Hepatic stellate cell-targeted imatinib nanomedicine versus conventional imatinib: A novel strategy with potent efficacy in experimental liver fibrosis

El–Mezayen, Nesrine S.; El-Hadidy, Wessam F.; El-Refaie, Wessam M.; Shalaby, Thanaa I.; Khattab, Mahmoud M.; El-Khatib, Aiman S.

doi:10.1016/j.jconrel.2017.09.035

Cited by 49 publications

(39 citation statements)

References 75 publications

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“…Several independent studies have already shown that imatinib, via its inhibitory effect on PDGFR, and sorafenib, via its double inhibitory action on VEGFR/PDGFR and RAF/MEK/ERK pathways, play an important anti-fibrotic role both in vitro and in vivo [ 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ]. In the present study, we aimed to test the effects of these drugs in a different model of liver fibrosis which more closely resembles the liver degeneration and fibrotis processes that occur with immune-mediated liver disorders such as autoimmune hepatitis, acute viral hepatitis, and drug-induced immune activation [ 31 , 32 ].…”

Section: Discussionmentioning

confidence: 99%

Effects of Combined Admistration of Imatinib and Sorafenib in a Murine Model of Liver Fibrosis

Pesce

Bramanti

Iapichino³

et al. 2020

Molecules

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Liver fibrosis is defined as excessive extracellular matrix deposition in the hepatic parenchyma as a consequence of complex interactions among matrix-producing hepatic stellate cells (HSCs) and liver-resident and infiltrating cells. In addition to the liver, the process of fibrosis may represent end-stage disease of several diseases including kidneys, lungs, spleens, heart, muscles and at certain extent, the central nervous system and the peripheral nerves. To date, antifibrotic treatment of fibrosis represents an unconquered area for drug development. The aim of the present study was to test the efficacy of a new drug combination for the treatment of hepatic fibrosis in order to provide a proof-of-concept for the use of therapeutic agents in clinical practice. For this purpose, we have studied the effects of the PDGF inhibitor imatinib and the angiogenesis inhibitor sorafenib, administered alone or in combination, in reducing the progression of the fibrogenetic process in a pre-clinical model of liver damage induced in mice by repeated administration of Concanavalin A (ConA), resembling long-tern autoimmune hepatitis. Our results suggest that treatments with imatinib and sorafenib can modulate potently and, in a superimposable fashion, the fibrinogenic process when administered alone. However, and in agreement with the computational data presently generated, they only exert partial overlapping antifibrotic effects in modulating the main pathways involved in the process of liver fibrosis, without significant additive or synergist effects, when administered in combination.

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Section: Discussionmentioning

confidence: 99%

Effects of Combined Admistration of Imatinib and Sorafenib in a Murine Model of Liver Fibrosis

Pesce

Bramanti

Iapichino³

et al. 2020

Molecules

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“…Vitamin A-loaded liposomes have gained much attention as HSC-specific carriers since the first publication by Sato et al [33]. Using vitamin A-decorated nanoparticles, recent studies showed successful delivery to HSC of several compounds such as siRNA and anti-miR33 [77], BMP4 siRNA [78], the Rhokinase inhibitor Y27632 [79], and Imatinib [37]. All these different types of drugs in vitamin A-coated liposomes nicely illustrate the versatility of liposomes as vehicles for drug delivery.…”

Section: Cell-specific Delivery Of Antifibrotic Drugs: Homing Devicesmentioning

confidence: 97%

“…The mannose-6-phosphate/insulin-like growth factor II (IGFII) receptor was the first receptor studied for this purpose [29], followed by the collagen type VI receptor [30], and the PDGF-β-receptor [17,31]. A monoclonal antibody against the synaptophysin receptor also has been tested, but without follow-up [32], and in the recent years, many studies have been published using the vitamin A receptor upon HSC as target receptor for antifibrotic compounds [33][34][35][36][37]. A lipid nanoparticle functionalized with vitamin A and containing siRNA against heat shock protein 47 (HSP47) is now being tested in clinical phase 2 trials (www.…”

Section: Uptake Of Drugs and Nanomedicines In The Livermentioning

confidence: 99%

Innovative Nanotechnological Formulations to Reach the Hepatic Stellate Cell

Poelstra

2020

Curr. Tissue Microenviron. Rep.

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Purpose of Review Treatment of liver fibrosis benefits from hepatic stellate cell (HSC)-specific delivery. Since the description of first carrier to HSC, many developments have taken place in this area. The purpose is to give an overview of the different carriers and homing moieties that are available for HSC targeting and illustrate the opportunities and hurdles they provide. Recent Findings There is a growing number of homing devices to deliver drugs to HSC, and options to deliver siRNA to HSC have emerged. Other developments include controlling corona formation, development of linker technology, and design of theranostic approaches. We are on the eve of reaching the clinic with innovative HSC-specific compounds. Summary An overview of different core molecules is presented together with an overview of targeting strategies toward different receptors on HSC, providing a versatile toolbox. Many therapeutics, ranging from small chemical entities and proteins to RNAor DNA-modulating substances, have already been incorporated in these constructs in the recent years.

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“…Subsequently, supernatants were extracted from the lysates following centrifugation at 11,000 x g at 4˚C for 15 min. Equal amounts of protein (30 µg/lane) were separated using 10% SDS-PAGE at 300 mA for 2 h and transferred onto a polyvinylidene fluoride membrane, as previously reported (10). The following primary antibodies were used: β-Actin (cat.…”

Section: Isolation and Culture Of Rat Hepatic Stellate Cells (Hscs)mentioning

confidence: 99%

“…Transforming growth factor (TGF)-β is a key regulator in chronic liver disease where it promotes the process of fibrogenesis through inflammation (9). Within the liver, TGF-β is secreted by platelets and Kupffer cells upon stimulation of the inflammatory response (10). A significant enhancement in TGF-β expression is identified in the activated hepatic stellate cells, which is accompanied by the accelerated accumulation of ECM (11).…”

Section: Introductionmentioning

confidence: 99%

miR‑219‑3p regulates the occurrence of hepatic fibrosis by targeting Smad2

Zhang

Zhu

et al. 2019

Exp Ther Med

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Abnormal expression of microRNA (miR)-219-3p has been widely identified in different tumors. However, whether miR-219-3p is involved in the progression of hepatic fibrosis (HF) has never been explored. The present study showed that compared with healthy controls, the levels of miR-291-3p in peripheral blood were decreased in patients with HF. Furthermore, much lower levels of miR-291-3p were identified in fibrotic liver tissues compared with that of normal liver tissues. Receiver operating characteristic curve analysis showed that the levels of miR-291-3p in peripheral blood may screen patients with HF from healthy controls. Reverse transcription quantitative polymerase chain reaction analysis showed that overexpression of miR-291-3p significantly suppressed the mRNA levels of Snai1, vascular endothelial-specific cadherin (VE-cadherin), Vimentin, transforming growth factor (TGF)-β1, and glial fibrillary acidic protein (GFAP). The protein levels of Snai1, VE-cadherin, Vimentin, TGF-β1, and GFAP were also decreased in hepatic stellate cells transfected with miR-291-3p mimics. Further study indicated that mothers against decapentaplegic homolog 2 (Smad2) was a target gene of miR-291-3p. More importantly, silencing of Smad2 could abolish miR-291-3p inhibition-induced TGF-β1 signaling activation. In summary, reduced peripheral blood miR-291-3p may be involved in the progression of HF via targeting Smad2.

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Hepatic stellate cell-targeted imatinib nanomedicine versus conventional imatinib: A novel strategy with potent efficacy in experimental liver fibrosis

Cited by 49 publications

References 75 publications

Effects of Combined Admistration of Imatinib and Sorafenib in a Murine Model of Liver Fibrosis

Effects of Combined Admistration of Imatinib and Sorafenib in a Murine Model of Liver Fibrosis

Innovative Nanotechnological Formulations to Reach the Hepatic Stellate Cell

miR‑219‑3p regulates the occurrence of hepatic fibrosis by targeting Smad2

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