A Dual Receptor Targeting- and BBB Penetrating- Peptide Functionalized Polyethyleneimine Nanocomplex for Secretory Endostatin Gene Delivery to Malignant Glioma

Lu Lu,1 Hongyuan Chen,2 Longkun Wang,1 Lin Zhao,3 Yanna Cheng,3 Aijun Wang,4 Fengshan Wang,1 Xinke Zhang3 1Key Laboratory of Chemical Biology (Ministry of Education), Institute of Biochemical and Biotechnological Drug, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong Universi...

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Autores principales:	Lu L, Chen H, Wang L, Zhao L, Cheng Y, Wang A, Wang F, Zhang X
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2020
Materias:	vegfr-2 and nrp-1 receptor targeting glioma penetration multifunctional peptide anti-angiogenesis gene delivery system Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/04bb6da301634f7b91909f24d9dfa919
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id	oai:doaj.org-article:04bb6da301634f7b91909f24d9dfa919
record_format	dspace
institution	DOAJ
collection	DOAJ
language	EN
topic	vegfr-2 and nrp-1 receptor targeting glioma penetration multifunctional peptide anti-angiogenesis gene delivery system Medicine (General) R5-920
spellingShingle	vegfr-2 and nrp-1 receptor targeting glioma penetration multifunctional peptide anti-angiogenesis gene delivery system Medicine (General) R5-920 Lu L Chen H Wang L Zhao L Cheng Y Wang A Wang F Zhang X A Dual Receptor Targeting- and BBB Penetrating- Peptide Functionalized Polyethyleneimine Nanocomplex for Secretory Endostatin Gene Delivery to Malignant Glioma
description	Lu Lu,1 Hongyuan Chen,2 Longkun Wang,1 Lin Zhao,3 Yanna Cheng,3 Aijun Wang,4 Fengshan Wang,1 Xinke Zhang3 1Key Laboratory of Chemical Biology (Ministry of Education), Institute of Biochemical and Biotechnological Drug, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China; 2Department of General Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China; 3Key Laboratory of Chemical Biology (Ministry of Education), Department of Pharmacology, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China; 4Surgical Bioengineering Laboratory, Department of Surgery, UC Davis Health Medical Center, Sacramento, CA, USACorrespondence: Fengshan Wang; Xinke ZhangSchool of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, No. 44 Wenhuaxi Road, Jinan 250012, People’s Republic of ChinaTel/Fax +86 531 88382490Email fswang@sdu.edu.cn; zhangxinke@sdu.edu.cnPurpose: Vascular endothelial growth factor receptor 2 (VEGFR-2) and neuropilin-1 (NRP-1) are two prominent synergistic receptors overexpressed on new blood vessels in glioma and may be promising targets for antiglioma therapy. The aim of this study was to design a dual receptor targeting and blood-brain barrier (BBB) penetrating peptide-modified polyethyleneimine (PEI) nanocomplex that can efficiently deliver the angiogenesis-inhibiting secretory endostatin gene (pVAXI-En) to treat glioma.Materials and Methods: We first constructed the tandem peptide TAT-AT7 by conjugating AT7 to TAT and evaluated its binding affinity to VEGFR-2 and NRP-1, vasculature-targeting ability and BBB crossing capacity. Then, TAT-AT7-modified PEI polymer (PPTA) was synthesized, and a pVAXI-En-loaded PPTA nanocomplex (PPTA/pVAXI-En) was prepared. The physicochemical properties, cytotoxicity, transfection efficiency, capacities to cross the BBB and BTB (blood-tumor barrier) and glioma-targeting properties of PPTA/pVAXI-En were investigated. Moreover, the in vivo anti-angiogenic behaviors and anti-glioma effects of PPTA/pVAXI-En were evaluated in nude mice.Results: The binding affinity of TAT-AT7 to VEGFR-2 and NRP-1 was approximately 3 to 10 times greater than that of AT7 or TAT. The cellular uptake of TAT-AT7 in endothelial cells was 5-fold and 119-fold greater than that of TAT and AT7 alone, respectively. TAT-AT7 also displayed remarkable efficiency in penetrating the BBB and glioma tissue in vivo. PPTA/pVAXI-En exhibited lower cytotoxicity, stronger BBB and BTB traversing abilities, higher selective glioma targeting and better gene transfection efficiency than PEI/pVAXI-En. More importantly, PPTA/pVAXI-En significantly suppressed the tube formation and migration of endothelial cells, inhibited glioma growth, and reduced the microvasculature in orthotopic U87 glioma-bearing nude mice.Conclusion: Our study demonstrates that PPTA/pVAXI-En can be exploited as an efficient dual-targeting nanocomplex to cross the BBB and BTB, and hence it represents a feasible and promising nonviral gene delivery system for effective glioma therapy.Keywords: VEGFR-2 and NRP-1 targeting, glioma penetration, multifunctional peptide, anti-angiogenesis, gene delivery system
format	article
author	Lu L Chen H Wang L Zhao L Cheng Y Wang A Wang F Zhang X
author_facet	Lu L Chen H Wang L Zhao L Cheng Y Wang A Wang F Zhang X
author_sort	Lu L
title	A Dual Receptor Targeting- and BBB Penetrating- Peptide Functionalized Polyethyleneimine Nanocomplex for Secretory Endostatin Gene Delivery to Malignant Glioma
title_short	A Dual Receptor Targeting- and BBB Penetrating- Peptide Functionalized Polyethyleneimine Nanocomplex for Secretory Endostatin Gene Delivery to Malignant Glioma
title_full	A Dual Receptor Targeting- and BBB Penetrating- Peptide Functionalized Polyethyleneimine Nanocomplex for Secretory Endostatin Gene Delivery to Malignant Glioma
title_fullStr	A Dual Receptor Targeting- and BBB Penetrating- Peptide Functionalized Polyethyleneimine Nanocomplex for Secretory Endostatin Gene Delivery to Malignant Glioma
title_full_unstemmed	A Dual Receptor Targeting- and BBB Penetrating- Peptide Functionalized Polyethyleneimine Nanocomplex for Secretory Endostatin Gene Delivery to Malignant Glioma
title_sort	dual receptor targeting- and bbb penetrating- peptide functionalized polyethyleneimine nanocomplex for secretory endostatin gene delivery to malignant glioma
publisher	Dove Medical Press
publishDate	2020
url	https://doaj.org/article/04bb6da301634f7b91909f24d9dfa919
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spelling	oai:doaj.org-article:04bb6da301634f7b91909f24d9dfa9192021-12-02T14:58:29ZA Dual Receptor Targeting- and BBB Penetrating- Peptide Functionalized Polyethyleneimine Nanocomplex for Secretory Endostatin Gene Delivery to Malignant Glioma1178-2013https://doaj.org/article/04bb6da301634f7b91909f24d9dfa9192020-11-01T00:00:00Zhttps://www.dovepress.com/a-dual-receptor-targeting--and-bbb-penetrating--peptide-functionalized-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Lu Lu,1 Hongyuan Chen,2 Longkun Wang,1 Lin Zhao,3 Yanna Cheng,3 Aijun Wang,4 Fengshan Wang,1 Xinke Zhang3 1Key Laboratory of Chemical Biology (Ministry of Education), Institute of Biochemical and Biotechnological Drug, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China; 2Department of General Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China; 3Key Laboratory of Chemical Biology (Ministry of Education), Department of Pharmacology, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China; 4Surgical Bioengineering Laboratory, Department of Surgery, UC Davis Health Medical Center, Sacramento, CA, USACorrespondence: Fengshan Wang; Xinke ZhangSchool of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, No. 44 Wenhuaxi Road, Jinan 250012, People’s Republic of ChinaTel/Fax +86 531 88382490Email fswang@sdu.edu.cn; zhangxinke@sdu.edu.cnPurpose: Vascular endothelial growth factor receptor 2 (VEGFR-2) and neuropilin-1 (NRP-1) are two prominent synergistic receptors overexpressed on new blood vessels in glioma and may be promising targets for antiglioma therapy. The aim of this study was to design a dual receptor targeting and blood-brain barrier (BBB) penetrating peptide-modified polyethyleneimine (PEI) nanocomplex that can efficiently deliver the angiogenesis-inhibiting secretory endostatin gene (pVAXI-En) to treat glioma.Materials and Methods: We first constructed the tandem peptide TAT-AT7 by conjugating AT7 to TAT and evaluated its binding affinity to VEGFR-2 and NRP-1, vasculature-targeting ability and BBB crossing capacity. Then, TAT-AT7-modified PEI polymer (PPTA) was synthesized, and a pVAXI-En-loaded PPTA nanocomplex (PPTA/pVAXI-En) was prepared. The physicochemical properties, cytotoxicity, transfection efficiency, capacities to cross the BBB and BTB (blood-tumor barrier) and glioma-targeting properties of PPTA/pVAXI-En were investigated. Moreover, the in vivo anti-angiogenic behaviors and anti-glioma effects of PPTA/pVAXI-En were evaluated in nude mice.Results: The binding affinity of TAT-AT7 to VEGFR-2 and NRP-1 was approximately 3 to 10 times greater than that of AT7 or TAT. The cellular uptake of TAT-AT7 in endothelial cells was 5-fold and 119-fold greater than that of TAT and AT7 alone, respectively. TAT-AT7 also displayed remarkable efficiency in penetrating the BBB and glioma tissue in vivo. PPTA/pVAXI-En exhibited lower cytotoxicity, stronger BBB and BTB traversing abilities, higher selective glioma targeting and better gene transfection efficiency than PEI/pVAXI-En. More importantly, PPTA/pVAXI-En significantly suppressed the tube formation and migration of endothelial cells, inhibited glioma growth, and reduced the microvasculature in orthotopic U87 glioma-bearing nude mice.Conclusion: Our study demonstrates that PPTA/pVAXI-En can be exploited as an efficient dual-targeting nanocomplex to cross the BBB and BTB, and hence it represents a feasible and promising nonviral gene delivery system for effective glioma therapy.Keywords: VEGFR-2 and NRP-1 targeting, glioma penetration, multifunctional peptide, anti-angiogenesis, gene delivery systemLu LChen HWang LZhao LCheng YWang AWang FZhang XDove Medical Pressarticlevegfr-2 and nrp-1 receptor targetingglioma penetrationmultifunctional peptideanti-angiogenesisgene delivery systemMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 15, Pp 8875-8892 (2020)

A Dual Receptor Targeting- and BBB Penetrating- Peptide Functionalized Polyethyleneimine Nanocomplex for Secretory Endostatin Gene Delivery to Malignant Glioma

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