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Engineered Microparticles for Treatment of Murine Brain Metastasis by Reprograming Tumor Microenvironment and Inhibiting MAPK Pathway

Brain metastases (BRM) are common in advanced lung cancer. However, their treatment is challenging due to the blood‐brain barrier (BBB) and the immunosuppressive tumor microenvironment (ITME). Microparticles (MPs), a type of extracellular vesicle, can serve as biocompatible drug delivery vehicles th...

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Autores principales: Lu, Lisen, Zi, Huaduan, Zhou, Jie, Huang, Jing, Deng, Zihan, Tang, Zijian, Li, Li, Shi, Xiujuan, Lo, Pui‐Chi, Lovell, Jonathan F., Deng, Deqiang, Wan, Chao, Jin, Honglin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10015898/
https://www.ncbi.nlm.nih.gov/pubmed/36698296
http://dx.doi.org/10.1002/advs.202206212
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author Lu, Lisen
Zi, Huaduan
Zhou, Jie
Huang, Jing
Deng, Zihan
Tang, Zijian
Li, Li
Shi, Xiujuan
Lo, Pui‐Chi
Lovell, Jonathan F.
Deng, Deqiang
Wan, Chao
Jin, Honglin
author_facet Lu, Lisen
Zi, Huaduan
Zhou, Jie
Huang, Jing
Deng, Zihan
Tang, Zijian
Li, Li
Shi, Xiujuan
Lo, Pui‐Chi
Lovell, Jonathan F.
Deng, Deqiang
Wan, Chao
Jin, Honglin
author_sort Lu, Lisen
collection PubMed
description Brain metastases (BRM) are common in advanced lung cancer. However, their treatment is challenging due to the blood‐brain barrier (BBB) and the immunosuppressive tumor microenvironment (ITME). Microparticles (MPs), a type of extracellular vesicle, can serve as biocompatible drug delivery vehicles that can be further modulated with genetic engineering techniques. MPs prepared from cells induced with different insults are compared and it is found that radiation‐treated cell‐released microparticles (RMPs) achieve optimal targeting and macrophage activation. The enzyme ubiquitin‐specific protease 7 (USP7), which simultaneously regulates tumor growth and reprograms M2 macrophages (M2Φ), is found to be expressed in BRM. Engineered RMPs are then constructed that comprise: 1) the RMP carrier that targets and reprograms M2Φ; 2) a genetically expressed SR‐B1‐targeting peptide for improved BBB permeability; and 3) a USP7 inhibitor to kill tumor cells and reprogram M2Φ. These RMPs successfully cross the BBB and target M2Φ in vitro and in vivo in mice, effectively reprogramming M2Φ and improving survival in a murine BRM model. Therapeutic effects are further augmented when combined with immune checkpoint blockade. This study provides proof‐of‐concept for the use of genetically engineered MPs for the treatment of BRM.
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spelling pubmed-100158982023-03-16 Engineered Microparticles for Treatment of Murine Brain Metastasis by Reprograming Tumor Microenvironment and Inhibiting MAPK Pathway Lu, Lisen Zi, Huaduan Zhou, Jie Huang, Jing Deng, Zihan Tang, Zijian Li, Li Shi, Xiujuan Lo, Pui‐Chi Lovell, Jonathan F. Deng, Deqiang Wan, Chao Jin, Honglin Adv Sci (Weinh) Research Articles Brain metastases (BRM) are common in advanced lung cancer. However, their treatment is challenging due to the blood‐brain barrier (BBB) and the immunosuppressive tumor microenvironment (ITME). Microparticles (MPs), a type of extracellular vesicle, can serve as biocompatible drug delivery vehicles that can be further modulated with genetic engineering techniques. MPs prepared from cells induced with different insults are compared and it is found that radiation‐treated cell‐released microparticles (RMPs) achieve optimal targeting and macrophage activation. The enzyme ubiquitin‐specific protease 7 (USP7), which simultaneously regulates tumor growth and reprograms M2 macrophages (M2Φ), is found to be expressed in BRM. Engineered RMPs are then constructed that comprise: 1) the RMP carrier that targets and reprograms M2Φ; 2) a genetically expressed SR‐B1‐targeting peptide for improved BBB permeability; and 3) a USP7 inhibitor to kill tumor cells and reprogram M2Φ. These RMPs successfully cross the BBB and target M2Φ in vitro and in vivo in mice, effectively reprogramming M2Φ and improving survival in a murine BRM model. Therapeutic effects are further augmented when combined with immune checkpoint blockade. This study provides proof‐of‐concept for the use of genetically engineered MPs for the treatment of BRM. John Wiley and Sons Inc. 2023-01-25 /pmc/articles/PMC10015898/ /pubmed/36698296 http://dx.doi.org/10.1002/advs.202206212 Text en © 2023 The Authors. Advanced Science published by Wiley‐VCH GmbH https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Lu, Lisen
Zi, Huaduan
Zhou, Jie
Huang, Jing
Deng, Zihan
Tang, Zijian
Li, Li
Shi, Xiujuan
Lo, Pui‐Chi
Lovell, Jonathan F.
Deng, Deqiang
Wan, Chao
Jin, Honglin
Engineered Microparticles for Treatment of Murine Brain Metastasis by Reprograming Tumor Microenvironment and Inhibiting MAPK Pathway
title Engineered Microparticles for Treatment of Murine Brain Metastasis by Reprograming Tumor Microenvironment and Inhibiting MAPK Pathway
title_full Engineered Microparticles for Treatment of Murine Brain Metastasis by Reprograming Tumor Microenvironment and Inhibiting MAPK Pathway
title_fullStr Engineered Microparticles for Treatment of Murine Brain Metastasis by Reprograming Tumor Microenvironment and Inhibiting MAPK Pathway
title_full_unstemmed Engineered Microparticles for Treatment of Murine Brain Metastasis by Reprograming Tumor Microenvironment and Inhibiting MAPK Pathway
title_short Engineered Microparticles for Treatment of Murine Brain Metastasis by Reprograming Tumor Microenvironment and Inhibiting MAPK Pathway
title_sort engineered microparticles for treatment of murine brain metastasis by reprograming tumor microenvironment and inhibiting mapk pathway
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10015898/
https://www.ncbi.nlm.nih.gov/pubmed/36698296
http://dx.doi.org/10.1002/advs.202206212
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