Renal Targeting: Peptide-Based Drug Delivery to Proximal Tubule Cells

Wischnjow, Artjom; Sarko, Dikran; Janzer, Maria; Kaufman, Christina L.; Beijer, Barbro; Brings, Sebastian; Haberkorn, Uwe; Larbig, Gregor; Kübelbeck, Armin; Mier, Walter

doi:10.1021/acs.bioconjchem.6b00057

Cited by 64 publications

(43 citation statements)

References 40 publications

(73 reference statements)

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“…The delivery of an effective senolytic drug dose inside targeted cells would be accomplished by internalization of the functionalized compound triggered by binding to the cell surface receptors specifically expressed by certain cell types in the kidney (Falke et al 2015 ). There is a variety of compounds that can carry therapeutic agents, including glucosamine conjugates, poly vinylpyrrolidone (PVP)-derivatives, lysozyme conjugates and other low molecular weight protein (LMWP)-carriers, and also the targeting peptide (KKEEE)3 K (Franssen et al 1993 ; Kamada et al 2003 ; Lin et al 2013 ; Falke et al 2015 ; Wischnjow et al 2016 ). The kidney is eminently qualified for such targeting strategies, as kidney cells possess several relatively specific cell surface receptors, including LDL receptor-related protein 2 (commonly known as megalin/cubulin), integrin α8, E-selectin, podocyte-specific antigen and folate receptor 1α (Falke et al 2015 ).…”

Section: Targeting Strategiesmentioning

confidence: 99%

Cellular senescence in the aging and diseased kidney

Valentijn

Falke

Nguyen

et al. 2017

J. Cell Commun. Signal.

118

105

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The program of cellular senescence is involved in both the G1 and G2 phase of the cell cycle, limiting G1/S and G2/M progression respectively, and resulting in prolonged cell cycle arrest. Cellular senescence is involved in normal wound healing. However, multiple organs display increased senescent cell numbers both during natural aging and after injury, suggesting that senescent cells can have beneficial as well as detrimental effects in organismal aging and disease. Also in the kidney, senescent cells accumulate in various compartments with advancing age and renal disease. In experimental studies, forced apoptosis induction through the clearance of senescent cells leads to better preservation of kidney function during aging. Recent groundbreaking studies demonstrate that senescent cell depletion through INK-ATTAC transgene-mediated or cell-penetrating FOXO4-DRI peptide induced forced apoptosis, reduced age-associated damage and dysfunction in multiple organs, in particular the kidney, and increased performance and lifespan. Senescence is also involved in oncology and therapeutic depletion of senescent cells by senolytic drugs has been studied in experimental and human cancers. Although studies with senolytic drugs in models of kidney injury are lacking, their dose limiting side effects on other organs suggest that targeted delivery might be needed for successful application of senolytic drugs for treatment of kidney disease. In this review, we discuss (i) current understanding of the mechanisms and associated pathways of senescence, (ii) evidence of senescence occurrence and causality with organ injury, and (iii) therapeutic strategies for senescence depletion (senotherapy) including targeting, all in the context of renal aging and disease.

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Section: Targeting Strategiesmentioning

confidence: 99%

Cellular senescence in the aging and diseased kidney

Valentijn

Falke

Nguyen

et al. 2017

J. Cell Commun. Signal.

118

105

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“…In addition, the novel peptide carrier-peptide sequence (KKEEE)3K was found to be exceptional renal specificity at high accumulation rates and endocytosed by proximal tubule cells via megalin receptor-mediated mechanism. 28,105 The immunofluorescence analysis of FITC-labeled (KKEEE)3K by Wischnjow et al 28 revealed that the carrier was exclusively accumulated at the apical side of proximal tubule cells, indicating that the potential of (KKEEE)3K as a promising candidate for kidney-targeted drug-delivery system.…”

Section: Protein-based and Peptide-based Carriersmentioning

confidence: 99%

Targeting strategies for drug delivery to the kidney: From renal glomeruli to tubules

Liu

Lin

et al. 2018

Medicinal Research Reviews

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Kidney diseases have become a global public health problem. The application of kidney-targeted drug-delivery systems in the management of kidney diseases has profound transformative potential. Kidney-targeted drug delivery can reduce the undesired side effects of often potent drugs and enhance drug efficacy in alleviating the kidney disease. Here, we review the literature on the potential strategies for targeting drugs to the kidneys. Specifically, we provide a broad overview of the targeting vectors and targeting pathways for renal tubules and glomeruli, as well as how the unique structural features of the glomerulus and the receptor-mediated internalization pathways of the tubules allows for drug targeting. Finally, we summarized the literature examples of drug delivery to the kidneys and elaborated strategies suitable for renal targeting to provide new therapeutic approaches for kidney diseases.

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“…developed the peptide sequence (KKEEE) 3 K. 49 They showed that the targeting peptide had high renal specificity and accumulation in proximal tubule cells, making it an ideal kidney-specific carrier for drug delivery and the treatment of kidney diseases (Fig. 5).…”

Section: Peptide Ligandsmentioning

confidence: 99%

Peptide and antibody ligands for renal targeting: nanomedicine strategies for kidney disease

2017

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The kidney is one of the body’s main filtration organs, and hence, opportunity exists for designing nanomedicine that can naturally accumulate in the kidneys for renal diseases. In addition to traditional physiochemical properties for kidney accumulation, such as size and charge, synthesized nanoparticles can be conjugated with targeting ligands which further home the nanocarriers to cell types of interest In this review, we highlight key studies that have shown success in utilizing peptide- or antibody-based ligands in nanoparticles to target the glomerulus, podocytes, or renal tubule cells in the kidney. In addition, other ligand candidates which have shown renal affinity, but have not yet been integrated into a nanoparticle are also presented. These studies can provide insight into the design of novel clinical solutions for improved detection, prevention, and treatment of renal diseases using nanomedicine efforts

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Renal Targeting: Peptide-Based Drug Delivery to Proximal Tubule Cells

Cited by 64 publications

References 40 publications

Cellular senescence in the aging and diseased kidney

Cellular senescence in the aging and diseased kidney

Targeting strategies for drug delivery to the kidney: From renal glomeruli to tubules

Peptide and antibody ligands for renal targeting: nanomedicine strategies for kidney disease

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