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52. Partitioning and Spatial Distribution of Drugs in Ocular Surface Tissues

Author

Balla, Anusha, Auriola, Seppo, Grey, Angus C., Demarais, Nicholas J., Valtari, Annika, Heikkinen, Emma M., Toropainen, Elisa, Urtti, Arto, Vellonen, Kati-Sisko, Ruponen, Marika, Drug Research Program, Drug Delivery, Drug Delivery Unit, and Division of Pharmaceutical Biosciences

Subjects
PHARMACOKINETICS, conjunctiva, PIGMENTED RABBIT, genetic structures, drug absorption, MALDI-IMS, beta-blocking agent, Article, eye diseases, RS1-441, OPHTHALMIC EMULSION, Pharmacy and materia medica, 317 Pharmacy, CORNEAL, cornea, CYCLOSPORINE, permeation, PERMEABILITY, PENETRATION, sense organs, PILOCARPINE, SYSTEMIC ABSORPTION, CONJUNCTIVAL
Abstract

Ocular drug absorption after eye drop instillation has been widely studied, but partitioning phenomena and spatial drug distribution are poorly understood. We investigated partitioning of seven beta-blocking drugs in corneal epithelium, corneal stroma, including endothelium and conjunctiva, using isolated porcine tissues and cultured human corneal epithelial cells. The chosen beta-blocking drugs had a wide range (−1.76–0.79) of n-octanol/buffer solution distribution coefficients at pH 7.4 (Log D7.4). In addition, the ocular surface distribution of three beta-blocking drugs was determined by matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS) after their simultaneous application in an eye drop to the rabbits in vivo. Studies with isolated porcine corneas revealed that the distribution coefficient (Kp) between the corneal epithelium and donor solution showed a positive relationship and good correlation with Log D7.4 and about a 50-fold range of Kp values (0.1–5). On the contrary, Kp between corneal stroma and epithelium showed an inverse (negative) relationship and correlation with Log D7.4 based on a seven-fold range of Kp values. In vitro corneal cell uptake showed a high correlation with the ex vivo corneal epithelium/donor Kp values. Partitioning of the drugs into the porcine conjunctiva also showed a positive relationship with lipophilicity, but the range of Kp values was less than with the corneal epithelium. MALDI-IMS allowed simultaneous detection of three compounds in the cornea, showed data in line with other experiments, and revealed uneven spatial drug distribution in the cornea. Our data indicate the importance of lipophilicity in defining the corneal pharmacokinetics and the Kp values are a useful building block in the kinetic simulation models for topical ocular drug administration.

Published
2021

54. Biopharmaceutics of Topical Ophthalmic Suspensions: Importance of Viscosity and Particle Size in Ocular Absorption of Indomethacin

Author

Toropainen, Elisa, primary, Fraser-Miller, Sara J., additional, Novakovic, Dunja, additional, Del Amo, Eva M., additional, Vellonen, Kati-Sisko, additional, Ruponen, Marika, additional, Viitala, Tapani, additional, Korhonen, Ossi, additional, Auriola, Seppo, additional, Hellinen, Laura, additional, Reinisalo, Mika, additional, Tengvall, Unni, additional, Choi, Stephanie, additional, Absar, Mohammad, additional, Strachan, Clare, additional, and Urtti, Arto, additional

Published
2021
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56. Drug Flux Across RPE Cell Models: The Hunt for An Appropriate Outer Blood–Retinal Barrier Model for Use in Early Drug Discovery

Author

Hellinen, Laura, Hongisto, Heidi, Ramsay, Eva, Kaarniranta, Kai, Vellonen, Kati-Sisko, Skottman, Heli, Ruponen, Marika, Lääketieteen ja terveysteknologian tiedekunta - Faculty of Medicine and Health Technology, Tampere University, Drug Delivery Unit, Division of Pharmaceutical Biosciences, and Drug Research Program

Subjects
PIGMENT EPITHELIUM, EXPRESSION, tight junctions, PREDICTION, Biolääketieteet - Biomedicine, retinal pigment epithelium, drug permeation, lcsh:RS1-441, Retinal barrier, MELANIN BINDING, ocular drug delivery, Article, lcsh:Pharmacy and materia medica, Drug permeation, PLASMA-MEMBRANES, PERMEABILITY, Retinal pigment epithelium, Tight junctions, Ocular drug delivery, Outer blood, Cell models, outer blood-retinal barrier, ARPE-19 CELLS, differentiation, eye diseases, cell models, TISSUE, 317 Pharmacy, Differentiation, sense organs, outer blood–retinal barrier, Farmasia - Pharmacy
Abstract

The retinal pigment epithelial (RPE) cell monolayer forms the outer blood−retinal barrier and has a crucial role in ocular pharmacokinetics. Although several RPE cell models are available, there have been no systematic comparisons of their barrier properties with respect to drug permeability. We compared the barrier properties of several RPE secondary cell lines (ARPE19, ARPE19mel, and LEPI) and both primary (hfRPE) and stem-cell derived RPE (hESC-RPE) cells by investigating the permeability of nine drugs (aztreonam, ciprofloxacin, dexamethasone, fluconazole, ganciclovir, ketorolac, methotrexate, voriconazole, and quinidine) across cell monolayers. ARPE19, ARPE19mel, and hfRPE cells displayed a narrow Papp value range, with relatively high permeation rates (5.2−26 × 10−6 cm/s. In contrast, hESC-RPE and LEPI cells efficiently restricted the drug flux, and displayed even lower Papp values than those reported for bovine RPE-choroid, with the range of 0.4−32 cm−6/s (hESC-RPE cells) and 0.4−29 × 10−6 cm/s, (LEPI cells). Therefore, ARPE19, ARPE19mel, and hfRPE cells failed to form a tight barrier, whereas hESC-RPE and LEPI cells restricted the drug flux to a similar extent as bovine RPE-choroid. Therefore, LEPI and hESC-RPE cells are valuable tools in ocular drug discovery.

Published
2020

57. Supplemental_Material_for_Microflow-Based_Device_for_in_Vitro_and_ex_Vivo_drug_Permeability_Studies_by_Hemmila,_et_al – Supplemental material for Microflow-Based Device for In Vitro and Ex Vivo Drug Permeability Studies

Author

Hemmilä, Samu, Ruponen, Marika, Toropainen, Elisa, Tengvall-Unadike, Unni, Urtti, Arto, and Kallio, Pasi

Subjects
FOS: Clinical medicine, 111599 Pharmacology and Pharmaceutical Sciences not elsewhere classified
Abstract

Supplemental material, Supplemental_Material_for_Microflow-Based_Device_for_in_Vitro_and_ex_Vivo_drug_Permeability_Studies_by_Hemmila,_et_al for Microflow-Based Device for In Vitro and Ex Vivo Drug Permeability Studies by Samu Hemmilä, Marika Ruponen, Elisa Toropainen, Unni Tengvall-Unadike, Arto Urtti and Pasi Kallio in SLAS Technology

Published
2020
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58. Characterization, stability, and in vivo efficacy studies of recombinant human CNTF and its permeation into the neural retina in ex vivo organotypic retinal explant culture models

Author

Itkonen, Jaakko, Annala, Ada, Tavakoli, Shirin, Arango-Gonzalez, Blanca, Ueffing, Marius, Toropainen, Elisa, Ruponen, Marika, Casteleijn, Marco G., Urtti, Arto, Division of Pharmaceutical Biosciences, Drug Delivery Unit, Drug Research Program, and Drug Delivery

Subjects
MOUSE-MODEL, lcsh:RS1-441, DRUG STABILITY, PHOTORECEPTOR SURVIVAL, Article, intravitreal delivery, protein aggregation, Intravitreal delivery, lcsh:Pharmacy and materia medica, OUTER SEGMENTS, SDG 3 - Good Health and Well-being, CNTF, Retinal penetration, retinal penetration, INTRAOCULAR GENE-TRANSFER, stability, eye diseases, Neuroprotection, CILIARY NEUROTROPHIC FACTOR, INTERLEUKIN-6 RECEPTOR, 317 Pharmacy, neuroprotection, sense organs, Protein aggregation, PROTEIN STABILITY, Stability, GANGLION-CELL SURVIVAL, INTRAVITREAL INJECTION
Abstract

Ciliary neurotrophic factor (CNTF) is one of the most studied neuroprotective agents with acknowledged potential in treating diseases of the posterior eye segment. Although its efficacy and mechanisms of action in the retina have been studied extensively, it is still not comprehensively understood which retinal cells mediate the therapeutic effects of CNTF. As with therapeutic proteins in general, it is poorly elucidated whether exogenous CNTF administered into the vitreous can enter and distribute into the retina and hence reach potentially responsive target cells. Here, we have characterized our purified recombinant human CNTF (rhCNTF), studied the protein&rsquo, s in vitro bioactivity in a cell-based assay, and evaluated the thermodynamic and oligomeric status of the protein during storage. Biological activity of rhCNTF was further evaluated in vivo in an animal model of retinal degeneration. The retinal penetration and distribution of rhCNTF after 24 h was studied utilizing two ex vivo retina models. Based on our characterization findings, our rhCNTF is correctly folded and biologically active. Moreover, based on initial screening and subsequent follow-up, we identified two buffers in which rhCNTF retains its stability during storage. Whereas rhCNTF did not show photoreceptor preservative effect or improve the function of photoreceptors in vivo, this could possibly be due to the used disease model or the short duration of action with a single intravitreal injection of rhCNTF. On the other hand, the lack of in vivo efficacy was shown to not be due to distribution limitations, permeation into the retina was observed in both retinal explant models as in 24 h rhCNTF penetrated the inner limiting membrane, and being mostly observed in the ganglion cell layer, distributed to different layers of the neural retina. As rhCNTF can reach deeper retinal layers, in general, having direct effects on resident CNTF-responsive target cells is plausible.

Published
2020

66. Characterization, Stability, and In Vivo Efficacy Studies of Recombinant Human CNTF and Its Permeation into the Neural Retina in Ex Vivo Organotypic Retinal Explant Culture Models

Author

Itkonen, Jaakko, primary, Annala, Ada, additional, Tavakoli, Shirin, additional, Arango-Gonzalez, Blanca, additional, Ueffing, Marius, additional, Toropainen, Elisa, additional, Ruponen, Marika, additional, Casteleijn, Marco G., additional, and Urtti, Arto, additional

Published
2020
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68. Electrical synapses interconnecting axons in the optic nerve head–a novel model of optic nerve function

Author

Pietrucha‐Dutczak, Marita, primary, Akhtar, Saeed, additional, Liu, Xiaonan, additional, Podracka, Lucia, additional, Toropainen, Elisa, additional, Alkanaan, Aljoharah, additional, Ruponen, Marika, additional, Urtti, Arto, additional, Varjosalo, Markku, additional, Kaarniranta, Kai, additional, Lewin‐Kowalik, Joanna, additional, and Smedowski, Adrian, additional

Published
2019
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74. Expression, activity and pharmacokinetic impact of ocular transporters

Author

Vellonen, Kati-Sisko, Hellinen, Laura, Mannermaa, Eliisa, Ruponen, Marika, Urtti, Arto, Kidron, Heidi, Faculty of Pharmacy, Division of Pharmaceutical Biosciences, Drug Delivery, Drug Research Program, Doctoral Programme in Drug Research, Doctoral Programme in Materials Research and Nanosciences, and Drug Delivery Unit

Subjects
BLOOD-RETINAL BARRIER, AMINO-ACID TRANSPORTER, CORNEAL EPITHELIAL-CELLS, P-GLYCOPROTEIN, AQUEOUS HUMOR BARRIER, ORGANIC CATION TRANSPORTERS, eye diseases, Neural retina, Cornea, Pharmacogenetics, INTRAOCULAR-PRESSURE RESPONSE, TARGETED ABSOLUTE PROTEOMICS, 317 Pharmacy, CARRIER-MEDIATED TRANSPORT, Blood-aqueous barrier, sense organs, OPEN-ANGLE GLAUCOMA, Active transport, Conjunctiva
Abstract

The eye is protected by several tissues that limit the permeability and entry of potentially harmful substances, but also hamper the delivery of drugs in the treatment of ocular diseases. Active transport across the ocular barriers may affect drug distribution, but the impact of drug transporters on ocular drug delivery is not well known. We have collected and critically reviewed the literature for ocular expression and activity of known drug transporters. The review concentrates on drug transporters that have been functionally characterized in ocular tissues or primary cells and on transporters for which there is available expression data at the protein level. Species differences are highlighted, since these may explain observed inconsistencies in the influence of specific transporters on drug disposition. There is variable evidence about the pharmacokinetic role of transporters in ocular tissues. The strongest evidence for the role of active transport is available for the blood-retinal barrier. We explored the role of active transport in the cornea and blood retinal barrier with pharmacokinetic simulations. The simulations show that the active transport is important only in the case of specific parameter combinations. (C) 2017 Elsevier B.V. All rights reserved.

Published
2018

75. Highly hydrophilic 1,3-oxazol-5-yl benzenesulfonamide inhibitors of carbonic anhydrase II for reduction of glaucoma-related intraocular pressure

Author

Kalinin, Stanislav, primary, Valtari, Annika, additional, Ruponen, Marika, additional, Toropainen, Elisa, additional, Kovalenko, Alexander, additional, Nocentini, Alessio, additional, Gureev, Maxim, additional, Dar'in, Dmitry, additional, Urtti, Arto, additional, Supuran, Claudiu T., additional, and Krasavin, Mikhail, additional

Published
2019
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77. Electrical synapses interconnecting axons revealed in the optic nerve head – a novel model of gap junctions’ involvement in optic nerve function

Author

Smedowski, Adrian, primary, Akhtar, Saeed, additional, Liu, Xiaonan, additional, Pietrucha‐Dutczak, Marita, additional, Podracka, Lucia, additional, Toropainen, Elisa, additional, Alkanaan, Aljoharah, additional, Ruponen, Marika, additional, Urtti, Arto, additional, Varjosalo, Markku, additional, Kaarniranta, Kai, additional, and Lewin‐Kowalik, Joanna, additional

Published
2019
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81. Distribution of Small Molecular Weight Drugs into the Porcine Lens: Studies on Imaging Mass Spectrometry, Partition Coefficients, and Implications in Ocular Pharmacokinetics

Author

Heikkinen, Emma M., primary, Auriola, Seppo, additional, Ranta, Veli-Pekka, additional, Demarais, Nicholas J., additional, Grey, Angus C., additional, del Amo, Eva M., additional, Toropainen, Elisa, additional, Vellonen, Kati-Sisko, additional, Urtti, Arto, additional, and Ruponen, Marika, additional

Published
2019
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83. Electrical synapses interconnecting axons revealed in the optic nerve head – a novel model of gap junctions' involvement in optic nerve function.

Author

Smedowski, Adrian, Akhtar, Saeed, Liu, Xiaonan, Pietrucha‐Dutczak, Marita, Podracka, Lucia, Toropainen, Elisa, Alkanaan, Aljoharah, Ruponen, Marika, Urtti, Arto, Varjosalo, Markku, Kaarniranta, Kai, and Lewin‐Kowalik, Joanna

Subjects
OPTIC nerve, GLIAL fibrillary acidic protein, SYNAPSES, VISUAL evoked potentials, AXONS
Abstract

Purpose: To characterize newly discovered electrical synapses, formed by connexin (Cx) 36 and 45, between neighbouring axons within the optic nerve head. Methods: Twenty‐five Wistar rats were killed by CO2 inhalation. Proximal and distal optic nerve (ON) stumps were collected and processed for immunostainings, electron microscopy (EM) with immunogold labelling, PCR and Western blots (WB). Additional 15 animals were deeply anaesthetized, and flash visual evoked potentials (fVEP) after retrobulbar injection of saline (negative control) or 100 μm meclofenamic acid solution (gap junctions' blocker) were recorded. Human paraffin cross‐sections of eyeballs for immunostainings were obtained from the Human Eye Biobank for Research. Results: Immunostainings of both rat and human ON revealed the presence of Cx45 and 36 colocalizing with β3‐tubulin, but not with glial fibrillary acidic protein (GFAP). In WB, Cx36 content in optic nerve was approximately halved when compared with retina (0.58 ± 0.005 in proximal stump and 0.44 ± 0.02 in distal stump), Cx45 showed higher levels (0.68 ± 0.01 in proximal stump and 0.9 ± 0.07 in distal stump). In immunogold‐EM of optic nerve sections, we found electric synapses (formed mostly by Cx45) directly coupling neighbouring axons. In fVEP, blocking of gap junctions with meclofenamic acid resulted in significant prolongation of the latency of P1 wave up to 160% after 30 min (p < 0.001). Conclusions: Optic nerve (ON) axons are equipped with electrical synapses composed of neuronal connexins, especially Cx45, creating direct morphological and functional connections between each other. This finding could have substantial implications for understanding of the pathogenesis of various optic neuropathies and identifies a new potential target for a therapeutic approach. [ABSTRACT FROM AUTHOR]

Published
2020
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88. Increased intraocular pressure alters the cellular distribution of HuR protein in retinal ganglion cells – A possible sign of endogenous neuroprotection failure

Author

Smedowski, Adrian, primary, Liu, Xiaonan, additional, Podracka, Lucia, additional, Akhtar, Saeed, additional, Trzeciecka, Anna, additional, Pietrucha-Dutczak, Marita, additional, Lewin-Kowalik, Joanna, additional, Urtti, Arto, additional, Ruponen, Marika, additional, Kaarniranta, Kai, additional, Varjosalo, Markku, additional, and Amadio, Marialaura, additional

Published
2018
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89. Pharmacokinetic aspects of retinal drug delivery

Author

University of Helsinki, Faculty of Pharmacy, University of Helsinki, Lääkkeen keksintä- ja kehitysteknologian keskus (DDTC) (-2009), del Amo, Eva M., Rimpelä, Anna-Kaisa Irmeli, Heikkinen, Emma, Kari, Otto K., Ramsay, Eva, Lajunen, Tatu, Schmitt, Mechthild, Pelkonen, Laura, Bhattacharya, Madhushree, Richardson, Dominique, Subrizi, Astrid, Turunen, Tiina, Reinisalo, Mika, Itkonen, Jaakko, Toropainen, Elisa, Casteleijn, Marco G., Kidron, Heidi, Antopolsky, Maxim, Vellonen, Kati-Sisko, Ruponen, Marika, Urtti, Arto, University of Helsinki, Faculty of Pharmacy, University of Helsinki, Lääkkeen keksintä- ja kehitysteknologian keskus (DDTC) (-2009), del Amo, Eva M., Rimpelä, Anna-Kaisa Irmeli, Heikkinen, Emma, Kari, Otto K., Ramsay, Eva, Lajunen, Tatu, Schmitt, Mechthild, Pelkonen, Laura, Bhattacharya, Madhushree, Richardson, Dominique, Subrizi, Astrid, Turunen, Tiina, Reinisalo, Mika, Itkonen, Jaakko, Toropainen, Elisa, Casteleijn, Marco G., Kidron, Heidi, Antopolsky, Maxim, Vellonen, Kati-Sisko, Ruponen, Marika, and Urtti, Arto

Abstract

Drug delivery to the posterior eye segment is an important challenge in ophthalmology, because many diseases affect the retina and choroid leading to impaired vision or blindness. Currently, intravitreal injections are the method of choice to administer drugs to the retina, but this approach is applicable only in selected cases (e.g. anti-VEGF antibodies and soluble receptors). There are two basic approaches that can be adopted to improve retinal drug delivery: prolonged and/or retina targeted delivery of intravitreal drugs and use of other routes of drug administration, such as periocular, suprachoroidal, sub-retinal, systemic, or topical. Properties of the administration route, drug and delivery system determine the efficacy and safety of these approaches. Pharmacokinetic and pharmacodynamic factors determine the required dosing rates and doses that are needed for drug action. In addition, tolerability factors limit the use of many materials in ocular drug delivery. This review article provides a critical discussion of retinal drug delivery, particularly from the pharmacokinetic point of view. This article does not include an extensive review of drug delivery technologies, because they have already been reviewed several times recently. Instead, we aim to provide a systematic and quantitative view on the pharmacokinetic factors in drug delivery to the posterior eye segment. This review is based on the literature and unpublished data from the authors' laboratory.

Published
2017

91. Creation of a library of induced pluripotent stem cells from Parkinsonian patients

Author

Holmqvist, Staffan, primary, Lehtonen, Šárka, additional, Chumarina, Margarita, additional, Puttonen, Katja A, additional, Azevedo, Carla, additional, Lebedeva, Olga, additional, Ruponen, Marika, additional, Oksanen, Minna, additional, Djelloul, Mehdi, additional, Collin, Anna, additional, Goldwurm, Stefano, additional, Meyer, Morten, additional, Lagarkova, Maria, additional, Kiselev, Sergei, additional, Koistinaho, Jari, additional, and Roybon, Laurent, additional

Published
2016
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95. Transplanted Human Induced Pluripotent Stem Cell-Derived Neural Progenitor Cells Do Not Promote Functional Recovery of Pharmacologically Immunosuppressed Mice with Contusion Spinal Cord Injury

Author

Pomeshchik, Yuriy, primary, Puttonen, Katja A., additional, Kidin, Iurii, additional, Ruponen, Marika, additional, Lehtonen, Sarka, additional, Malm, Tarja, additional, Åkesson, Elisabet, additional, Hovatta, Outi, additional, and Koistinaho, Jari, additional

Published
2015
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98. Chondrogenic differentiation of human pluripotent stem cells in chondrocyte co-culture

Author

Qu, Chengjuan, Puttonen, Katja, Lindeberg, Heli, Ruponen, Marika, Hovatta, Outi, Koistinaho, Jari, Lammi, Mikko, Qu, Chengjuan, Puttonen, Katja, Lindeberg, Heli, Ruponen, Marika, Hovatta, Outi, Koistinaho, Jari, and Lammi, Mikko

Abstract

Chondrogenic differentiation of human embryonic (hESCs) or induced pluripotent stem cells (hiPSCs) has been achieved in embryoid bodies (EBs) by adding selected growth factors to the medium. Also chondrocyte-secreted factors have been considered to promote the chondrogenic differentiation. Hence, we studied whether co-culture with primary chondrocytes can induce hESCs or hiPSCs to differentiate into chondrocyte lineage. Co-culture of hESCs or hiPSCs was established in a transwell insert system in feeder-free culture conditions, while hESCs or hiPSCs grown alone in the wells were used as controls. After 3-week co-culture with weekly replenished chondrocytes, the chondrogenically committed cells (hCCCs) were evaluated by morphology, immunocytochemistry, quantitative real-time RT-PCR, and analysis of chondrogenic, osteogenic and adipogenic differentiation markers. The expressions of chondrocyte- and pluripotency-associated genes were frequently measured during the monolayer expansion of hCCCs from passage 1 to 10. Human CCCs displayed morphology similar to chondrocytes, and expressed chondrocyte-associated genes, which were declined following passaging, similarly to passaged chondrocytes. They also formed a chondrogenic cell pellet, and differentiated into chondrocytic cells, which secreted abundant extracellular matrix. Human CCCs also proliferated rapidly. However, they did not show osteogenic or adipogenic differentiation capacity. Our results show that co-culture of hESCs or hiPSCs with primary chondrocytes could induce specific chondrogenic differentiation.

Published
2013
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