Peritumoral implantation of hydrogel-containing nanoparticles and losartan for enhanced nanoparticle penetration and antitumor effect

Haijun Shen,1 Qianqian Gao,1 Qi Ye,1 Shiyun Yang,1 Yuqian Wu,1 Qin Huang,1 Xiaona Wang,2 Zhenhua Sun3 1Department of Preventive Medicine and Public Health Laboratory Science, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu Province, China; 2Department of Internal Medicine of Jiangsu Univ...

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Autores principales:	Shen H, Gao Q, Ye Q, Yang S, Wu Y, Huang Q, Wang X, Sun Z
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2018
Materias:	Localized drug delivery Tumor penetration Tumor extracellular matrix Collagen Matrix metalloproteinase Breast cancer Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/11d128319aec4390a5b836360816cc99
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spelling	oai:doaj.org-article:11d128319aec4390a5b836360816cc992021-12-02T04:56:10ZPeritumoral implantation of hydrogel-containing nanoparticles and losartan for enhanced nanoparticle penetration and antitumor effect1178-2013https://doaj.org/article/11d128319aec4390a5b836360816cc992018-11-01T00:00:00Zhttps://www.dovepress.com/peritumoral-implantation-of-hydrogel-containing-nanoparticles-and-losa-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Haijun Shen,1 Qianqian Gao,1 Qi Ye,1 Shiyun Yang,1 Yuqian Wu,1 Qin Huang,1 Xiaona Wang,2 Zhenhua Sun3 1Department of Preventive Medicine and Public Health Laboratory Science, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu Province, China; 2Department of Internal Medicine of Jiangsu University Hospital Workers, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu Province, China; 3Department of Thyroid and Breast Surgery, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu Province, China Background and purpose: Nanoparticle-loaded hydrogels – localized drug delivery devices containing a combination of therapeutic nanoparticles and implantable hydrogel – have been recipients of increased focus and interest for cancer treatment. However, it is difficult for the released nanoparticles to penetrate deeply into tumors because of the dense collagen network in the tumor extracellular matrix, which greatly limits their antitumor effect. We hypothesized that the implantation of a hydrogel loaded with both nanoparticles and losartan (Los) might enhance penetration because Los has been proven to effectively reduce collagen levels in various tumors. Herein, we developed a nanoparticle/Los-loaded hydrogel system and evaluated the intratumoral distribution and anticancer effect after peritumoral implantation of nanoparticles. Methods: Fluorescent polystyrene nanoparticles (FPNPs, size ~100 nm) and Los were simultaneously encapsulated in a polyethylene glycol (PEG) hydrogel to form the FPNP/Los-loaded hydrogel. After peritumoral implantation in 4T1 tumor-bearing mice for 2 weeks, intratumoral distributions of FPNPs and collagen level were determined. Based on the results, liposomal doxorubicin (Doxil, ~100 nm) was subsequently substituted for FPNPs in the hydrogel. The cellular uptake and cytotoxicity of the Doxil/Los-loaded hydrogel were studied, and the in vivo antitumor efficacy after peritumoral implantation was evaluated. Results: Compared with a standard FPNP-loaded hydrogel, the FPNP/Los-loaded hydrogel resulted in enhanced penetration and reduced collagen levels after implantation. Thereafter, the potential of a Doxil/Los-loaded hydrogel for cancer treatment was studied. Doxorubicin was released from the hydrogel and induced effective cytotoxicity against 4T1 cells. The Doxil/Los-loaded hydrogel showed synergistic antitumor effects in 4T1 tumor-bearing mice and was more effective at tumor inhibition than the Doxil-loaded hydrogel. Conclusion: This study provides a proof of principle that the implantation of nanoparticles/Los-loaded hydrogel can increase the intratumoral distribution and antitumor efficacy of nanoparticles, owing to collagen depletion by Los. Future studies may build on this strategy for enhanced tumor penetration of nanoparticles. Keywords: localized drug delivery, tumor penetration, tumor extracellular matrix, collagen, matrix metalloproteinase, breast cancerShen HGao QYe QYang SWu YHuang QWang XSun ZDove Medical PressarticleLocalized drug deliveryTumor penetrationTumor extracellular matrixCollagenMatrix metalloproteinaseBreast cancerMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 13, Pp 7409-7426 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Localized drug delivery Tumor penetration Tumor extracellular matrix Collagen Matrix metalloproteinase Breast cancer Medicine (General) R5-920
spellingShingle	Localized drug delivery Tumor penetration Tumor extracellular matrix Collagen Matrix metalloproteinase Breast cancer Medicine (General) R5-920 Shen H Gao Q Ye Q Yang S Wu Y Huang Q Wang X Sun Z Peritumoral implantation of hydrogel-containing nanoparticles and losartan for enhanced nanoparticle penetration and antitumor effect
description	Haijun Shen,1 Qianqian Gao,1 Qi Ye,1 Shiyun Yang,1 Yuqian Wu,1 Qin Huang,1 Xiaona Wang,2 Zhenhua Sun3 1Department of Preventive Medicine and Public Health Laboratory Science, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu Province, China; 2Department of Internal Medicine of Jiangsu University Hospital Workers, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu Province, China; 3Department of Thyroid and Breast Surgery, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu Province, China Background and purpose: Nanoparticle-loaded hydrogels – localized drug delivery devices containing a combination of therapeutic nanoparticles and implantable hydrogel – have been recipients of increased focus and interest for cancer treatment. However, it is difficult for the released nanoparticles to penetrate deeply into tumors because of the dense collagen network in the tumor extracellular matrix, which greatly limits their antitumor effect. We hypothesized that the implantation of a hydrogel loaded with both nanoparticles and losartan (Los) might enhance penetration because Los has been proven to effectively reduce collagen levels in various tumors. Herein, we developed a nanoparticle/Los-loaded hydrogel system and evaluated the intratumoral distribution and anticancer effect after peritumoral implantation of nanoparticles. Methods: Fluorescent polystyrene nanoparticles (FPNPs, size ~100 nm) and Los were simultaneously encapsulated in a polyethylene glycol (PEG) hydrogel to form the FPNP/Los-loaded hydrogel. After peritumoral implantation in 4T1 tumor-bearing mice for 2 weeks, intratumoral distributions of FPNPs and collagen level were determined. Based on the results, liposomal doxorubicin (Doxil, ~100 nm) was subsequently substituted for FPNPs in the hydrogel. The cellular uptake and cytotoxicity of the Doxil/Los-loaded hydrogel were studied, and the in vivo antitumor efficacy after peritumoral implantation was evaluated. Results: Compared with a standard FPNP-loaded hydrogel, the FPNP/Los-loaded hydrogel resulted in enhanced penetration and reduced collagen levels after implantation. Thereafter, the potential of a Doxil/Los-loaded hydrogel for cancer treatment was studied. Doxorubicin was released from the hydrogel and induced effective cytotoxicity against 4T1 cells. The Doxil/Los-loaded hydrogel showed synergistic antitumor effects in 4T1 tumor-bearing mice and was more effective at tumor inhibition than the Doxil-loaded hydrogel. Conclusion: This study provides a proof of principle that the implantation of nanoparticles/Los-loaded hydrogel can increase the intratumoral distribution and antitumor efficacy of nanoparticles, owing to collagen depletion by Los. Future studies may build on this strategy for enhanced tumor penetration of nanoparticles. Keywords: localized drug delivery, tumor penetration, tumor extracellular matrix, collagen, matrix metalloproteinase, breast cancer
format	article
author	Shen H Gao Q Ye Q Yang S Wu Y Huang Q Wang X Sun Z
author_facet	Shen H Gao Q Ye Q Yang S Wu Y Huang Q Wang X Sun Z
author_sort	Shen H
title	Peritumoral implantation of hydrogel-containing nanoparticles and losartan for enhanced nanoparticle penetration and antitumor effect
title_short	Peritumoral implantation of hydrogel-containing nanoparticles and losartan for enhanced nanoparticle penetration and antitumor effect
title_full	Peritumoral implantation of hydrogel-containing nanoparticles and losartan for enhanced nanoparticle penetration and antitumor effect
title_fullStr	Peritumoral implantation of hydrogel-containing nanoparticles and losartan for enhanced nanoparticle penetration and antitumor effect
title_full_unstemmed	Peritumoral implantation of hydrogel-containing nanoparticles and losartan for enhanced nanoparticle penetration and antitumor effect
title_sort	peritumoral implantation of hydrogel-containing nanoparticles and losartan for enhanced nanoparticle penetration and antitumor effect
publisher	Dove Medical Press
publishDate	2018
url	https://doaj.org/article/11d128319aec4390a5b836360816cc99
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Peritumoral implantation of hydrogel-containing nanoparticles and losartan for enhanced nanoparticle penetration and antitumor effect

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