Enhancing Radiotherapeutic Effect With Nanoparticle-Mediated Radiosensitizer Delivery Guided By Focused Gamma Rays In Lewis Lung Carcinoma-Bearing Mouse Brain Tumor Models

Sa-Hoe Lim,1,2 Chun-Hao Li,3 Young-Il Jeong,4 Woo-Youl Jang,1,2 Jin-Myung Choi,2 Shin Jung1,2 1Department of Neurosurgery, Chonnam National University Medical School and Hwasun Hospital, Hwasun, Korea; 2Brain Tumor Research Laboratory, Chonnam National University Research Institute of Medical Scienc...

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Autores principales:	Lim SH, Li CH, Jeong YI, Jang WY, Choi JM, Jung S
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2019
Materias:	combination therapy radiotherapy tip-1 receptor nanoparticles ph-sensitive Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/ea0c0d65a4704826b681cb797e973055
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spelling	oai:doaj.org-article:ea0c0d65a4704826b681cb797e9730552021-12-02T12:02:27ZEnhancing Radiotherapeutic Effect With Nanoparticle-Mediated Radiosensitizer Delivery Guided By Focused Gamma Rays In Lewis Lung Carcinoma-Bearing Mouse Brain Tumor Models1178-2013https://doaj.org/article/ea0c0d65a4704826b681cb797e9730552019-11-01T00:00:00Zhttps://www.dovepress.com/enhancing-radiotherapeutic-effect-with-nanoparticle-mediated-radiosens-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Sa-Hoe Lim,1,2 Chun-Hao Li,3 Young-Il Jeong,4 Woo-Youl Jang,1,2 Jin-Myung Choi,2 Shin Jung1,2 1Department of Neurosurgery, Chonnam National University Medical School and Hwasun Hospital, Hwasun, Korea; 2Brain Tumor Research Laboratory, Chonnam National University Research Institute of Medical Sciences, Chonnam National University Hwasun Hospital, Hwasun, Korea; 3Department of Neurosurgery, Affiliated Hospital of Yanbian University, Yanji, Jilin 133000, People’s Republic of China; 4Biomedical Research Institute, Pusan National University Hospital, Pusan 602-739, Republic of KoreaCorrespondence: Shin JungDepartment of Neurosurgery, Chonnam National University Hwasun Hospital, 322, Seoyang-ro, Hwasun-eup, Hwasun-Gun, Jeollanam-do 519-763, Republic of KoreaTel +82-61-379-8588Fax +82-61-379-7181Email sjung@chonnam.ac.krBackground: Targeting radiosensitizer-incorporated nanoparticles to a tumor could allow for less normal tissue toxicity with more efficient drug release, thus improving the efficacy and safety of radiation treatment. The aim of this study was to improve tumor-specific delivery and bioavailability of a nanoparticle-mediated radiosensitizer in mouse brain tumor models.Methods: A pH-sensitive nanoparticle, chitoPEGAcHIS, was conjugated to recombinant peptide HVGGSSV that could bind to tax-interaction protein 1 (TIP-1) as a radiation-inducible receptor. Then the c-Jun N-terminal kinase (JNK) inhibitor, SP600125 was incorporated into this copolymer to fabricate a HVGGSSV-chitoPEGAcHIS-SP600125 (HVSP-NP) nanoradiosensitizer. In vitro and in vivo radiation treatment were performed using a Gamma Knife unit. The tumor targetability of HVSP-NP was estimated by optical bioluminescence. Synergistic therapeutic effects of radiation treatment and HVSP-NP were investigated in Lewis lung carcinoma (LLC) cell-bearing mouse brain tumor models.Results: The SP600125 JNK inhibitor effectively reduced DNA damage repair to irradiated LLC cells. A pH sensitivity assay indicated that HVSP-NP swelled at acidic pH and increased in diameter, and its release rate gradually increased. Optical bioluminescence assay showed that radiation induced TIP-1 expression in mouse brain tumor and that the nanoradiosensitizer selectively targeted irradiated tumors. Radiation treatment with HVSP-NP induced greater apoptosis and significantly inhibited tumor growth compared to radiation alone.Conclusion: As a novel nanoradiosensitizer, HVSP-NP was found to be able to selectively target irradiated tumors and significantly increase tumor growth delay in LLC-bearing mouse brain tumor models. This research shows that delivering a pH-sensitive nanoradiosensitizer to a brain tumor in which TIP-1 is induced by radiation can result in improved radiosensitizer-release in an acidic microenvironment of tumor tissue and in created synergistic effects in radiation treatment.Keywords: brain neoplasms, radiotherapy, TIP-1 receptor, nanoparticles, radiosensitizerLim SHLi CHJeong YIJang WYChoi JMJung SDove Medical Pressarticlecombination therapyradiotherapytip-1 receptornanoparticlesph-sensitiveMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 14, Pp 8861-8874 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	combination therapy radiotherapy tip-1 receptor nanoparticles ph-sensitive Medicine (General) R5-920
spellingShingle	combination therapy radiotherapy tip-1 receptor nanoparticles ph-sensitive Medicine (General) R5-920 Lim SH Li CH Jeong YI Jang WY Choi JM Jung S Enhancing Radiotherapeutic Effect With Nanoparticle-Mediated Radiosensitizer Delivery Guided By Focused Gamma Rays In Lewis Lung Carcinoma-Bearing Mouse Brain Tumor Models
description	Sa-Hoe Lim,1,2 Chun-Hao Li,3 Young-Il Jeong,4 Woo-Youl Jang,1,2 Jin-Myung Choi,2 Shin Jung1,2 1Department of Neurosurgery, Chonnam National University Medical School and Hwasun Hospital, Hwasun, Korea; 2Brain Tumor Research Laboratory, Chonnam National University Research Institute of Medical Sciences, Chonnam National University Hwasun Hospital, Hwasun, Korea; 3Department of Neurosurgery, Affiliated Hospital of Yanbian University, Yanji, Jilin 133000, People’s Republic of China; 4Biomedical Research Institute, Pusan National University Hospital, Pusan 602-739, Republic of KoreaCorrespondence: Shin JungDepartment of Neurosurgery, Chonnam National University Hwasun Hospital, 322, Seoyang-ro, Hwasun-eup, Hwasun-Gun, Jeollanam-do 519-763, Republic of KoreaTel +82-61-379-8588Fax +82-61-379-7181Email sjung@chonnam.ac.krBackground: Targeting radiosensitizer-incorporated nanoparticles to a tumor could allow for less normal tissue toxicity with more efficient drug release, thus improving the efficacy and safety of radiation treatment. The aim of this study was to improve tumor-specific delivery and bioavailability of a nanoparticle-mediated radiosensitizer in mouse brain tumor models.Methods: A pH-sensitive nanoparticle, chitoPEGAcHIS, was conjugated to recombinant peptide HVGGSSV that could bind to tax-interaction protein 1 (TIP-1) as a radiation-inducible receptor. Then the c-Jun N-terminal kinase (JNK) inhibitor, SP600125 was incorporated into this copolymer to fabricate a HVGGSSV-chitoPEGAcHIS-SP600125 (HVSP-NP) nanoradiosensitizer. In vitro and in vivo radiation treatment were performed using a Gamma Knife unit. The tumor targetability of HVSP-NP was estimated by optical bioluminescence. Synergistic therapeutic effects of radiation treatment and HVSP-NP were investigated in Lewis lung carcinoma (LLC) cell-bearing mouse brain tumor models.Results: The SP600125 JNK inhibitor effectively reduced DNA damage repair to irradiated LLC cells. A pH sensitivity assay indicated that HVSP-NP swelled at acidic pH and increased in diameter, and its release rate gradually increased. Optical bioluminescence assay showed that radiation induced TIP-1 expression in mouse brain tumor and that the nanoradiosensitizer selectively targeted irradiated tumors. Radiation treatment with HVSP-NP induced greater apoptosis and significantly inhibited tumor growth compared to radiation alone.Conclusion: As a novel nanoradiosensitizer, HVSP-NP was found to be able to selectively target irradiated tumors and significantly increase tumor growth delay in LLC-bearing mouse brain tumor models. This research shows that delivering a pH-sensitive nanoradiosensitizer to a brain tumor in which TIP-1 is induced by radiation can result in improved radiosensitizer-release in an acidic microenvironment of tumor tissue and in created synergistic effects in radiation treatment.Keywords: brain neoplasms, radiotherapy, TIP-1 receptor, nanoparticles, radiosensitizer
format	article
author	Lim SH Li CH Jeong YI Jang WY Choi JM Jung S
author_facet	Lim SH Li CH Jeong YI Jang WY Choi JM Jung S
author_sort	Lim SH
title	Enhancing Radiotherapeutic Effect With Nanoparticle-Mediated Radiosensitizer Delivery Guided By Focused Gamma Rays In Lewis Lung Carcinoma-Bearing Mouse Brain Tumor Models
title_short	Enhancing Radiotherapeutic Effect With Nanoparticle-Mediated Radiosensitizer Delivery Guided By Focused Gamma Rays In Lewis Lung Carcinoma-Bearing Mouse Brain Tumor Models
title_full	Enhancing Radiotherapeutic Effect With Nanoparticle-Mediated Radiosensitizer Delivery Guided By Focused Gamma Rays In Lewis Lung Carcinoma-Bearing Mouse Brain Tumor Models
title_fullStr	Enhancing Radiotherapeutic Effect With Nanoparticle-Mediated Radiosensitizer Delivery Guided By Focused Gamma Rays In Lewis Lung Carcinoma-Bearing Mouse Brain Tumor Models
title_full_unstemmed	Enhancing Radiotherapeutic Effect With Nanoparticle-Mediated Radiosensitizer Delivery Guided By Focused Gamma Rays In Lewis Lung Carcinoma-Bearing Mouse Brain Tumor Models
title_sort	enhancing radiotherapeutic effect with nanoparticle-mediated radiosensitizer delivery guided by focused gamma rays in lewis lung carcinoma-bearing mouse brain tumor models
publisher	Dove Medical Press
publishDate	2019
url	https://doaj.org/article/ea0c0d65a4704826b681cb797e973055
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Enhancing Radiotherapeutic Effect With Nanoparticle-Mediated Radiosensitizer Delivery Guided By Focused Gamma Rays In Lewis Lung Carcinoma-Bearing Mouse Brain Tumor Models

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