Targeting drug delivery in the vascular system: Focus on endothelium

Glassman, Patrick M.; Myerson, Jacob W.; Ferguson, Laura; Kiseleva, Raisa; Shuvaev, Vladimir V.; Brenner, J.; Muzykantov, Vladimir R.

doi:10.1016/j.addr.2020.06.013

Cited by 86 publications

(63 citation statements)

References 354 publications

(455 reference statements)

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“…In precision medicine, therapeutically modulating a specific characteristic of inflamed vascular endothelial cells by vascular-targeted nanocarriers is a potential strategy to reduce inter-individual variability in drug response and local toxicity (Eelen et al, 2015;Glassman et al, 2020). Therefore, targeting vascular endothelial CYP1A1 and CYP1B1 by their inhibitors loaded in nanocarriers conjugated with affinity ligands of inflamed endothelial markers may be a potential strategy to modulate myocardial pharmacokinetics of CYP1A1 and CYPB1 substrates in diseases associated with Wnt5A.…”

Section: Discussionmentioning

confidence: 99%

“…However, there has been no study performed yet to investigate whether inflammation that has an established role in affecting pharmacokinetics pathways in hepatocytes, enterocytes and renal tubular epithelium (Morgan, 2009;König et al, 2013;Wu and Lin, 2019), regulates the expression of drug and xenobiotic metabolizing enzymes and transporters in human cardiac vascular endothelial cells. In precision medicine, a comprehensive knowledge of the regulation of pharmacokinetic pathways in vascular endothelial cells by specific inflammatory mediators is crucial for developing vascular-targeted therapy to reduce inter-individual variability in drug response and local and systemic toxicity (Eelen et al, 2015;Fatunde and Brown, 2020;Glassman et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

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Transcriptional Regulation of Drug Metabolizing CYP Enzymes by Proinflammatory Wnt5A Signaling in Human Coronary Artery Endothelial Cells

2021

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Downregulation of drug metabolizing enzymes and transporters by proinflammatory mediators in hepatocytes, enterocytes and renal tubular epithelium is an established mechanism affecting pharmacokinetics. Emerging evidences indicate that vascular endothelial cell expression of drug metabolizing enzymes and transporters may regulate pharmacokinetic pathways in heart to modulate local drug bioavailability and toxicity. However, whether inflammation regulates pharmacokinetic pathways in human cardiac vascular endothelial cells remains largely unknown. The lipid modified protein Wnt5A is emerging as a critical mediator of proinflammatory responses and disease severity in sepsis, hypertension and COVID-19. In the present study, we employed transcriptome profiling and gene ontology analyses to investigate the regulation of expression of drug metabolizing enzymes and transporters by Wnt5A in human coronary artery endothelial cells. Our study shows for the first time that Wnt5A induces the gene expression of CYP1A1 and CYP1B1 enzymes involved in phase I metabolism of a broad spectrum of drugs including chloroquine (the controversial drug for COVID-19) that is known to cause toxicity in myocardium. Further, the upregulation of CYP1A1 and CYP1B1 expression is preserved even during inflammatory crosstalk between Wnt5A and the prototypic proinflammatory IL-1β in human coronary artery endothelial cells. These findings stimulate further studies to test the critical roles of vascular endothelial cell CYP1A1 and CYP1B1, and the potential of vascular-targeted therapy with CYP1A1/CYP1B1 inhibitors in modulating myocardial pharmacokinetics in Wnt5A-associated inflammatory and cardiovascular diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Transcriptional Regulation of Drug Metabolizing CYP Enzymes by Proinflammatory Wnt5A Signaling in Human Coronary Artery Endothelial Cells

2021

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“…Despite their debatable resemblance with their primary counterparts, patient-specific endothelial cells derived from pluripotent stem cells have emerged as a promising tool with the added value of their potential for more personalized drug development [197]. While the heterogeneity of endothelial cells represents a challenge for designing tailored revascularization strategies, it also generates opportunities for vascular bed-specific and more efficient delivery of drugs, as recently reviewed [198].…”

Section: Impact Of Endothelial Cell Heterogeneity On Drug Developmentmentioning

confidence: 99%

Organ-Specific Endothelial Cell Differentiation and Impact of Microenvironmental Cues on Endothelial Heterogeneity

Gifre-Renom

Daems

Luttun

et al. 2022

IJMS

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Endothelial cells throughout the body are heterogeneous, and this is tightly linked to the specific functions of organs and tissues. Heterogeneity is already determined from development onwards and ranges from arterial/venous specification to microvascular fate determination in organ-specific differentiation. Acknowledging the different phenotypes of endothelial cells and the implications of this diversity is key for the development of more specialized tissue engineering and vascular repair approaches. However, although novel technologies in transcriptomics and proteomics are facilitating the unraveling of vascular bed-specific endothelial cell signatures, still much research is based on the use of insufficiently specialized endothelial cells. Endothelial cells are not only heterogeneous, but their specialized phenotypes are also dynamic and adapt to changes in their microenvironment. During the last decades, strong collaborations between molecular biology, mechanobiology, and computational disciplines have led to a better understanding of how endothelial cells are modulated by their mechanical and biochemical contexts. Yet, because of the use of insufficiently specialized endothelial cells, there is still a huge lack of knowledge in how tissue-specific biomechanical factors determine organ-specific phenotypes. With this review, we want to put the focus on how organ-specific endothelial cell signatures are determined from development onwards and conditioned by their microenvironments during adulthood. We discuss the latest research performed on endothelial cells, pointing out the important implications of mimicking tissue-specific biomechanical cues in culture.

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“…An array of different nanocarriers (e.g., liposomes, polymer-based NPs, magnetic NPs, dendrimers, quantum dots, Figure 1B ) have been used for designing and constructing CAM-targeted NMs ( 61 ).…”

Section: Nanomedicines Targeting Camsmentioning

confidence: 99%

Endothelial Cell Adhesion Molecules- (un)Attainable Targets for Nanomedicines

Milošević

Rütter

David

2022

Front. Med. Technol.

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Endothelial cell adhesion molecules have long been proposed as promising targets in many pathologies. Despite promising preclinical data, several efforts to develop small molecule inhibitors or monoclonal antibodies (mAbs) against cell adhesion molecules (CAMs) ended in clinical-stage failure. In parallel, many well-validated approaches for targeting CAMs with nanomedicine (NM) were reported over the years. A wide range of potential applications has been demonstrated in various preclinical studies, from drug delivery to the tumor vasculature, imaging of the inflamed endothelium, or blocking immune cells infiltration. However, no NM drug candidate emerged further into clinical development. In this review, we will summarize the most advanced examples of CAM-targeted NMs and juxtapose them with known traditional drugs against CAMs, in an attempt to identify important translational hurdles. Most importantly, we will summarize the proposed strategies to enhance endothelial CAM targeting by NMs, in an attempt to offer a catalog of tools for further development.

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Targeting drug delivery in the vascular system: Focus on endothelium

Cited by 86 publications

References 354 publications

Transcriptional Regulation of Drug Metabolizing CYP Enzymes by Proinflammatory Wnt5A Signaling in Human Coronary Artery Endothelial Cells

Transcriptional Regulation of Drug Metabolizing CYP Enzymes by Proinflammatory Wnt5A Signaling in Human Coronary Artery Endothelial Cells

Organ-Specific Endothelial Cell Differentiation and Impact of Microenvironmental Cues on Endothelial Heterogeneity

Endothelial Cell Adhesion Molecules- (un)Attainable Targets for Nanomedicines

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