Dual-Functional Nanoparticles Targeting CXCR4 and Delivering Antiangiogenic siRNA Ameliorate Liver Fibrosis

Liu, Chun-Hung; Chan, Kun‐Ming; Chiang, Tsaiyu; Liu, Jiayu; Chern, Guann-Gen; Hsu, Fu-Fei; Wu, Yu‐Hsuan; Liu, Ya-Chi; Chen, Yunching

doi:10.1021/acs.molpharmaceut.5b00913

Cited by 30 publications

(16 citation statements)

References 35 publications

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“…CXCR4 is a chemokine receptor induced in activated HSCs by various cellular stresses during the progression of liver fibrosis 16 , 26 , 27 . Thus, we developed CXCR4-targeted NPs to more selectively target activated HSCs in fibrotic livers 27 . In this study, to improve safety and efficacy of the drug cocktail, we co-formulated sorafenib and AZD6244 in CXCR4-targeted lipid-coated PLGA NPs modified with CTCE9908, a CXCR4 antagonist peptide.…”

Section: Resultsmentioning

confidence: 99%

Combined delivery of sorafenib and a MEK inhibitor using CXCR4-targeted nanoparticles reduces hepatic fibrosis and prevents tumor development

et al. 2018

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Liver damage and fibrosis are precursors of hepatocellular carcinoma (HCC). In HCC patients, sorafenib—a multikinase inhibitor drug—has been reported to exert anti-fibrotic activity. However, incomplete inhibition of RAF activity by sorafenib may also induce paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway in malignant cells. The consequence of this effect in non-malignant disease (hepatic fibrosis) remains unknown. This study aimed to examine the effects of sorafenib on activated hepatic stellate cells (HSCs), and develop effective therapeutic approaches to treat liver fibrosis and prevent cancer development.Methods: We first examined the effects of sorafenib in combination with MEK inhibitors on fibrosis pathogenesis in vitro and in vivo. To improve the bioavailability and absorption by activated HSCs, we developed CXCR4-targeted nanoparticles (NPs) to co-deliver sorafenib and a MEK inhibitor to mice with liver damage.Results: We found that sorafenib induced MAPK activation in HSCs, and promoted their myofibroblast differentiation. Combining sorafenib with a MEK inhibitor suppressed both paradoxical MAPK activation and HSC activation in vitro, and alleviated liver fibrosis in a CCl4-induced murine model of liver damage. Furthermore, treatment with sorafenib/MEK inhibitor-loaded CXCR4-targeted NPs significantly suppressed hepatic fibrosis progression and further prevented fibrosis-associated HCC development and liver metastasis.Conclusions: Our results show that combined delivery of sorafenib and a MEK inhibitor via CXCR4-targeted NPs can prevent activation of ERK in activated HSCs and has anti-fibrotic effects in the CCl4-induced murine model. Targeting HSCs represents a promising strategy to prevent the development and progression of fibrosis-associated HCC.

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Section: Resultsmentioning

confidence: 99%

Combined delivery of sorafenib and a MEK inhibitor using CXCR4-targeted nanoparticles reduces hepatic fibrosis and prevents tumor development

et al. 2018

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“…As the ATP‐binding pocket is the core structure of the catalytic domain of ALK5, this interaction could, at least partially, explain the down‐regulation of TGF‐β1/Smad2/3 signalling after kaempferol intervention. Similarly, small interfering RNAs (siRNAs) could also target specific proteins such as VEGF, MMP‐2 and Foxf1 to attenuate extracellular matrix deposition and liver fibrosis formation. However, how to delivery siRNAs into targeted cells effectively and efficiently remains to be a problem that needs to be solved .…”

Section: Discussionmentioning

confidence: 99%

Kaempferol attenuates liver fibrosis by inhibiting activin receptor–like kinase 5

Huang

et al. 2019

J Cellular Molecular Medi

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Liver fibrosis is a common public health problem. Patients with liver fibrosis are more likely to develop cirrhosis, or hepatocellular carcinoma (HCC) as a more serious consequence. Numerous therapeutic approaches have emerged, but the final clinical outcome remains unsatisfactory. Here, we discovered a flavonoid natural product kaempferol that could dramatically ameliorate liver fibrosis formation. Our data showed that intraperitoneal injection of kaempferol could significantly decrease the necroinflammatory scores and collagen deposition in the liver tissue. In addition, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), laminin (LN) and hyaluronic acid (HA) levels were significantly down‐regulated in kaempferol treatment group compared with those in the control group. Our study also demonstrated that kaempferol markedly inhibited the synthesis of collagen and activation of hepatic stellate cells (HSCs) both in vivo and in vitro. Furthermore, the results of Western blotting revealed that kaempferol could down‐regulate Smad2/3 phosphorylation dose‐dependently. These bioactivities of kaempferol may result from its targeted binding to the ATP‐binding pocket of activin receptor–like kinase 5 (ALK5), as suggested by the molecular docking study and LanthaScreen Eu kinase binding assay. Above all, our data indicate that kaempferol may prove to be a novel agent for the treatment of liver fibrosis or other fibroproliferative diseases.

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“…A study used pPB-modified liposomes to deliver recombinant human tumor necrosis factor-related apoptosis-inducing ligand (rhTRAIL) to the HSC membrane, prolonging rhTRAIL circulation in vivo and alleviating fibrosis both in vitro and in vivo [ 90 ]. Similarly, the CXCR4 antagonist AMD3100 could target HSCs [ 91 ]. AMD3100-conjugated liposomes efficiently delivered therapeutic VEGF siRNAs to activate CXCR4-overexpressed HSCs both in vitro and in vivo.…”

Section: Nanomedicine For Liver Fibrosis Therapymentioning

confidence: 99%

Recent Advances in Nanomedicine for the Diagnosis and Therapy of Liver Fibrosis

Bai

Zhai

2020

Nanomaterials

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Liver fibrosis, a reversible pathological process of inflammation and fiber deposition caused by chronic liver injury and can cause severe health complications, including liver failure, liver cirrhosis, and liver cancer. Traditional diagnostic methods and drug-based therapy have several limitations, such as lack of precision and inadequate therapeutic efficiency. As a medical application of nanotechnology, nanomedicine exhibits great potential for liver fibrosis diagnosis and therapy. Nanomedicine enhances imaging contrast and improves tissue penetration and cellular internalization; it simultaneously achieves targeted drug delivery, combined therapy, as well as diagnosis and therapy (i.e., theranostics). In this review, recent designs and development efforts of nanomedicine systems for the diagnosis, therapy, and theranostics of liver fibrosis are introduced. Relative to traditional methods, these nanomedicine systems generally demonstrate significant improvement in liver fibrosis treatment. Perspectives and challenges related to these nanomedicine systems translated from laboratory to clinical use are also discussed.

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Dual-Functional Nanoparticles Targeting CXCR4 and Delivering Antiangiogenic siRNA Ameliorate Liver Fibrosis

Cited by 30 publications

References 35 publications

Combined delivery of sorafenib and a MEK inhibitor using CXCR4-targeted nanoparticles reduces hepatic fibrosis and prevents tumor development

Combined delivery of sorafenib and a MEK inhibitor using CXCR4-targeted nanoparticles reduces hepatic fibrosis and prevents tumor development

Kaempferol attenuates liver fibrosis by inhibiting activin receptor–like kinase 5

Recent Advances in Nanomedicine for the Diagnosis and Therapy of Liver Fibrosis

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