CXCL12/CXCR4 Axis-Targeted Dual-Functional Nano-Drug Delivery System Against Ovarian Cancer

Jiyang Xue1 ,* Ruixiang Li2 ,* Dingding Gao,2 Fenghua Chen,3 Hongjuan Xie1 1Department of Pharmacy, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204, People’s Republic of China; 2Innovation Research Institute of Traditional Chinese Medicin...

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Autores principales:	Xue J, Li R, Gao D, Chen F, Xie H
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2020
Materias:	amd3100 paclitaxel nanoparticle cxcl12/cxcr4 axis ovarian cancer Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/3298513a32ec4ace9a65bb7cd2881bc5
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spelling	oai:doaj.org-article:3298513a32ec4ace9a65bb7cd2881bc52021-12-02T12:24:17ZCXCL12/CXCR4 Axis-Targeted Dual-Functional Nano-Drug Delivery System Against Ovarian Cancer1178-2013https://doaj.org/article/3298513a32ec4ace9a65bb7cd2881bc52020-08-01T00:00:00Zhttps://www.dovepress.com/cxcl12cxcr4-axis-targeted-dual-functional-nano-drug-delivery-system-ag-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Jiyang Xue1 ,* Ruixiang Li2 ,* Dingding Gao,2 Fenghua Chen,3 Hongjuan Xie1 1Department of Pharmacy, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204, People’s Republic of China; 2Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, People’s Republic of China; 3Department of Ultrasonography, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jiyang Xue; Hongjuan XieDepartment of Pharmacy, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204, People’s Republic of ChinaTel +86-21-20261152Email xuejiyang7635@163.com; xiehongjuan@51mch.comIntroduction: Traditional chemotherapy for ovarian cancer is limited due to drug resistance and systemic side effects. Although various targeted drug delivery strategies have been designed to enhance drug accumulation at the tumor site, simply improvement of targeting capability has not consistently led to satisfactory outcomes. Herein, AMD3100 was selected as the targeting ligand because of its high affinity to chemokine receptor 4 (CXCR4), which was highly expressed on ovarian cancer cells. Moreover, the AMD3100 has been proved having blockage capability of stromal cell-derived factor 1 (SDF-1 or CXCL12)/CXCR4 axis and to be a sensitizer of chemotherapeutic therapy. We designed a dual-functional targeting delivery system by modifying paclitaxel (PTX)-loaded PEGylation bovine serum albumin (BSA) nanoparticles (NPs) with AMD3100 (AMD-NP-PTX), which can not only achieve specific tumor-targeting efficiency but also enhance the therapeutic outcomes.Methods: AMD3100 was chemically modified to Mal-PEG-NHS followed by reacting with BSA, then AMD-NP-PTX was synthesized and characterized. The targeting efficiency of AMD-NP was evaluated both in vitro and in vivo. The anticancer effect of AMD-NP-PTX was determined on Caov3 cells and ovarian cancer-bearing nude mice. Finally, the potential therapeutic mechanism was studied.Results: AMD-NP-PTX was synthesized successfully and well characterized. Cellular uptake assay and in vivo imaging experiments demonstrated that NPs could be internalized by Caov3 cells more efficiently after modification of AMD3100. Furthermore, the AMD-NP-PTX exhibited significantly enhanced inhibition effect on tumor growth and metastasis compared with PTX, NP-PTX and free AMD3100 plus NP-PTX both in vitro and in vivo, and demonstrated improved safety profile. We also confirmed that AMD-NP-PTX worked through targeting CXCL12/CXCR4 axis, thereby disturbing its downstream signaling pathways including epithelial–mesenchymal transition (EMT) processes and nuclear factor κB (NF-κB) pathway.Conclusion: The AMD-NP-PTX we designed would open a new avenue for dual-functional NPs in ovarian cancer therapy.Keywords: AMD3100, paclitaxel, nanoparticle, CXCL12/CXCR4 axis, ovarian cancerXue JLi RGao DChen FXie HDove Medical Pressarticleamd3100paclitaxelnanoparticlecxcl12/cxcr4 axisovarian cancerMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 15, Pp 5701-5718 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	amd3100 paclitaxel nanoparticle cxcl12/cxcr4 axis ovarian cancer Medicine (General) R5-920
spellingShingle	amd3100 paclitaxel nanoparticle cxcl12/cxcr4 axis ovarian cancer Medicine (General) R5-920 Xue J Li R Gao D Chen F Xie H CXCL12/CXCR4 Axis-Targeted Dual-Functional Nano-Drug Delivery System Against Ovarian Cancer
description	Jiyang Xue1 ,* Ruixiang Li2 ,* Dingding Gao,2 Fenghua Chen,3 Hongjuan Xie1 1Department of Pharmacy, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204, People’s Republic of China; 2Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, People’s Republic of China; 3Department of Ultrasonography, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jiyang Xue; Hongjuan XieDepartment of Pharmacy, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204, People’s Republic of ChinaTel +86-21-20261152Email xuejiyang7635@163.com; xiehongjuan@51mch.comIntroduction: Traditional chemotherapy for ovarian cancer is limited due to drug resistance and systemic side effects. Although various targeted drug delivery strategies have been designed to enhance drug accumulation at the tumor site, simply improvement of targeting capability has not consistently led to satisfactory outcomes. Herein, AMD3100 was selected as the targeting ligand because of its high affinity to chemokine receptor 4 (CXCR4), which was highly expressed on ovarian cancer cells. Moreover, the AMD3100 has been proved having blockage capability of stromal cell-derived factor 1 (SDF-1 or CXCL12)/CXCR4 axis and to be a sensitizer of chemotherapeutic therapy. We designed a dual-functional targeting delivery system by modifying paclitaxel (PTX)-loaded PEGylation bovine serum albumin (BSA) nanoparticles (NPs) with AMD3100 (AMD-NP-PTX), which can not only achieve specific tumor-targeting efficiency but also enhance the therapeutic outcomes.Methods: AMD3100 was chemically modified to Mal-PEG-NHS followed by reacting with BSA, then AMD-NP-PTX was synthesized and characterized. The targeting efficiency of AMD-NP was evaluated both in vitro and in vivo. The anticancer effect of AMD-NP-PTX was determined on Caov3 cells and ovarian cancer-bearing nude mice. Finally, the potential therapeutic mechanism was studied.Results: AMD-NP-PTX was synthesized successfully and well characterized. Cellular uptake assay and in vivo imaging experiments demonstrated that NPs could be internalized by Caov3 cells more efficiently after modification of AMD3100. Furthermore, the AMD-NP-PTX exhibited significantly enhanced inhibition effect on tumor growth and metastasis compared with PTX, NP-PTX and free AMD3100 plus NP-PTX both in vitro and in vivo, and demonstrated improved safety profile. We also confirmed that AMD-NP-PTX worked through targeting CXCL12/CXCR4 axis, thereby disturbing its downstream signaling pathways including epithelial–mesenchymal transition (EMT) processes and nuclear factor κB (NF-κB) pathway.Conclusion: The AMD-NP-PTX we designed would open a new avenue for dual-functional NPs in ovarian cancer therapy.Keywords: AMD3100, paclitaxel, nanoparticle, CXCL12/CXCR4 axis, ovarian cancer
format	article
author	Xue J Li R Gao D Chen F Xie H
author_facet	Xue J Li R Gao D Chen F Xie H
author_sort	Xue J
title	CXCL12/CXCR4 Axis-Targeted Dual-Functional Nano-Drug Delivery System Against Ovarian Cancer
title_short	CXCL12/CXCR4 Axis-Targeted Dual-Functional Nano-Drug Delivery System Against Ovarian Cancer
title_full	CXCL12/CXCR4 Axis-Targeted Dual-Functional Nano-Drug Delivery System Against Ovarian Cancer
title_fullStr	CXCL12/CXCR4 Axis-Targeted Dual-Functional Nano-Drug Delivery System Against Ovarian Cancer
title_full_unstemmed	CXCL12/CXCR4 Axis-Targeted Dual-Functional Nano-Drug Delivery System Against Ovarian Cancer
title_sort	cxcl12/cxcr4 axis-targeted dual-functional nano-drug delivery system against ovarian cancer
publisher	Dove Medical Press
publishDate	2020
url	https://doaj.org/article/3298513a32ec4ace9a65bb7cd2881bc5
work_keys_str_mv	AT xuej cxcl12cxcr4axistargeteddualfunctionalnanodrugdeliverysystemagainstovariancancer AT lir cxcl12cxcr4axistargeteddualfunctionalnanodrugdeliverysystemagainstovariancancer AT gaod cxcl12cxcr4axistargeteddualfunctionalnanodrugdeliverysystemagainstovariancancer AT chenf cxcl12cxcr4axistargeteddualfunctionalnanodrugdeliverysystemagainstovariancancer AT xieh cxcl12cxcr4axistargeteddualfunctionalnanodrugdeliverysystemagainstovariancancer
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CXCL12/CXCR4 Axis-Targeted Dual-Functional Nano-Drug Delivery System Against Ovarian Cancer

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