The antifibrotic potential of a sustained release formulation of a PDGFβ-receptor targeted rho kinase inhibitor

Dijk, F; Teekamp, Naomi; Post, Eduard; Schuppan, Detlef; Kim, Y.O.; Zuidema, Johan; Steendam, Rob; Klose, Matthias H. M.; Meier‐Menches, Samuel M.; Casini, Angela; Horvatovich, Péter; Sijbrandi, Niels J.; Frijlink, Henderik W.; Hinrichs, Wouter L. J.; Poelstra, Klaas; Beljaars, Leonie; Olinga, Peter

doi:10.1016/j.jconrel.2018.12.039

Cited by 17 publications

(10 citation statements)

References 33 publications

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“…Later studies confirmed that Rho-kinase signaling regulates HSC activation and migration [ 146 , 147 , 148 ]. Several other studies demonstrated the beneficial effects of selective delivery of Rho kinase inhibitor to HSCs on the development of hepatic fibrosis in vivo [ 146 , 149 , 150 , 151 ].…”

Section: Camp Signaling In Aldmentioning

confidence: 99%

cAMP Signaling in Pathobiology of Alcohol Associated Liver Disease

et al. 2020

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The importance of cyclic adenosine monophosphate (cAMP) in cellular responses to extracellular signals is well established. Many years after discovery, our understanding of the intricacy of cAMP signaling has improved dramatically. Multiple layers of regulation exist to ensure the specificity of cellular cAMP signaling. Hence, disturbances in cAMP homeostasis could arise at multiple levels, from changes in G protein coupled receptors and production of cAMP to the rate of degradation by phosphodiesterases. cAMP signaling plays critical roles in metabolism, inflammation and development of fibrosis in several tissues. Alcohol-associated liver disease (ALD) is a multifactorial condition ranging from a simple steatosis to steatohepatitis and fibrosis and ultimately cirrhosis, which might lead to hepatocellular cancer. To date, there is no FDA-approved therapy for ALD. Hence, identifying the targets for the treatment of ALD is an important undertaking. Several human studies have reported the changes in cAMP homeostasis in relation to alcohol use disorders. cAMP signaling has also been extensively studied in in vitro and in vivo models of ALD. This review focuses on the role of cAMP in the pathobiology of ALD with emphasis on the therapeutic potential of targeting cAMP signaling for the treatment of various stages of ALD.

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Section: Camp Signaling In Aldmentioning

confidence: 99%

cAMP Signaling in Pathobiology of Alcohol Associated Liver Disease

et al. 2020

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“…Using this approach, Poosti et al successfully prepared an IFNγ conjugate targeted to PDGFRβ that mitigated fibrogenesis in murine PCKS [ 33 ]. In another study, it was demonstrated that sustained systemic delivery of a similar anti-fibrotic construct could be achieved following a single subcutaneous injection of construct-loaded polymeric microspheres [ 34 ]. These exciting advances in drug formulation will allow us to directly target complex systems such as tryptophan metabolism to treat disease without causing severe side effects.…”

Section: Discussionmentioning

confidence: 99%

Local Inhibition of Indoleamine 2,3-Dioxygenase Mitigates Renal Fibrosis

Jensen

Tingskov

et al. 2021

Biomedicines

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Chronic kidney disease (CKD) is a major global health concern and renal fibrosis is an integral part of the pathophysiological mechanism underlying disease progression. In CKD patients, the majority of metabolic pathways are in disarray and perturbations in enzyme activity most likely contribute to the wide variety of comorbidities observed in these patients. To illustrate, catabolism of tryptophan by indoleamine 2,3-dioxygenase (IDO) gives rise to numerous biologically active metabolites implicated in CKD progression. Here, we evaluated the effect of antagonizing IDO on renal fibrogenesis. To this end, we antagonized IDO using 1-methyl-D-tryptophan (1-MT) and BMS-98620 in TGF-β-treated murine precision-cut kidney slices (mPCKS) and in mice subjected to unilateral ureteral obstruction (UUO). The fibrotic response was evaluated on both the gene and protein level using qPCR and western blotting. Our results demonstrated that treatment with 1-MT or BMS-985205 markedly reduced TGF-β-mediated fibrosis in mPCKS, as seen by a decreased expression of collagen type 1, fibronectin, and α-smooth muscle actin. Moreover, IDO protein expression clearly increased following UUO, however, treatment of UUO mice with either 1-MT or BMS-986205 did not significantly affect the gene and protein expression of the tested fibrosis markers. However, both inhibitors significantly reduced the renal deposition of collagen in UUO mice as shown by Sirius red and trichrome staining. In conclusion, this study demonstrates that IDO antagonism effectively mitigates fibrogenesis in mPCKS and reduces renal collagen accumulation in UUO mice. These findings warrant further research into the clinical application of IDO inhibitors for the treatment of renal fibrosis.

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“…For pPB it was demonstrated that at least two peptides are required to achieve binding to the dimeric PDGF-βR [63]. In particular the pPB-based carrier and the M6P-based carriers have been extensively used for the delivery of many antifibrotic compounds to this cell-type including anti-proliferative drugs (doxorubicin [65], mycophenolic acid [66]), apoptosis-inducing drugs (gliotoxin [67], 15-d-Prostaglandin J2 [68]), anti-inflammatory drugs (pentoxifyline [69], Interleukin 10 [70], Prostaglandin E2 [57]), collagen synthesis inhibitors (an ALK5 inhibitor [71]) a Rho-kinase inhibitor (Y27632 [72][73][74][75]), a tyrosine kinase inhibitor (Imatinib [76]) and other inhibitors of HSC activation (the Angiotensin Receptor I antagonist Losartan [77]. These are listed in Table 1.…”

Section: Drug Targeting Approaches In Fibrotic Liversmentioning

confidence: 99%

Drug Targeting and Nanomedicine: Lessons Learned from Liver Targeting and Opportunities for Drug Innovation

Salvati

Poelstra

2022

Pharmaceutics

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Drug targeting and nanomedicine are different strategies for improving the delivery of drugs to their target. Several antibodies, immuno-drug conjugates and nanomedicines are already approved and used in clinics, demonstrating the potential of such approaches, including the recent examples of the DNA- and RNA-based vaccines against COVID-19 infections. Nevertheless, targeting remains a major challenge in drug delivery and different aspects of how these objects are processed at organism and cell level still remain unclear, hampering the further development of efficient targeted drugs. In this review, we compare properties and advantages of smaller targeted drug constructs on the one hand, and larger nanomedicines carrying higher drug payload on the other hand. With examples from ongoing research in our Department and experiences from drug delivery to liver fibrosis, we illustrate opportunities in drug targeting and nanomedicine and current challenges that the field needs to address in order to further improve their success.

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The antifibrotic potential of a sustained release formulation of a PDGFβ-receptor targeted rho kinase inhibitor

Cited by 17 publications

References 33 publications

cAMP Signaling in Pathobiology of Alcohol Associated Liver Disease

cAMP Signaling in Pathobiology of Alcohol Associated Liver Disease

Local Inhibition of Indoleamine 2,3-Dioxygenase Mitigates Renal Fibrosis

Drug Targeting and Nanomedicine: Lessons Learned from Liver Targeting and Opportunities for Drug Innovation

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