RETRACTED: Drug Flux across RPE Cell Models: The Hunt for an Appropriate Outer Blood–Retinal Barrier Model for Use in Early Drug Discovery

Hellinen, Laura; Hongisto, Heidi; Ramsay, Eva; Vellonen, Kati‐Sisko; Skottman, Heli; Ruponen, Marika

doi:10.3390/pharmaceutics12020176

Cited by 9 publications

(11 citation statements)

References 39 publications

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“…To evaluate the use of Caco-2 permeability as a model for ocular permeability in comparison with other permeability models, we predicted vitreal CL for up to eight compounds based on permeabilities measured in different RPE cell models obtained from literature. , Unfortunately, four of these eight compounds reported (aztreonam, ganciclovir, ketorolac, and methotrexate) have a low maximum possible fold error (<3.0) and are therefore not very suitable for the estimation of the goodness of the permeability model.…”

Section: Resultsmentioning

confidence: 99%

Mechanistic Model for the Prediction of Small-Molecule Vitreal Clearance Combining Diffusion-Limited and Permeability-Limited Clearance

2021

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The discovery of new small-molecule drugs for intravitreal administration would benefit from simple models to predict vitreal clearance (CL). The current models available have limitations in their applicability to small-molecule drugs and translatability to humans. We developed a mechanistic model combining the diffusion rate of the molecule in the vitreous and permeability across posterior segment tissues and applied it to 30 small molecules with observed CL available mostly from literature. We used Caco-2 permeability as a surrogate for ocular tissue permeability. The model predicted rabbit vitreal CL well, with 80% of the predictions being within a 2-fold range of the observed CL. For an accurate prediction, it was crucial to consider the anterior diffusion CL from the vitreous to the aqueous and a limiting diffusion CL for the whole eye. We observed no major differences in model accuracy when using literature permeability values from retinal pigment epithelial cell models. Importantly, by adopting the specific dimensions of the human eye, the model was able to accurately predict vitreal CL of four compounds for which human vitreal CL data are available. In summary, this mechanistic model enables a simple, accurate, and translatable estimation of smallmolecule vitreal CL.

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Section: Resultsmentioning

confidence: 99%

Mechanistic Model for the Prediction of Small-Molecule Vitreal Clearance Combining Diffusion-Limited and Permeability-Limited Clearance

2021

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“…Madin-Darby canine kidney (MDCK) II is an epithelial cell line with short doubling time, and when cultured at specific conditions, cells acquire cobblestone morphology, cellular polarity, form microvilli and intercellular junctions (barrier function) [ 22 , 23 ]. MDCK II cells were kindly provided by Prof. Arto Urtti (University of Eastern Finland, Kuopio, Finland) and were maintained in DMEM/F12 medium (Gibco, New York, NY, USA) supplemented with 10% ( v / v ) FBS and 1% ( v / v ) L-glutamine (Sigma-Aldrich, Steinheim, Germany).…”

Section: Methodsmentioning

confidence: 99%

The Effect of Microbubble-Assisted Ultrasound on Molecular Permeability across Cell Barriers

et al. 2022

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The combination of ultrasound and microbubbles (USMB) has been applied to enhance drug permeability across tissue barriers. Most studies focused on only one physicochemical aspect (i.e., molecular weight of the delivered molecule). Using an in vitro epithelial (MDCK II) cell barrier, we examined the effects of USMB on the permeability of five molecules varying in molecular weight (182 Da to 20 kDa) and hydrophilicity (LogD at pH 7.4 from 1.5 to highly hydrophilic). Treatment of cells with USMB at increasing ultrasound pressures did not have a significant effect on the permeability of small molecules (molecular weight 259 to 376 Da), despite their differences in hydrophilicity (LogD at pH 7.4 from −3.2 to 1.5). The largest molecules (molecular weight 4 and 20 kDa) showed the highest increase in the epithelial permeability (3-7-fold). Simultaneously, USMB enhanced intracellular accumulation of the same molecules. In the case of the clinically relevant anti- C-X-C Chemokine Receptor Type 4 (CXCR4) nanobody (molecular weight 15 kDa), USMB enhanced paracellular permeability by two-fold and increased binding to retinoblastoma cells by five-fold. Consequently, USMB is a potential tool to improve the efficacy and safety of the delivery of drugs to organs protected by tissue barriers, such as the eye and the brain.

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“…The suitability of a certain carrier varies depending on the tissue, thus careful in vitro testing in physiologically relevant tissue models is required to select the optimal siRNA delivery system for the tissue of interest. In the case of the RPE, various carriers have been evaluated for their siRNA knockdown efficacy in vitro [22][23][24][25][26]; unfortunately, these studies have been performed using dividing cells that do not appropriately represent the terminally differentiated, post-mitotic RPE found in vivo [27]. For example, our recent study [28] has shown that the promising knockdown levels obtained with dividing RPE cells did not translate to adequate efficacy in differentiated cells.…”

Section: Introductionmentioning

confidence: 99%

Avoiding the Pitfalls of siRNA Delivery to the Retinal Pigment Epithelium with Physiologically Relevant Cell Models

et al. 2020

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Inflammation is involved in the pathogenesis of several age-related ocular diseases, such as macular degeneration (AMD), diabetic retinopathy, and glaucoma. The delivery of anti-inflammatory siRNA to the retinal pigment epithelium (RPE) may become a promising therapeutic option for the treatment of inflammation, if the efficient delivery of siRNA to target cells is accomplished. Unfortunately, so far, the siRNA delivery system selection performed in dividing RPE cells in vitro has been a poor predictor of the in vivo efficacy. Our study evaluates the silencing efficiency of polyplexes, lipoplexes, and lipidoid-siRNA complexes in dividing RPE cells as well as in physiologically relevant RPE cell models. We find that RPE cell differentiation alters their endocytic activity and causes a decrease in the uptake of siRNA complexes. In addition, we determine that melanosomal sequestration is another significant and previously unexplored barrier to gene silencing in pigmented cells. In summary, this study highlights the importance of choosing a physiologically relevant RPE cell model for the selection of siRNA delivery systems. Such cell models are expected to enable the identification of carriers with a high probability of success in vivo, and thus propel the development of siRNA therapeutics for ocular disease.

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RETRACTED: Drug Flux across RPE Cell Models: The Hunt for an Appropriate Outer Blood–Retinal Barrier Model for Use in Early Drug Discovery

Cited by 9 publications

References 39 publications

Mechanistic Model for the Prediction of Small-Molecule Vitreal Clearance Combining Diffusion-Limited and Permeability-Limited Clearance

Mechanistic Model for the Prediction of Small-Molecule Vitreal Clearance Combining Diffusion-Limited and Permeability-Limited Clearance

The Effect of Microbubble-Assisted Ultrasound on Molecular Permeability across Cell Barriers

Avoiding the Pitfalls of siRNA Delivery to the Retinal Pigment Epithelium with Physiologically Relevant Cell Models

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