Gene Therapy for Drug-Resistant Glioblastoma via Lipid-Polymer Hybrid Nanoparticles Combined with Focused Ultrasound

Qiang Yang,1 Yanghao Zhou,1 Jin Chen,1 Ning Huang,1 Zhigang Wang,2 Yuan Cheng1 1Department of Neurosurgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, People’s Republic of China; 2Institute of Ultrasound Imaging, The Second Affiliated Hospital of Chon...

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Autores principales:	Yang Q, Zhou Y, Chen J, Huang N, Wang Z, Cheng Y
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2021
Materias:	crispr/cas9 lphns fus microbubbles glioblastoma Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/307941c7896b4752b1bc282157e0ecc8
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spelling	oai:doaj.org-article:307941c7896b4752b1bc282157e0ecc82021-12-02T13:35:41ZGene Therapy for Drug-Resistant Glioblastoma via Lipid-Polymer Hybrid Nanoparticles Combined with Focused Ultrasound1178-2013https://doaj.org/article/307941c7896b4752b1bc282157e0ecc82021-01-01T00:00:00Zhttps://www.dovepress.com/gene-therapy-for-drug-resistant-glioblastoma-via-lipid-polymer-hybrid--peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Qiang Yang,1 Yanghao Zhou,1 Jin Chen,1 Ning Huang,1 Zhigang Wang,2 Yuan Cheng1 1Department of Neurosurgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, People’s Republic of China; 2Institute of Ultrasound Imaging, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, People’s Republic of ChinaCorrespondence: Yuan ChengDepartment of Neurosurgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, People’s Republic of ChinaTel +86 023 63693540Email chengyuan@hospital.cqmu.edu.cnBackground: Therapy for glioblastoma (GBM) has always been very challenging, not only because of the presence of the blood-brain barrier (BBB) but also due to susceptibility to drug resistance. Recently, the clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (CRISPR/Cas9) has revolutionized gene editing technology and is capable of treating a variety of genetic diseases, including human tumors, but there is a lack of safe and effective targeting delivery systems in vivo, especially in the central nervous system (CNS).Methods: Lipid-polymer hybrid nanoparticles (LPHNs-cRGD) were constructed for efficient and targeting delivery of CRISPR/Cas9 plasmids targeting O6-methylguanine-DNA methyltransferase (MGMT), a drug-resistance gene to temozolomide (TMZ). Focused ultrasound (FUS)-microbubbles (MBs) were used to non-invasively and locally open the BBB to further facilitate gene delivery into glioblastoma in vivo. The gene editing efficiency and drug sensitivity changes were evaluated both in vitro and in vivo.Results: The gene-loaded LPHNs-cRGD were successfully synthesized and could protect pCas9/MGMT from enzyme degradation. LPHNs-cRGD could target GBM cells and mediate the transfection of pCas9/MGMT to downregulate the expression of MGMT, resulting in an increased sensitivity of GBM cells to TMZ. MBs-LPHNs-cRGD complexes could safely and locally increase the permeability of the BBB with FUS irradiation in vivo and facilitated the accumulation of nanoparticles at the tumor region in orthotopic tumor-bearing mice. Furthermore, the FUS-assisted MBs-LPHNspCas9/MGMT-cRGD enhanced the therapeutic effects of TMZ in glioblastoma, inhibited tumor growth, and prolonged survival of tumor-bearing mice, with a high level of biosafety.Conclusion: In this work, we constructed LPHNs-cRGD for targeting delivery of the CRISPR/Cas9 system, in combination with FUS-MBs to open the BBB. The MBs-LPHNs-cRGD delivery system could be a potential alternative for efficient targeting gene delivery for the treatment of glioblastoma.Keywords: CRISPR/Cas9, LPHNs, FUS, microbubbles, glioblastomaYang QZhou YChen JHuang NWang ZCheng YDove Medical Pressarticlecrispr/cas9lphnsfusmicrobubblesglioblastomaMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 16, Pp 185-199 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	crispr/cas9 lphns fus microbubbles glioblastoma Medicine (General) R5-920
spellingShingle	crispr/cas9 lphns fus microbubbles glioblastoma Medicine (General) R5-920 Yang Q Zhou Y Chen J Huang N Wang Z Cheng Y Gene Therapy for Drug-Resistant Glioblastoma via Lipid-Polymer Hybrid Nanoparticles Combined with Focused Ultrasound
description	Qiang Yang,1 Yanghao Zhou,1 Jin Chen,1 Ning Huang,1 Zhigang Wang,2 Yuan Cheng1 1Department of Neurosurgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, People’s Republic of China; 2Institute of Ultrasound Imaging, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, People’s Republic of ChinaCorrespondence: Yuan ChengDepartment of Neurosurgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, People’s Republic of ChinaTel +86 023 63693540Email chengyuan@hospital.cqmu.edu.cnBackground: Therapy for glioblastoma (GBM) has always been very challenging, not only because of the presence of the blood-brain barrier (BBB) but also due to susceptibility to drug resistance. Recently, the clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (CRISPR/Cas9) has revolutionized gene editing technology and is capable of treating a variety of genetic diseases, including human tumors, but there is a lack of safe and effective targeting delivery systems in vivo, especially in the central nervous system (CNS).Methods: Lipid-polymer hybrid nanoparticles (LPHNs-cRGD) were constructed for efficient and targeting delivery of CRISPR/Cas9 plasmids targeting O6-methylguanine-DNA methyltransferase (MGMT), a drug-resistance gene to temozolomide (TMZ). Focused ultrasound (FUS)-microbubbles (MBs) were used to non-invasively and locally open the BBB to further facilitate gene delivery into glioblastoma in vivo. The gene editing efficiency and drug sensitivity changes were evaluated both in vitro and in vivo.Results: The gene-loaded LPHNs-cRGD were successfully synthesized and could protect pCas9/MGMT from enzyme degradation. LPHNs-cRGD could target GBM cells and mediate the transfection of pCas9/MGMT to downregulate the expression of MGMT, resulting in an increased sensitivity of GBM cells to TMZ. MBs-LPHNs-cRGD complexes could safely and locally increase the permeability of the BBB with FUS irradiation in vivo and facilitated the accumulation of nanoparticles at the tumor region in orthotopic tumor-bearing mice. Furthermore, the FUS-assisted MBs-LPHNspCas9/MGMT-cRGD enhanced the therapeutic effects of TMZ in glioblastoma, inhibited tumor growth, and prolonged survival of tumor-bearing mice, with a high level of biosafety.Conclusion: In this work, we constructed LPHNs-cRGD for targeting delivery of the CRISPR/Cas9 system, in combination with FUS-MBs to open the BBB. The MBs-LPHNs-cRGD delivery system could be a potential alternative for efficient targeting gene delivery for the treatment of glioblastoma.Keywords: CRISPR/Cas9, LPHNs, FUS, microbubbles, glioblastoma
format	article
author	Yang Q Zhou Y Chen J Huang N Wang Z Cheng Y
author_facet	Yang Q Zhou Y Chen J Huang N Wang Z Cheng Y
author_sort	Yang Q
title	Gene Therapy for Drug-Resistant Glioblastoma via Lipid-Polymer Hybrid Nanoparticles Combined with Focused Ultrasound
title_short	Gene Therapy for Drug-Resistant Glioblastoma via Lipid-Polymer Hybrid Nanoparticles Combined with Focused Ultrasound
title_full	Gene Therapy for Drug-Resistant Glioblastoma via Lipid-Polymer Hybrid Nanoparticles Combined with Focused Ultrasound
title_fullStr	Gene Therapy for Drug-Resistant Glioblastoma via Lipid-Polymer Hybrid Nanoparticles Combined with Focused Ultrasound
title_full_unstemmed	Gene Therapy for Drug-Resistant Glioblastoma via Lipid-Polymer Hybrid Nanoparticles Combined with Focused Ultrasound
title_sort	gene therapy for drug-resistant glioblastoma via lipid-polymer hybrid nanoparticles combined with focused ultrasound
publisher	Dove Medical Press
publishDate	2021
url	https://doaj.org/article/307941c7896b4752b1bc282157e0ecc8
work_keys_str_mv	AT yangq genetherapyfordrugresistantglioblastomavialipidpolymerhybridnanoparticlescombinedwithfocusedultrasound AT zhouy genetherapyfordrugresistantglioblastomavialipidpolymerhybridnanoparticlescombinedwithfocusedultrasound AT chenj genetherapyfordrugresistantglioblastomavialipidpolymerhybridnanoparticlescombinedwithfocusedultrasound AT huangn genetherapyfordrugresistantglioblastomavialipidpolymerhybridnanoparticlescombinedwithfocusedultrasound AT wangz genetherapyfordrugresistantglioblastomavialipidpolymerhybridnanoparticlescombinedwithfocusedultrasound AT chengy genetherapyfordrugresistantglioblastomavialipidpolymerhybridnanoparticlescombinedwithfocusedultrasound
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Gene Therapy for Drug-Resistant Glioblastoma via Lipid-Polymer Hybrid Nanoparticles Combined with Focused Ultrasound

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