Integration of Dual Targeting and Dual Therapeutic Modules Endows Self-Assembled Nanoparticles with Anti-Tumor Growth and Metastasis Functions

Biao Chen,1 Xiaoqi Dong,2 Xiyuan Dong,1 Quan Wang,2 Meng Wu,1 Jun Wu,2 Xiaoding Lou,2 Fan Xia,2 Wenwen Wang,1 Jun Dai,1 Shixuan Wang1 1Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Re...

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Autores principales:	Chen B, Dong X, Wang Q, Wu M, Wu J, Lou X, Xia F, Wang W, Dai J, Wang S
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2021
Materias:	modular peptide nanofiber anti-tumor anti-metastasis transcriptome sequencing Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/99523b1bc22f43b4a627926029393907
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spelling	oai:doaj.org-article:99523b1bc22f43b4a6279260293939072021-12-02T14:18:12ZIntegration of Dual Targeting and Dual Therapeutic Modules Endows Self-Assembled Nanoparticles with Anti-Tumor Growth and Metastasis Functions1178-2013https://doaj.org/article/99523b1bc22f43b4a6279260293939072021-02-01T00:00:00Zhttps://www.dovepress.com/integration-of-dual-targeting-and-dual-therapeutic-modules-endows-self-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Biao Chen,1 Xiaoqi Dong,2 Xiyuan Dong,1 Quan Wang,2 Meng Wu,1 Jun Wu,2 Xiaoding Lou,2 Fan Xia,2 Wenwen Wang,1 Jun Dai,1 Shixuan Wang1 1Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China; 2Engineering Research Center of Nano-Geomaterials of the Ministry of Education, Faculty of Materials Science and Chemistry, China University of Geosciences, Wuhan, 430074, People’s Republic of ChinaCorrespondence: Wenwen Wang; Jun Dai 1095 Jiefang Avenue, Wuhan, Hubei, People’s Republic of ChinaTel +86-0276868907; +86-0276868907Email petrawang@163.com; dj_hust1987@sina.comObject: High targeting and efficient cytotoxicity toward tumor cells endow NPs excellent anti-tumor activity. Herein, a peptide polymer possessing dual-targeting ability and double therapeutic activity was developed and named TGMF, which can form NPs through self-assembly. It is composed of four functional modules: 1) Active targeting peptide TMTP1 (T) deliver NPs to tumors specifically; 2) Therapeutic peptide GO-203 (G), which can significantly inhibit tumor growth by disrupting the redox balance in cells; 3) A passively targeted enzyme-responsive peptide PLGLGA (M), which can be cleaved specifically by metalloproteinase-2 (MMP-2) highly expressed in the tumor microenvironment (TME); and 4) Hexadecyl (F), which has strong hydrophobicity, can promote the self-assembly of TGMF NPs.Methods: Five modular peptide probes, namely, TGF, TMF, TGM, GMF, and TGMF were synthesized and self-assembled into NPs in solution. The characterization, enzyme reactivity, and cytotoxicity of NPs were evaluated in vitro, and the pharmacokinetics, bio-distribution, anti-tumor activity of NPs were investigated in vivo. In addition, transcriptome sequencing identified the intracellular signaling pathway-related genes involved in the anti-tumor effect of TGMF.Results: Upon enzyme cleavage, two types of nanostructure, NPs and nanofibers (NFs), were detected under TEM. Moreover, the cytotoxicity and anti-invasion activity of TGMF against tumor cells used were strongest among the five modular probes examined in vitro. TGMF increased reactive oxygen species (ROS) levels in cytoplasm and produced numerous NFs in extracellular interval and intracellular space. Transcriptome sequencing revealed that TGMF caused 446 genes’ down-regulation and 270 genes’ up-regulation in HeLa cells. In vivo, TGMF has a good anti-tumor effect, effectively prolonging the survival time of HeLa-tumor-bearing mice without systemic side effects.Conclusion: Integration of multiple functional modules into NPs could be a promising strategy for the future of nanomedicine design towards tumor treatment.Keywords: modular peptide, nanofiber, anti-tumor, anti-metastasis, transcriptome sequencingChen BDong XDong XWang QWu MWu JLou XXia FWang WDai JWang SDove Medical Pressarticlemodular peptidenanofiberanti-tumoranti-metastasistranscriptome sequencingMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 16, Pp 1361-1376 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	modular peptide nanofiber anti-tumor anti-metastasis transcriptome sequencing Medicine (General) R5-920
spellingShingle	modular peptide nanofiber anti-tumor anti-metastasis transcriptome sequencing Medicine (General) R5-920 Chen B Dong X Dong X Wang Q Wu M Wu J Lou X Xia F Wang W Dai J Wang S Integration of Dual Targeting and Dual Therapeutic Modules Endows Self-Assembled Nanoparticles with Anti-Tumor Growth and Metastasis Functions
description	Biao Chen,1 Xiaoqi Dong,2 Xiyuan Dong,1 Quan Wang,2 Meng Wu,1 Jun Wu,2 Xiaoding Lou,2 Fan Xia,2 Wenwen Wang,1 Jun Dai,1 Shixuan Wang1 1Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China; 2Engineering Research Center of Nano-Geomaterials of the Ministry of Education, Faculty of Materials Science and Chemistry, China University of Geosciences, Wuhan, 430074, People’s Republic of ChinaCorrespondence: Wenwen Wang; Jun Dai 1095 Jiefang Avenue, Wuhan, Hubei, People’s Republic of ChinaTel +86-0276868907; +86-0276868907Email petrawang@163.com; dj_hust1987@sina.comObject: High targeting and efficient cytotoxicity toward tumor cells endow NPs excellent anti-tumor activity. Herein, a peptide polymer possessing dual-targeting ability and double therapeutic activity was developed and named TGMF, which can form NPs through self-assembly. It is composed of four functional modules: 1) Active targeting peptide TMTP1 (T) deliver NPs to tumors specifically; 2) Therapeutic peptide GO-203 (G), which can significantly inhibit tumor growth by disrupting the redox balance in cells; 3) A passively targeted enzyme-responsive peptide PLGLGA (M), which can be cleaved specifically by metalloproteinase-2 (MMP-2) highly expressed in the tumor microenvironment (TME); and 4) Hexadecyl (F), which has strong hydrophobicity, can promote the self-assembly of TGMF NPs.Methods: Five modular peptide probes, namely, TGF, TMF, TGM, GMF, and TGMF were synthesized and self-assembled into NPs in solution. The characterization, enzyme reactivity, and cytotoxicity of NPs were evaluated in vitro, and the pharmacokinetics, bio-distribution, anti-tumor activity of NPs were investigated in vivo. In addition, transcriptome sequencing identified the intracellular signaling pathway-related genes involved in the anti-tumor effect of TGMF.Results: Upon enzyme cleavage, two types of nanostructure, NPs and nanofibers (NFs), were detected under TEM. Moreover, the cytotoxicity and anti-invasion activity of TGMF against tumor cells used were strongest among the five modular probes examined in vitro. TGMF increased reactive oxygen species (ROS) levels in cytoplasm and produced numerous NFs in extracellular interval and intracellular space. Transcriptome sequencing revealed that TGMF caused 446 genes’ down-regulation and 270 genes’ up-regulation in HeLa cells. In vivo, TGMF has a good anti-tumor effect, effectively prolonging the survival time of HeLa-tumor-bearing mice without systemic side effects.Conclusion: Integration of multiple functional modules into NPs could be a promising strategy for the future of nanomedicine design towards tumor treatment.Keywords: modular peptide, nanofiber, anti-tumor, anti-metastasis, transcriptome sequencing
format	article
author	Chen B Dong X Dong X Wang Q Wu M Wu J Lou X Xia F Wang W Dai J Wang S
author_facet	Chen B Dong X Dong X Wang Q Wu M Wu J Lou X Xia F Wang W Dai J Wang S
author_sort	Chen B
title	Integration of Dual Targeting and Dual Therapeutic Modules Endows Self-Assembled Nanoparticles with Anti-Tumor Growth and Metastasis Functions
title_short	Integration of Dual Targeting and Dual Therapeutic Modules Endows Self-Assembled Nanoparticles with Anti-Tumor Growth and Metastasis Functions
title_full	Integration of Dual Targeting and Dual Therapeutic Modules Endows Self-Assembled Nanoparticles with Anti-Tumor Growth and Metastasis Functions
title_fullStr	Integration of Dual Targeting and Dual Therapeutic Modules Endows Self-Assembled Nanoparticles with Anti-Tumor Growth and Metastasis Functions
title_full_unstemmed	Integration of Dual Targeting and Dual Therapeutic Modules Endows Self-Assembled Nanoparticles with Anti-Tumor Growth and Metastasis Functions
title_sort	integration of dual targeting and dual therapeutic modules endows self-assembled nanoparticles with anti-tumor growth and metastasis functions
publisher	Dove Medical Press
publishDate	2021
url	https://doaj.org/article/99523b1bc22f43b4a627926029393907
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Integration of Dual Targeting and Dual Therapeutic Modules Endows Self-Assembled Nanoparticles with Anti-Tumor Growth and Metastasis Functions

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