Selective drug delivery to the retinal cells: Biological barriers and avenues

Ramsay, Eva; Lajunen, Tatu; Bhattacharya, Madhushree; Reinisalo, Mika; Rilla, Kirsi; Kidron, Heidi; Urtti, Arto

doi:10.1016/j.jconrel.2023.07.028

Cited by 6 publications

(7 citation statements)

References 201 publications

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“…This is supported by the observation that [ 11 C]erlotinib kinetics in the retina appeared to be less reversible than those in the brain (Figure ). The RPE forming the oBRB together with choroid tissues contains most of the eumelanin, which is the ocular melanin type mainly involved in drug binding. , A competition for melanin binding between [ 11 C]erlotinib and tariquidar or unlabeled erlotinib may thus have masked the effects of efflux transporter inhibition in the human retina and may explain the decrease in [ 11 C]erlotinib distribution to the retina in the case of concomitant administration of tariquidar or erlotinib. Radiolabeled tariquidar but also radiolabeled gefitinib, a first-generation EGFR-tyrosine kinase inhibitor like erlotinib, were shown to accumulate in melanin-rich tissues in animals, particularly in the eye. , Despite the lack of specific data in the literature on the binding capacity of erlotinib to melanin, its structural and physicochemical similarities to gefitinib (substituted quinazolines, p K a 5.4 for both drugs) suggest that erlotinib could also bind to melanin in the human retina.…”

Section: Discussionmentioning

confidence: 99%

“…The RPE forming the oBRB together with choroid tissues contains most of the eumelanin, which is the ocular melanin type mainly involved in drug binding. 5 , 47 A competition for melanin binding between [ 11 C]erlotinib and tariquidar or unlabeled erlotinib may thus have masked the effects of efflux transporter inhibition in the human retina and may explain the decrease in [ 11 C]erlotinib distribution to the retina in the case of concomitant administration of tariquidar or erlotinib. Radiolabeled tariquidar but also radiolabeled gefitinib, a first-generation EGFR-tyrosine kinase inhibitor like erlotinib, were shown to accumulate in melanin-rich tissues in animals, particularly in the eye.…”

Section: Discussionmentioning

confidence: 99%

“…The oBRB is formed by the tight retinal pigment epithelium (RPE), which separates the neural tissue at its apical side and the blood (i.e., choroidal circulation) at its basolateral side. 4,5 Efflux transporters of the ATP-binding cassette (ABC) family, i.e., P-glycoprotein (P-gp, encoded in humans by the ABCB1 gene and in rodents by the Abcb1a/b genes) and breast cancer resistance protein (BCRP, encoded in humans by the ABCG2 gene and in rodents by the Abcg2 gene), are coexpressed at the luminal (blood-facing) membrane of brain capillary endothelial cells and are key determinants of the barrier function of the BBB. 6 Dual substrates of P-gp and BCRP in most cases display a low brain distribution, as they are hindered by the combined action of P-gp and BCRP from crossing the BBB to reach the brain parenchyma.…”

Section: ■ Introductionmentioning

confidence: 99%

“…The distribution of systemically administered drugs from blood to the retina is tightly regulated by the blood–retina barrier (BRB), which comprises the inner (iBRB) and the outer BRB (oBRB). , The iBRB is formed by the endothelial cells from the intraretinal capillaries surrounded by pericytes, astrocytes, and Müller cells and is structurally similar to the blood–brain barrier (BBB), which is formed by the tight-junctional linking of brain capillary endothelial cells surrounded by astrocytes and pericytes. The oBRB is formed by the tight retinal pigment epithelium (RPE), which separates the neural tissue at its apical side and the blood (i.e., choroidal circulation) at its basolateral side. , …”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Dissimilar Effect of P-Glycoprotein and Breast Cancer Resistance Protein Inhibition on the Distribution of Erlotinib to the Retina and Brain in Humans and Mice

Biali,

Auvity,

Cisternino

et al. 2023

Mol. Pharmaceutics

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P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are two ATP-binding cassette efflux transporters that are coexpressed at the human blood−brain barrier (BBB) and blood−retina barrier (BRB). While pharmacological inhibition of P-gp and/or BCRP results in increased brain distribution of dual P-gp/BCRP substrate drugs, such as the tyrosine kinase inhibitor erlotinib, the effect of P-gp and/or BCRP inhibition on the retinal distribution of such drugs has hardly been investigated. In this study, we used positron emission tomography (PET) imaging to assess the effect of transporter inhibition on the distribution of [ 11 C]erlotinib to the human retina and brain. Twenty two healthy volunteers underwent two PET scans after intravenous (i.v.) injection of a microdose (<5 μg) of [ 11 C]erlotinib, a baseline scan, and a second scan either with concurrent i.v. infusion of tariquidar to inhibit P-gp (n = 5) or after oral intake of single ascending doses of erlotinib (300 mg, 650 mg, or 1000 mg, n = 17) to saturate erlotinib transport. In addition, transport of [ 3 H]erlotinib to the retina and brain was assessed in mice by in situ carotid perfusion under various drug transporter inhibition settings. In comparison to the baseline PET scan, coadministration of tariquidar or erlotinib led to a significant decrease of [ 11 C]erlotinib total volume of distribution (V T ) in the human retina by −25 ± 8% (p ≤ 0.05) and −41 ± 16% (p ≤ 0.001), respectively. In contrast, erlotinib intake led to a significant increase in [ 11 C]erlotinib V T in the human brain (+20 ± 16%, p ≤ 0.001), while administration of tariquidar did not result in any significant changes. In situ carotid perfusion experiments showed that both P-gp and BCRP significantly limit the distribution of erlotinib to the mouse retina and brain but revealed a similar discordant effect at the mouse BRB and BBB following co-perfusion with tariquidar and erlotinib as in humans. Co-perfusion with prototypical inhibitors of solute carrier transporters did not reveal a significant contribution of organic cation transporters (e.g., OCTs and OCTNs) and organic anion-transporting polypeptides (e.g., OATP2B1) to the retinal and cerebral distribution of erlotinib. In conclusion, we observed a dissimilar effect after P-gp and/or BCRP inhibition on the retinal and cerebral distribution of [ 11 C]erlotinib. The exact mechanism for this discrepancy remains unclear but may be related to the function of an unidentified erlotinib uptake carrier sensitive to tariquidar inhibition at the BRB. Our study highlights the great potential of PET to study drug distribution to the human retina and to assess the functional impact of membrane transporters on ocular drug distribution.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Dissimilar Effect of P-Glycoprotein and Breast Cancer Resistance Protein Inhibition on the Distribution of Erlotinib to the Retina and Brain in Humans and Mice

Biali,

Auvity,

Cisternino

et al. 2023

Mol. Pharmaceutics

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Recent Advances in Nanomedicine for Ocular Fundus Neovascularization Disease Management

Zhou,

Xu,

Shen

et al. 2024

Adv Healthcare Materials

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As an indispensable part of the human sensory system, visual acuity may be impaired and even develop into irreversible blindness due to various ocular pathologies. Among ocular diseases, fundus neovascularization diseases (FNDs) are prominent etiologies of visual impairment worldwide. Intravitreal injection of anti‐vascular endothelial growth factor drugs remains the primary therapy but is hurdled by common complications and incomplete potency. To renovate the current therapeutic modalities, nanomedicine emerged as the times required, which has been endowed with advanced capabilities, able to fulfill the effective ocular fundus drug delivery and achieve precise drug release control, thus further improving the therapeutic effect. This review provides a comprehensive summary of advances in nanomedicine for FND management from state‐of‐the‐art studies. Firstly, we thoroughly introduce the current therapeutic modalities for FNDs, focusing on the key challenges of ocular fundus drug delivery. Secondly, we comprehensively reviewed nanocarriers for ocular posterior drug delivery based on the nanostructures: polymer‐based nanocarriers, lipid‐based nanocarriers, and inorganic nanoparticles. Thirdly, we elaborate on the characteristics of the fundus microenvironment, their pathological changes during FNDs, and corresponding strategies for constructing smart nanocarriers. Furthermore, the challenges and prospects of nanomedicine for FND management are thoroughly discussed.This article is protected by copyright. All rights reserved

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