Prodrug polymeric micelles integrating cancer-associated fibroblasts deactivation and synergistic chemotherapy for gastric cancer

Abstract Background The prognosis of patients with advanced gastric cancer (GC) remains unsatisfactory owing to distant metastasis and resistance to concurrent systemic therapy. Cancer-associated fibroblasts (CAFs), as essential participators in the tumor microenvironment (TME), play a vital role in...

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Autores principales:	Sheng Zheng, Jiafeng Wang, Ning Ding, Wenwen Chen, Hongda Chen, Meng Xue, Fei Chen, Jiaojiao Ni, Zhuo Wang, Zhenghua Lin, Haiping Jiang, Xiangrui Liu, Liangjing Wang
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Gastric cancer Cancer-associated fibroblasts Tumor microenvironment Polymeric prodrug Triptolide SN38 Biotechnology TP248.13-248.65 Medical technology R855-855.5
Acceso en línea:	https://doaj.org/article/6145397e940c4526b0f8e554038217dc
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spelling	oai:doaj.org-article:6145397e940c4526b0f8e554038217dc2021-11-28T12:26:41ZProdrug polymeric micelles integrating cancer-associated fibroblasts deactivation and synergistic chemotherapy for gastric cancer10.1186/s12951-021-01127-51477-3155https://doaj.org/article/6145397e940c4526b0f8e554038217dc2021-11-01T00:00:00Zhttps://doi.org/10.1186/s12951-021-01127-5https://doaj.org/toc/1477-3155Abstract Background The prognosis of patients with advanced gastric cancer (GC) remains unsatisfactory owing to distant metastasis and resistance to concurrent systemic therapy. Cancer-associated fibroblasts (CAFs), as essential participators in the tumor microenvironment (TME), play a vital role in tumor progression. Thus, CAFs-targeting therapy is appealing for remodeling TME and sensitizing GC to conventional systemic therapy. Methods Amphiphilic SN38 prodrug polymeric micelles (PSN38) and encapsulated the hydrophobic esterase-responsive prodrug of Triptolide (TPL), triptolide-naphthalene sulfonamide (TPL-nsa), were synthesized to form PSN38@TPL-nsa nanoparticles. Then, CAFs were isolated from fresh GC tissues and immortalized. TPL at low dose concentration was used to investigate its effect on CAFs and CAFs-induced GC cells proliferation and migration. The synergistic mechanism and antitumor efficiency of SN38 and TPL co-delivery nanoparticle were investigated both in vitro and in vivo. Results Fibroblast activation protein (FAP), a marker of CAFs, was highly expressed in GC tissues and indicated poorer prognosis. TPL significantly reduced CAFs activity and inhibited CAFs-induced proliferation, migration and chemotherapy resistance of GC cells. In addition, TPL sensitized GC cells to SN38 treatment through attenuated NF-κB activation in both CAFs and GC cells. PSN38@TPL-nsa treatment reduced the expression of collagen, FAP, and α-smooth muscle actin (α-SMA) in tumors. Potent inhibition of primary tumor growth and vigorous anti-metastasis effect were observed after systemic administration of PSN38@TPL-nsa to CAFs-rich peritoneal disseminated tumor and patient-derived xenograft (PDX) model of GC. Conclusion TPL suppressed CAFs activity and CAFs-induced cell proliferation, migration and chemotherapy resistance to SN38 of GC. CAFs-targeted TPL and SN38 co-delivery nanoparticles exhibited potent efficacy of antitumor and reshaping TME, which was a promising strategy to treat advanced GC. Graphical AbstractSheng ZhengJiafeng WangNing DingWenwen ChenHongda ChenMeng XueFei ChenJiaojiao NiZhuo WangZhenghua LinHaiping JiangXiangrui LiuLiangjing WangBMCarticleGastric cancerCancer-associated fibroblastsTumor microenvironmentPolymeric prodrugTriptolideSN38BiotechnologyTP248.13-248.65Medical technologyR855-855.5ENJournal of Nanobiotechnology, Vol 19, Iss 1, Pp 1-18 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Gastric cancer Cancer-associated fibroblasts Tumor microenvironment Polymeric prodrug Triptolide SN38 Biotechnology TP248.13-248.65 Medical technology R855-855.5
spellingShingle	Gastric cancer Cancer-associated fibroblasts Tumor microenvironment Polymeric prodrug Triptolide SN38 Biotechnology TP248.13-248.65 Medical technology R855-855.5 Sheng Zheng Jiafeng Wang Ning Ding Wenwen Chen Hongda Chen Meng Xue Fei Chen Jiaojiao Ni Zhuo Wang Zhenghua Lin Haiping Jiang Xiangrui Liu Liangjing Wang Prodrug polymeric micelles integrating cancer-associated fibroblasts deactivation and synergistic chemotherapy for gastric cancer
description	Abstract Background The prognosis of patients with advanced gastric cancer (GC) remains unsatisfactory owing to distant metastasis and resistance to concurrent systemic therapy. Cancer-associated fibroblasts (CAFs), as essential participators in the tumor microenvironment (TME), play a vital role in tumor progression. Thus, CAFs-targeting therapy is appealing for remodeling TME and sensitizing GC to conventional systemic therapy. Methods Amphiphilic SN38 prodrug polymeric micelles (PSN38) and encapsulated the hydrophobic esterase-responsive prodrug of Triptolide (TPL), triptolide-naphthalene sulfonamide (TPL-nsa), were synthesized to form PSN38@TPL-nsa nanoparticles. Then, CAFs were isolated from fresh GC tissues and immortalized. TPL at low dose concentration was used to investigate its effect on CAFs and CAFs-induced GC cells proliferation and migration. The synergistic mechanism and antitumor efficiency of SN38 and TPL co-delivery nanoparticle were investigated both in vitro and in vivo. Results Fibroblast activation protein (FAP), a marker of CAFs, was highly expressed in GC tissues and indicated poorer prognosis. TPL significantly reduced CAFs activity and inhibited CAFs-induced proliferation, migration and chemotherapy resistance of GC cells. In addition, TPL sensitized GC cells to SN38 treatment through attenuated NF-κB activation in both CAFs and GC cells. PSN38@TPL-nsa treatment reduced the expression of collagen, FAP, and α-smooth muscle actin (α-SMA) in tumors. Potent inhibition of primary tumor growth and vigorous anti-metastasis effect were observed after systemic administration of PSN38@TPL-nsa to CAFs-rich peritoneal disseminated tumor and patient-derived xenograft (PDX) model of GC. Conclusion TPL suppressed CAFs activity and CAFs-induced cell proliferation, migration and chemotherapy resistance to SN38 of GC. CAFs-targeted TPL and SN38 co-delivery nanoparticles exhibited potent efficacy of antitumor and reshaping TME, which was a promising strategy to treat advanced GC. Graphical Abstract
format	article
author	Sheng Zheng Jiafeng Wang Ning Ding Wenwen Chen Hongda Chen Meng Xue Fei Chen Jiaojiao Ni Zhuo Wang Zhenghua Lin Haiping Jiang Xiangrui Liu Liangjing Wang
author_facet	Sheng Zheng Jiafeng Wang Ning Ding Wenwen Chen Hongda Chen Meng Xue Fei Chen Jiaojiao Ni Zhuo Wang Zhenghua Lin Haiping Jiang Xiangrui Liu Liangjing Wang
author_sort	Sheng Zheng
title	Prodrug polymeric micelles integrating cancer-associated fibroblasts deactivation and synergistic chemotherapy for gastric cancer
title_short	Prodrug polymeric micelles integrating cancer-associated fibroblasts deactivation and synergistic chemotherapy for gastric cancer
title_full	Prodrug polymeric micelles integrating cancer-associated fibroblasts deactivation and synergistic chemotherapy for gastric cancer
title_fullStr	Prodrug polymeric micelles integrating cancer-associated fibroblasts deactivation and synergistic chemotherapy for gastric cancer
title_full_unstemmed	Prodrug polymeric micelles integrating cancer-associated fibroblasts deactivation and synergistic chemotherapy for gastric cancer
title_sort	prodrug polymeric micelles integrating cancer-associated fibroblasts deactivation and synergistic chemotherapy for gastric cancer
publisher	BMC
publishDate	2021
url	https://doaj.org/article/6145397e940c4526b0f8e554038217dc
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Prodrug polymeric micelles integrating cancer-associated fibroblasts deactivation and synergistic chemotherapy for gastric cancer

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