-boron-delivery-of-irgd-modified-polymeric-nanoparticles-for-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Jiejian Chen,1,2 Qiyao Yang,1,2 Minchen Liu,3 Mengting Lin,2 Tiantian Wang,2 Zhentao Zhang,2 Xincheng Zhong,2 Ningning Guo,2 Yiying Lu,2 Jing Xu,1 Changsheng Wang,4 Min Han,2 Qichun Wei1 1Department of Radiation Oncology, Ministry of Education Key Laboratory of Cancer Prevention and Intervention, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310009, People’s Republic of China; 2Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, People’s Republic of China; 3Engineering Research Center of Modern Preparation Technology of TCM, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, People’s Republic of China; 4Department of Spinal Surgery, The First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, People’s Republic of ChinaCorrespondence: Qichun WeiDepartment of Radiation Oncology, Ministry of Education Key Laboratory of Cancer Prevention and Intervention, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310009, People’s Republic of ChinaTel +86 571 8778 3521Fax +86 571 8721 4404Email qichun_wei@zju.edu.cnChangsheng WangDepartment of Spinal Surgery, The First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, People’s Republic of ChinaEmail wangcs15@163.comPurpose: Boron neutron capture therapy (BNCT) is an emerging binary radiotherapy, which is limited for application due to the challenge of targeted delivery into tumor nowadays. Here, we propose the use of iRGD-modified polymeric nanoparticles for active targeted delivery of boron and doxorubicin (DOX) in BNCT.Methods: 10B-enriched BSH was covalently grafted to PEG-PCCL to prepare 10B-polymer, then surface-modified with iRGD. And, DOX was physically incorporated into polymers afterwards. Characterization of prepared polymers and in vitro release profile of DOX from polymers were determined by several methods. Cellular uptake of DOX was observed by confocal microscope. Accumulation of boron in cells and tissues was analyzed by ICP-MS. Biodistribution of DOX was studied by ex vivo fluorescence imaging and quantitative measurement. Tumor vascular normalization of Endostar for promoting delivery efficiency of boron on refractory B16F10 tumor was also studied.Results: The polymers were monodisperse and spheroidal in water with an average diameter of 24.97 nm, which were relatively stable at physiological pH and showed a sustained release of DOX, especially at endolysosomal pH. Enhanced cellular delivery of DOX was found in iRGD-modified polymer group. Cellular boron uptake of iRGD-modified polymers in A549 cells was remarkably raised fivefold (209.83 ng 10B/106 cells) compared with BSH. The polymers represented prolonged blood circulation, enhanced tumor accumulation of 10B against BSH, and favorable tumor:normal tissue boron concentration ratios (tumor:blood = 14.11, tumor:muscle = 19.49) in A549 tumor-bearing mice 24 hrs after injection. Both fluorescence imaging and quantitative measurement showed the highest tumor accumulation of DOX at 24 hrs after injecting of iRGD-modified polymers. Improvement of vascular integrity and reduction of vascular mimicries were found after Endostar injection, and raised tumor accumulation of boron as well.Conclusion: The developed nanoparticle is an inspiring candidate for the safe clinical application for BNCT.Keywords: BNCT, drug delivery, polymer–drug conjugate, BSH, doxorubicinChen JYang QLiu MLin MWang TZhang ZZhong XGuo NLu YXu JWang CHan MWei QDove Medical PressarticleBNCTdrug deliveryPolymer-drug conjugateBSHDoxorubicinMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 14, Pp 8161-8177 (2019)

Remarkable Boron Delivery Of iRGD-Modified Polymeric Nanoparticles For Boron Neutron Capture Therapy

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