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Ranch K, Chawnani D, Jani H, Acharya D, Patel CA, Jacob S, Babu RJ, Tiwari AK, Al-Tabakha MM, Boddu SHS. An update on the latest strategies in retinal drug delivery. Expert Opin Drug Deliv 2024; 21:695-712. [PMID: 38787783 DOI: 10.1080/17425247.2024.2358886] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Accepted: 05/20/2024] [Indexed: 05/26/2024]
Abstract
INTRODUCTION Retinal drug delivery has witnessed significant advancements in recent years, mainly driven by the prevalence of retinal diseases and the need for more efficient and patient-friendly treatment strategies. AREAS COVERED Advancements in nanotechnology have introduced novel drug delivery platforms to improve bioavailability and provide controlled/targeted delivery to specific retinal layers. This review highlights various treatment options for retinal diseases. Additionally, diverse strategies aimed at enhancing delivery of small molecules and antibodies to the posterior segment such as implants, polymeric nanoparticles, liposomes, niosomes, microneedles, iontophoresis and mixed micelles were emphasized. A comprehensive overview of the special technologies currently under clinical trials or already in the clinic was provided. EXPERT OPINION Ideally, drug delivery system for treating retinal diseases should be less invasive in nature and exhibit sustained release up to several months. Though topical administration in the form of eye drops offers better patient compliance, its clinical utility is limited by nature of the drug. There is a wide range of delivery platforms available, however, it is not easy to modify any single platform to accommodate all types of drugs. Coordinated efforts between ophthalmologists and drug delivery scientists are necessary while developing therapeutic compounds, right from their inception.
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Affiliation(s)
- Ketan Ranch
- Department of Pharmaceutics, L. M. College of Pharmacy, Ahmedabad, India
| | - Disha Chawnani
- Department of Pharmaceutics, L. M. College of Pharmacy, Ahmedabad, India
| | - Harshilkumar Jani
- Department of Pharmaceutics, L. M. College of Pharmacy, Ahmedabad, India
| | - Devarshi Acharya
- Department of Pharmaceutics, L. M. College of Pharmacy, Ahmedabad, India
| | - Chirag Amrutlal Patel
- Department of Pharmacology & Pharmacy practices, L. M. College of Pharmacy, Ahmedabad, India
| | - Shery Jacob
- Department of Pharmaceutical Sciences, College of Pharmacy, Gulf Medical University, Ajman, United Arab Emirates UAE
| | - R Jayachandra Babu
- Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, AL, USA
| | - Amit K Tiwari
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Moawia M Al-Tabakha
- Center of Medical and Bio-allied Health Sciences Research, Ajman University, Ajman, UAE
| | - Sai H S Boddu
- Center of Medical and Bio-allied Health Sciences Research, Ajman University, Ajman, UAE
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Haydinger CD, Ferreira LB, Williams KA, Smith JR. Mechanisms of macular edema. Front Med (Lausanne) 2023; 10:1128811. [PMID: 36960343 PMCID: PMC10027768 DOI: 10.3389/fmed.2023.1128811] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Accepted: 02/16/2023] [Indexed: 03/09/2023] Open
Abstract
Macular edema is the pathological accumulation of fluid in the central retina. It is a complication of many retinal diseases, including diabetic retinopathy, retinal vascular occlusions and uveitis, among others. Macular edema causes decreased visual acuity and, when chronic or refractory, can cause severe and permanent visual impairment and blindness. In most instances, it develops due to dysregulation of the blood-retinal barrier which permits infiltration of the retinal tissue by proteins and other solutes that are normally retained in the blood. The increase in osmotic pressure in the tissue drives fluid accumulation. Current treatments include vascular endothelial growth factor blockers, corticosteroids, and non-steroidal anti-inflammatory drugs. These treatments target vasoactive and inflammatory mediators that cause disruption to the blood-retinal barrier. In this review, a clinical overview of macular edema is provided, mechanisms of disease are discussed, highlighting processes targeted by current treatments, and areas of opportunity for future research are identified.
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Afarid M, Mahmoodi S, Baghban R. Recent achievements in nano-based technologies for ocular disease diagnosis and treatment, review and update. J Nanobiotechnology 2022; 20:361. [PMID: 35918688 PMCID: PMC9344723 DOI: 10.1186/s12951-022-01567-7] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 07/19/2022] [Indexed: 11/10/2022] Open
Abstract
Ocular drug delivery is one of the most challenging endeavors among the various available drug delivery systems. Despite having suitable drugs for the treatment of ophthalmic disease, we have not yet succeeded in achieving a proper drug delivery approach with the least adverse effects. Nanotechnology offers great opportunities to overwhelm the restrictions of common ocular delivery systems, including low therapeutic effects and adverse effects because of invasive surgery or systemic exposure. The present review is dedicated to highlighting and updating the recent achievements of nano-based technologies for ocular disease diagnosis and treatment. While further effort remains, the progress illustrated here might pave the way to new and very useful ocular nanomedicines.
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Affiliation(s)
- Mehrdad Afarid
- Poostchi Ophthalmology Research Center, Department of Ophthalmology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Shirin Mahmoodi
- Department of Medical Biotechnology, School of Medicine, Fasa University of Medical Sciences, Fasa, Iran
| | - Roghayyeh Baghban
- Poostchi Ophthalmology Research Center, Department of Ophthalmology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
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Non-vasogenic cystoid maculopathies. Prog Retin Eye Res 2022; 91:101092. [PMID: 35927124 DOI: 10.1016/j.preteyeres.2022.101092] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 05/30/2022] [Accepted: 06/01/2022] [Indexed: 11/23/2022]
Abstract
Besides cystoid macular edema due to a blood-retinal barrier breakdown, another type of macular cystoid spaces referred to as non-vasogenic cystoid maculopathies (NVCM) may be detected on optical coherence tomography but not on fluorescein angiography. Various causes may disrupt retinal cell cohesion or impair retinal pigment epithelium (RPE) and Müller cell functions in the maintenance of retinal dehydration, resulting in cystoid spaces formation. Tractional causes include vitreomacular traction, epiretinal membranes and myopic foveoschisis. Surgical treatment does not always allow cystoid space resorption. In inherited retinal dystrophies, cystoid spaces may be part of the disease as in X-linked retinoschisis or enhanced S-cone syndrome, or occur occasionally as in bestrophinopathies, retinitis pigmentosa and allied diseases, congenital microphthalmia, choroideremia, gyrate atrophy and Bietti crystalline dystrophy. In macular telangiectasia type 2, cystoid spaces and cavitations do not depend on the fluid leakage from telangiectasia. Various causes affecting RPE function may result in NVCM such as chronic central serous chorioretinopathy and paraneoplastic syndromes. Non-exudative age macular degeneration may also be complicated by intraretinal cystoid spaces in the absence of fluorescein leakage. In these diseases, cystoid spaces occur in a context of retinal cell loss. Various causes of optic atrophy, including open-angle glaucoma, result in microcystoid spaces in the inner nuclear layer due to a retrograde transsynaptic degeneration. Lastly, drug toxicity may also induce cystoid maculopathy. Identifying NVCM on multimodal imaging, including fluorescein angiography if needed, allows guiding the diagnosis of the causative disease and choosing adequate treatment when available.
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Herranz Cabarcos A, Quiroz Quiroga MJ, Alarcón Valero I, Castilla Martí M, Pospoki V, Vilaplana Blanch D. Vitrectomy with subretinal tissue plasminogen activator (r-TPA) and intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) for submacular hemorrhages treatment: Retrospective analysis of 22 cases. ARCHIVOS DE LA SOCIEDAD ESPANOLA DE OFTALMOLOGIA 2022; 97:391-395. [PMID: 35779895 DOI: 10.1016/j.oftale.2021.07.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 07/04/2021] [Indexed: 06/15/2023]
Abstract
BACKGROUND Macular hemorrhages are a severe complication of other retinal pathologies, such as age-related macular degeneration (AMD) or macroaneurysms. Their therapeutic approach is not standardized, and can vary from observation to surgical treatment. MATERIAL AND METHODS Retrospective analysis of 22 cases of macular hemorrhage, treated with vitrectomy associated to subretinal rTPA and intravitreal anti-VEGF over a period of 5 years. RESULTS 22 eyes of 22 patients were included, of which 12 (52%) were women. The mean age at diagnosis was 84.4 years. 13 patients were pseudophakic (54.1%) and 19 (86.36%) had previous ophthalmological comorbidities. The etiology of the macular hemorrhage was AMD in 19 patients (86.36%). The mean of best VA corrected at diagnosis was 24.55 (Early Treatment Diabetic Retinopathy Study score -ETDRS), with a statistically significant improvement to 36.78 3 months after surgery (p = 0.011). With an average of 23.5 months of follow-up, no differences in prognosis associated with the etiology or size of the hemorrhage were observed. CONCLUSION The treatment of macular hemorrhages by vitrectomy, subretinal rTPA and antiVEGF improves the visual prognosis of affected patients.
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Affiliation(s)
- A Herranz Cabarcos
- Departamento de Oftalmología, Consorci Sanitari Moisès Broggi, Barcelona, Spain.
| | - M J Quiroz Quiroga
- Departamento de Oftalmología, Hospital de l'Esperança - Parc de Salut Mar, Barcelona, Spain
| | - I Alarcón Valero
- Departamento de Oftalmología, Hospital de l'Esperança - Parc de Salut Mar, Barcelona, Spain
| | - M Castilla Martí
- Departamento de Oftalmología, Hospital de l'Esperança - Parc de Salut Mar, Barcelona, Spain
| | - V Pospoki
- Departamento de Oftalmología, Hospital de l'Esperança - Parc de Salut Mar, Barcelona, Spain
| | - D Vilaplana Blanch
- Departamento de Oftalmología, Hospital de l'Esperança - Parc de Salut Mar, Barcelona, Spain
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Cheng KJ, Hsieh CM, Nepali K, Liou JP. Ocular Disease Therapeutics: Design and Delivery of Drugs for Diseases of the Eye. J Med Chem 2020; 63:10533-10593. [PMID: 32482069 DOI: 10.1021/acs.jmedchem.9b01033] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The ocular drug discovery field has evidenced significant advancement in the past decade. The FDA approvals of Rhopressa, Vyzulta, and Roclatan for glaucoma, Brolucizumab for wet age-related macular degeneration (wet AMD), Luxturna for retinitis pigmentosa, Dextenza (0.4 mg dexamethasone intracanalicular insert) for ocular inflammation, ReSure sealant to seal corneal incisions, and Lifitegrast for dry eye represent some of the major developments in the field of ocular therapeutics. A literature survey also indicates that gene therapy, stem cell therapy, and target discovery through genomic research represent significant promise as potential strategies to achieve tissue repair or regeneration and to attain therapeutic benefits in ocular diseases. Overall, the emergence of new technologies coupled with first-in-class entries in ophthalmology are highly anticipated to restructure and boost the future trends in the field of ophthalmic drug discovery. This perspective focuses on various aspects of ocular drug discovery and the recent advances therein. Recent medicinal chemistry campaigns along with a brief overview of the structure-activity relationships of the diverse chemical classes and developments in ocular drug delivery (ODD) are presented.
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Affiliation(s)
- Kuei-Ju Cheng
- School of Pharmacy, College of Pharmacy, Taipei Medical University, 250 Wuxing Street, Taipei 11031, Taiwan.,Department of Pharmacy, Taipei Municipal Wanfang Hospital, Taipei Medical University, No. 111, Section 3, Xing-Long Road, Taipei 11696, Taiwan
| | - Chien-Ming Hsieh
- School of Pharmacy, College of Pharmacy, Taipei Medical University, 250 Wuxing Street, Taipei 11031, Taiwan
| | - Kunal Nepali
- School of Pharmacy, College of Pharmacy, Taipei Medical University, 250 Wuxing Street, Taipei 11031, Taiwan
| | - Jing-Ping Liou
- School of Pharmacy, College of Pharmacy, Taipei Medical University, 250 Wuxing Street, Taipei 11031, Taiwan
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Varela-Fernández R, Díaz-Tomé V, Luaces-Rodríguez A, Conde-Penedo A, García-Otero X, Luzardo-Álvarez A, Fernández-Ferreiro A, Otero-Espinar FJ. Drug Delivery to the Posterior Segment of the Eye: Biopharmaceutic and Pharmacokinetic Considerations. Pharmaceutics 2020; 12:E269. [PMID: 32188045 PMCID: PMC7151081 DOI: 10.3390/pharmaceutics12030269] [Citation(s) in RCA: 211] [Impact Index Per Article: 42.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2020] [Revised: 03/06/2020] [Accepted: 03/11/2020] [Indexed: 01/22/2023] Open
Abstract
The treatment of the posterior-segment ocular diseases, such as age-related eye diseases (AMD) or diabetic retinopathy (DR), present a challenge for ophthalmologists due to the complex anatomy and physiology of the eye. This specialized organ is composed of various static and dynamic barriers that restrict drug delivery into the target site of action. Despite numerous efforts, effective intraocular drug delivery remains unresolved and, therefore, it is highly desirable to improve the current treatments of diseases affecting the posterior cavity. This review article gives an overview of pharmacokinetic and biopharmaceutics aspects for the most commonly-used ocular administration routes (intravitreal, topical, systemic, and periocular), including information of the absorption, distribution, and elimination, as well as the benefits and limitations of each one. This article also encompasses different conventional and novel drug delivery systems designed and developed to improve drug pharmacokinetics intended for the posterior ocular segment treatment.
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Affiliation(s)
- Rubén Varela-Fernández
- Department of Pharmacology, Pharmacy and Pharmaceutical Technology, University of Santiago de Compostela (USC), Campus vida, 15782 Santiago de Compostela, Spain; (R.V.-F.); (V.D.-T.); (A.L.-R.); (A.C.-P.); (X.G.-O.); (A.L.-Á.)
- Clinical Neurosciences Group, University Clinical Hospital, Health Research Institute of Santiago de Compostela (IDIS), Travesía da Choupana s/n, 15706 Santiago de Compostela, Spain
| | - Victoria Díaz-Tomé
- Department of Pharmacology, Pharmacy and Pharmaceutical Technology, University of Santiago de Compostela (USC), Campus vida, 15782 Santiago de Compostela, Spain; (R.V.-F.); (V.D.-T.); (A.L.-R.); (A.C.-P.); (X.G.-O.); (A.L.-Á.)
- Clinical Pharmacology Group, University Clinical Hospital, Health Research Institute of Santiago de Compostela (IDIS), Travesía da Choupana s/n, 15706 Santiago de Compostela, Spain
| | - Andrea Luaces-Rodríguez
- Department of Pharmacology, Pharmacy and Pharmaceutical Technology, University of Santiago de Compostela (USC), Campus vida, 15782 Santiago de Compostela, Spain; (R.V.-F.); (V.D.-T.); (A.L.-R.); (A.C.-P.); (X.G.-O.); (A.L.-Á.)
- Clinical Pharmacology Group, University Clinical Hospital, Health Research Institute of Santiago de Compostela (IDIS), Travesía da Choupana s/n, 15706 Santiago de Compostela, Spain
| | - Andrea Conde-Penedo
- Department of Pharmacology, Pharmacy and Pharmaceutical Technology, University of Santiago de Compostela (USC), Campus vida, 15782 Santiago de Compostela, Spain; (R.V.-F.); (V.D.-T.); (A.L.-R.); (A.C.-P.); (X.G.-O.); (A.L.-Á.)
- Paraquasil Group, Health Research Institute of Santiago de Compostela (IDIS), Travesía da Choupana s/n, 15706 Santiago de Compostela, Spain
| | - Xurxo García-Otero
- Department of Pharmacology, Pharmacy and Pharmaceutical Technology, University of Santiago de Compostela (USC), Campus vida, 15782 Santiago de Compostela, Spain; (R.V.-F.); (V.D.-T.); (A.L.-R.); (A.C.-P.); (X.G.-O.); (A.L.-Á.)
- Molecular Imaging Group. University Clinical Hospital, Health Research Institute of Santiago de Compostela (IDIS), Travesía da Choupana s/n, 15706 Santiago de Compostela, Spain
| | - Asteria Luzardo-Álvarez
- Department of Pharmacology, Pharmacy and Pharmaceutical Technology, University of Santiago de Compostela (USC), Campus vida, 15782 Santiago de Compostela, Spain; (R.V.-F.); (V.D.-T.); (A.L.-R.); (A.C.-P.); (X.G.-O.); (A.L.-Á.)
- Paraquasil Group, Health Research Institute of Santiago de Compostela (IDIS), Travesía da Choupana s/n, 15706 Santiago de Compostela, Spain
| | - Anxo Fernández-Ferreiro
- Department of Pharmacology, Pharmacy and Pharmaceutical Technology, University of Santiago de Compostela (USC), Campus vida, 15782 Santiago de Compostela, Spain; (R.V.-F.); (V.D.-T.); (A.L.-R.); (A.C.-P.); (X.G.-O.); (A.L.-Á.)
- Clinical Pharmacology Group, University Clinical Hospital, Health Research Institute of Santiago de Compostela (IDIS), Travesía da Choupana s/n, 15706 Santiago de Compostela, Spain
| | - Francisco J. Otero-Espinar
- Department of Pharmacology, Pharmacy and Pharmaceutical Technology, University of Santiago de Compostela (USC), Campus vida, 15782 Santiago de Compostela, Spain; (R.V.-F.); (V.D.-T.); (A.L.-R.); (A.C.-P.); (X.G.-O.); (A.L.-Á.)
- Paraquasil Group, Health Research Institute of Santiago de Compostela (IDIS), Travesía da Choupana s/n, 15706 Santiago de Compostela, Spain
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De Matteis V, Rizzello L. Noble Metals and Soft Bio-Inspired Nanoparticles in Retinal Diseases Treatment: A Perspective. Cells 2020; 9:E679. [PMID: 32164376 PMCID: PMC7140625 DOI: 10.3390/cells9030679] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 03/06/2020] [Accepted: 03/08/2020] [Indexed: 02/06/2023] Open
Abstract
We are witnessing an exponential increase in the use of different nanomaterials in a plethora of biomedical fields. We are all aware of how nanoparticles (NPs) have influenced and revolutionized the way we supply drugs or how to use them as therapeutic agents thanks to their tunable physico-chemical properties. However, there is still a niche of applications where NP have not yet been widely explored. This is the field of ocular delivery and NP-based therapy, which characterizes the topic of the current review. In particular, many efforts are being made to develop nanosystems capable of reaching deeper sections of the eye such as the retina. Particular attention will be given here to noble metal (gold and silver), and to polymeric nanoparticles, systems consisting of lipid bilayers such as liposomes or vesicles based on nonionic surfactant. We will report here the most relevant literature on the use of different types of NPs for an efficient delivery of drugs and bio-macromolecules to the eyes or as active therapeutic tools.
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Affiliation(s)
- Valeria De Matteis
- Department of Mathematics and Physics “Ennio De Giorgi”, University of Salento, Via Arnesano, 73100 Lecce, Italy
| | - Loris Rizzello
- Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, UK;
- Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Baldiri Reixac 10-12, 08028 Barcelona, Spain
- Department of Pharmaceutical Sciences, University of Milan, via Mangiagalli 25, 20133 Milano, Italy
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Juliana FR, Kesse S, Boakye-Yiadom KO, Veroniaina H, Wang H, Sun M. Promising Approach in the Treatment of Glaucoma Using Nanotechnology and Nanomedicine-Based Systems. Molecules 2019; 24:E3805. [PMID: 31652593 PMCID: PMC6833088 DOI: 10.3390/molecules24203805] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Revised: 10/17/2019] [Accepted: 10/19/2019] [Indexed: 12/14/2022] Open
Abstract
Glaucoma is considered a leading cause of blindness with the human eye being one of the body's most delicate organs. Ocular diseases encompass diverse diseases affecting the anterior and posterior ocular sections, respectively. The human eye's peculiar and exclusive anatomy and physiology continue to pose a significant obstacle to researchers and pharmacologists in the provision of efficient drug delivery. Though several traditional invasive and noninvasive eye therapies exist, including implants, eye drops, and injections, there are still significant complications that arise which may either be their low bioavailability or the grave ocular adverse effects experienced thereafter. On the other hand, new nanoscience technology and nanotechnology serve as a novel approach in ocular disease treatment. In order to interact specifically with ocular tissues and overcome ocular challenges, numerous active molecules have been modified to react with nanocarriers. In the general population of glaucoma patients, disease growth and advancement cannot be contained by decreasing intraocular pressure (IOP), hence a spiking in future research for novel drug delivery systems and target therapeutics. This review focuses on nanotechnology and its therapeutic and diagnostic prospects in ophthalmology, specifically glaucoma. Nanotechnology and nanomedicine history, the human eye anatomy, research frontiers in nanomedicine and nanotechnology, its imaging modal quality, diagnostic and surgical approach, and its possible application in glaucoma will all be further explored below. Particular focus will be on the efficiency and safety of this new therapy and its advances.
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Affiliation(s)
| | - Samuel Kesse
- School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China.
- Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
| | - Kofi Oti Boakye-Yiadom
- School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China.
- Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
| | - Hanitrarimalala Veroniaina
- State Key Laboratory of Modern Chinese Medicine, China Pharmaceutical University, Nanjing 210009, China.
| | - Huihui Wang
- College of Chemistry and Life Sciences, Zhejiang Normal University, Jinhua 321004, China.
| | - Meihao Sun
- College of Chemistry and Life Sciences, Zhejiang Normal University, Jinhua 321004, China.
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Behar-Cohen F. Recent advances in slow and sustained drug release for retina drug delivery. Expert Opin Drug Deliv 2019; 16:679-686. [PMID: 31092046 DOI: 10.1080/17425247.2019.1618829] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/09/2023]
Abstract
INTRODUCTION Striking recent advance has occurred in the field of medical retina, greatly because intraocular drugs have been developed, enhancing their clinical efficacy while avoiding systemic side-effects. However, the burden of repeated intraocular administration makes limits the optimal efficacy of treatments, prompting the development of new drugs with prolonged half-life or of sustained drug delivery systems. AREAS COVERED In this review, we describe the various drugs and drug delivery systems that have reached the clinical stage and those that are in clinical development and we discuss the limitations to clinical translation. EXPERT OPINION Substantial fundamental work is still required to build guidelines on optimal animal models for ocular pharmacokinetics and safety studies depending on the target disease site and the on the type of therapeutic compounds. The effects of a drug administered as a bolus at high concentration in the vitreous might differ from those resulting from the sustained release of a lower concentration, and no delivery platform can be simply adapted to any drug. For the treatment of retinal diseases, development of therapeutic compounds should integrate from its early conception, the combination of an active drug with a specific drug delivery system, administered by a specific route.
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Affiliation(s)
- Francine Behar-Cohen
- a Inserm UMR_S 1138, Team 17, Physiopathology of ocular diseases: Therapeutic Innovations at Centre de recherche des Cordeliers, Ophthalmopole at Hôpital Cochin , Paris , France.,b Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers , Université Paris Descartes , Paris , France.,c UMR_S 1138, Centre de Recherche des Cordeliers , Sorbonne University, University of Pierre et Marie Curie , Paris , France.,d Assistance Publique-Hôpitaux de Paris , Hôtel-Dieu de , Paris , France
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11
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Huang D, Chen YS, Rupenthal ID. Overcoming ocular drug delivery barriers through the use of physical forces. Adv Drug Deliv Rev 2018; 126:96-112. [PMID: 28916492 DOI: 10.1016/j.addr.2017.09.008] [Citation(s) in RCA: 117] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2016] [Revised: 06/30/2017] [Accepted: 09/08/2017] [Indexed: 12/25/2022]
Abstract
Overcoming the physiological barriers in the eye remains a key obstacle in the field of ocular drug delivery. While ocular barriers naturally have a protective function, they also limit drug entry into the eye. Various pharmaceutical strategies, such as novel formulations and physical force-based techniques, have been investigated to weaken these barriers and transport therapeutic agents effectively to both the anterior and the posterior segments of the eye. This review summarizes and discusses the recent research progress in the field of ocular drug delivery with a focus on the application of physical methods, including electrical fields, sonophoresis, and microneedles, which can enhance penetration efficiency by transiently disrupting the ocular barriers in a minimally or non-invasive manner.
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12
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Mechanisms of macular edema: Beyond the surface. Prog Retin Eye Res 2017; 63:20-68. [PMID: 29126927 DOI: 10.1016/j.preteyeres.2017.10.006] [Citation(s) in RCA: 413] [Impact Index Per Article: 51.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2017] [Revised: 10/24/2017] [Accepted: 10/31/2017] [Indexed: 02/07/2023]
Abstract
Macular edema consists of intra- or subretinal fluid accumulation in the macular region. It occurs during the course of numerous retinal disorders and can cause severe impairment of central vision. Major causes of macular edema include diabetes, branch and central retinal vein occlusion, choroidal neovascularization, posterior uveitis, postoperative inflammation and central serous chorioretinopathy. The healthy retina is maintained in a relatively dehydrated, transparent state compatible with optimal light transmission by multiple active and passive systems. Fluid accumulation results from an imbalance between processes governing fluid entry and exit, and is driven by Starling equation when inner or outer blood-retinal barriers are disrupted. The multiple and intricate mechanisms involved in retinal hydro-ionic homeostasis, their molecular and cellular basis, and how their deregulation lead to retinal edema, are addressed in this review. Analyzing the distribution of junction proteins and water channels in the human macula, several hypotheses are raised to explain why edema forms specifically in the macular region. "Pure" clinical phenotypes of macular edema, that result presumably from a single causative mechanism, are detailed. Finally, diabetic macular edema is investigated, as a complex multifactorial pathogenic example. This comprehensive review on the current understanding of macular edema and its mechanisms opens perspectives to identify new preventive and therapeutic strategies for this sight-threatening condition.
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Weng Y, Liu J, Jin S, Guo W, Liang X, Hu Z. Nanotechnology-based strategies for treatment of ocular disease. Acta Pharm Sin B 2017; 7:281-291. [PMID: 28540165 PMCID: PMC5430571 DOI: 10.1016/j.apsb.2016.09.001] [Citation(s) in RCA: 217] [Impact Index Per Article: 27.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2016] [Revised: 05/24/2016] [Accepted: 07/06/2016] [Indexed: 01/02/2023] Open
Abstract
Ocular diseases include various anterior and posterior segment diseases. Due to the unique anatomy and physiology of the eye, efficient ocular drug delivery is a great challenge to researchers and pharmacologists. Although there are conventional noninvasive and invasive treatments, such as eye drops, injections and implants, the current treatments either suffer from low bioavailability or severe adverse ocular effects. Alternatively, the emerging nanoscience and nanotechnology are playing an important role in the development of novel strategies for ocular disease therapy. Various active molecules have been designed to associate with nanocarriers to overcome ocular barriers and intimately interact with specific ocular tissues. In this review, we highlight the recent attempts of nanotechnology-based systems for imaging and treating ocular diseases, such as corneal d iseases, glaucoma, retina diseases, and choroid diseases. Although additional work remains, the progress described herein may pave the way to new, highly effective and important ocular nanomedicines.
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Del Amo EM, Rimpelä AK, Heikkinen E, Kari OK, Ramsay E, Lajunen T, Schmitt M, Pelkonen L, Bhattacharya M, Richardson D, Subrizi A, Turunen T, Reinisalo M, Itkonen J, Toropainen E, Casteleijn M, Kidron H, Antopolsky M, Vellonen KS, Ruponen M, Urtti A. Pharmacokinetic aspects of retinal drug delivery. Prog Retin Eye Res 2016; 57:134-185. [PMID: 28028001 DOI: 10.1016/j.preteyeres.2016.12.001] [Citation(s) in RCA: 446] [Impact Index Per Article: 49.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2016] [Revised: 11/25/2016] [Accepted: 12/01/2016] [Indexed: 12/14/2022]
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.
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Affiliation(s)
- Eva M Del Amo
- School of Pharmacy, University of Eastern Finland, Kuopio, Finland
| | - Anna-Kaisa Rimpelä
- Centre for Drug Research, Division of Pharmaceutical Biosciences, University of Helsinki, Helsinki, Finland
| | - Emma Heikkinen
- School of Pharmacy, University of Eastern Finland, Kuopio, Finland
| | - Otto K Kari
- Centre for Drug Research, Division of Pharmaceutical Biosciences, University of Helsinki, Helsinki, Finland
| | - Eva Ramsay
- School of Pharmacy, University of Eastern Finland, Kuopio, Finland
| | - Tatu Lajunen
- Centre for Drug Research, Division of Pharmaceutical Biosciences, University of Helsinki, Helsinki, Finland
| | - Mechthild Schmitt
- Centre for Drug Research, Division of Pharmaceutical Biosciences, University of Helsinki, Helsinki, Finland
| | - Laura Pelkonen
- School of Pharmacy, University of Eastern Finland, Kuopio, Finland
| | - Madhushree Bhattacharya
- Centre for Drug Research, Division of Pharmaceutical Biosciences, University of Helsinki, Helsinki, Finland
| | - Dominique Richardson
- Centre for Drug Research, Division of Pharmaceutical Biosciences, University of Helsinki, Helsinki, Finland
| | - Astrid Subrizi
- School of Pharmacy, University of Eastern Finland, Kuopio, Finland
| | - Tiina Turunen
- Centre for Drug Research, Division of Pharmaceutical Biosciences, University of Helsinki, Helsinki, Finland
| | - Mika Reinisalo
- School of Pharmacy, University of Eastern Finland, Kuopio, Finland
| | - Jaakko Itkonen
- Centre for Drug Research, Division of Pharmaceutical Biosciences, University of Helsinki, Helsinki, Finland
| | - Elisa Toropainen
- School of Pharmacy, University of Eastern Finland, Kuopio, Finland
| | - Marco Casteleijn
- Centre for Drug Research, Division of Pharmaceutical Biosciences, University of Helsinki, Helsinki, Finland
| | - Heidi Kidron
- Centre for Drug Research, Division of Pharmaceutical Biosciences, University of Helsinki, Helsinki, Finland
| | - Maxim Antopolsky
- Centre for Drug Research, Division of Pharmaceutical Biosciences, University of Helsinki, Helsinki, Finland
| | | | - Marika Ruponen
- School of Pharmacy, University of Eastern Finland, Kuopio, Finland
| | - Arto Urtti
- Centre for Drug Research, Division of Pharmaceutical Biosciences, University of Helsinki, Helsinki, Finland; School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
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15
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Lajunen T, Nurmi R, Kontturi L, Viitala L, Yliperttula M, Murtomäki L, Urtti A. Light activated liposomes: Functionality and prospects in ocular drug delivery. J Control Release 2016; 244:157-166. [PMID: 27565215 DOI: 10.1016/j.jconrel.2016.08.024] [Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2016] [Revised: 08/08/2016] [Accepted: 08/21/2016] [Indexed: 12/17/2022]
Abstract
Ocular drug delivery, especially to the retina and choroid, is a major challenge in drug development. Liposome technology may be useful in ophthalmology in enabling new routes of delivery, prolongation of drug action and intracellular drug delivery, but drug release from the liposomes should be controlled. For that purpose, light activation may be an approach to release drug at specified time and site in the eye. Technical advances have been made in the field of light activated drug release, particularly indocyanine green loaded liposomes are a promising approach with safe materials and effective light triggered release of small and large molecules. This review discusses the liposomal drug delivery with light activated systems in the context of ophthalmic drug delivery challenges.
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Affiliation(s)
- Tatu Lajunen
- Centre for Drug Research, Division of Pharmaceutical Biosciences, University of Helsinki, Viikinkaari 5 E, 00790 Helsinki, Finland
| | - Riikka Nurmi
- Centre for Drug Research, Division of Pharmaceutical Biosciences, University of Helsinki, Viikinkaari 5 E, 00790 Helsinki, Finland
| | - Leena Kontturi
- Centre for Drug Research, Division of Pharmaceutical Biosciences, University of Helsinki, Viikinkaari 5 E, 00790 Helsinki, Finland; Department of Pharmaceutics, University of Utrecht, Utrecht, The Netherlands
| | - Lauri Viitala
- Department of Chemistry, Aalto University, Espoo, Finland
| | - Marjo Yliperttula
- Centre for Drug Research, Division of Pharmaceutical Biosciences, University of Helsinki, Viikinkaari 5 E, 00790 Helsinki, Finland; Department of Pharmaceutical Sciences, University of Padova, Padova, Italy
| | | | - Arto Urtti
- Centre for Drug Research, Division of Pharmaceutical Biosciences, University of Helsinki, Viikinkaari 5 E, 00790 Helsinki, Finland; School of Pharmacy, University of Eastern Finland, 70211 Kuopio, Finland.
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16
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Hu S, Koevary S. Efficacy of Antibody Delivery to the Retina and Optic Nerve by Topical Administration. J Ocul Pharmacol Ther 2016; 32:203-10. [PMID: 26771217 DOI: 10.1089/jop.2015.0111] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
PURPOSE The purpose of this study was to determine whether nonspecific and ICAM-1-specific IgG1 antibodies can accumulate in the rat retina following topical application, and to develop a model system to show that antibodies that reach the posterior segment retain their pharmacological properties. METHODS Eye drops containing mouse IgG1 or anti-ICAM-1 and the permeation enhancer saponin were topically applied to the eyes of Lewis rats. Concentrations were determined in the retina and optic nerve up to 30 min later using ELISA assays. We also developed an in vitro model to assess the pharmacologic activity of topically delivered antibodies in the retina based on the requirement of human umbilical vein endothelial cells (HUVECs) for vascular endothelial growth factor (VEGF) for growth. Rat eyes were treated with anti-VEGF antibody in the same manner as above; their retinas, harvested shortly thereafter, were added to HUVECs cultured in VEGF-containing media. The effect of these retinal homogenates on HUVEC proliferation was then assessed. RESULTS Significant concentrations of IgG1 were detected in the optic nerve (P < 0.001) and retina (P < 0.0001) following topical application. Anti-ICAM-1 antibody also accumulated in the retina after topical application, though levels were less than those seen with IgG1 probably owing to a lower starting concentration. Retinal homogenates from eyes treated with anti-VEGF antibody significantly suppressed HUVEC proliferation (P < 0.0001). CONCLUSIONS Our data support the contention that topically applied antibodies can accumulate in the posterior segment, and suggest they retain their pharmacological properties.
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Affiliation(s)
- Stacy Hu
- 1 Group Health Cooperative , Tacoma, Washington
| | - Steven Koevary
- 2 New England College of Optometry , Boston, Massachusetts
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17
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Kwatra D, Mitra AK. Drug delivery in ocular diseases: Barriers and strategies. World J Pharmacol 2013; 2:78-83. [DOI: 10.5497/wjp.v2.i4.78] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2012] [Accepted: 08/29/2013] [Indexed: 02/06/2023] Open
Abstract
The eye is a complex organ made up of diversified cells with specified functions. Presence of anatomical, physiological and physiochemical barriers make it difficult to deliver drugs in therapeutic amounts at intended sites. To overcome these, drug delivery scientists have followed two distinct yet complimentary approaches. The first involves using alternate delivery routes to conventional ones allowing for more direct access to intended target sites. Second approach involves development of novel drug delivery systems providing better permeability, treatability and controlled release at target site. Combination of both these approaches are being utilized and optimized in order to achieve optimal therapy with minimal adverse effects.
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18
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Abstract
The eye is a highly protected organ, and designing an effective therapy is often considered a challenging task. The anatomical and physiological barriers result in low ocular bioavailability of drugs. Due to these constraints, less than 5% of the administered dose is absorbed from the conventional ophthalmic dosage forms. Further, physicochemical properties such as lipophilicity, molecular weight and charge modulate the permeability of drug molecules. Vision-threatening diseases such as glaucoma, diabetic macular edema, cataract, wet and dry age-related macular degeneration, proliferative vitreoretinopathy, uveitis, and cytomegalovirus retinitis alter the pathophysiological and molecular mechanisms. Understanding these mechanisms may result in the development of novel treatment modalities. Recently, transporter/receptor targeted prodrug approach has generated significant interest in ocular drug delivery. These transporters and receptors are involved in the transport of essential nutrients, vitamins, and xenobiotics across biological membranes. Several influx transporters (peptides, amino acids, glucose, lactate and nucleosides/nucleobases) and receptors (folate and biotin) have been identified on conjunctiva, cornea, and retina. Structural and functional delineation of these transporters will enable more drugs targeting the posterior segment to be successfully delivered topically. Prodrug derivatization targeting transporters and receptors expressed on ocular tissues has been the subject of intense research. Several prodrugs have been designed to target these transporters and enhance the absorption of poorly permeating parent drug. Moreover, this approach might be used in gene delivery to modify cellular function and membrane receptors. This review provides comprehensive information on ocular drug delivery, with special emphasis on the use of transporters and receptors to improve drug bioavailability.
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19
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Marmor MF. Mechanisms of Normal Retinal Adhesion. Retina 2013. [DOI: 10.1016/b978-1-4557-0737-9.00019-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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20
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Cholkar K, Vadlapudi AD, Trinh HM, Mitra AK. Compositions, Formulation, Pharmacology, Pharmacokinetics, and Toxicity of Topical, Periocular, and Intravitreal Ophthalmic Drugs. METHODS IN PHARMACOLOGY AND TOXICOLOGY 2013. [DOI: 10.1007/7653_2013_10] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
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21
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Drug delivery to the posterior segment of the eye. Drug Discov Today 2010; 16:270-7. [PMID: 21167306 DOI: 10.1016/j.drudis.2010.12.004] [Citation(s) in RCA: 225] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2010] [Revised: 10/28/2010] [Accepted: 12/06/2010] [Indexed: 12/18/2022]
Abstract
Delivery of drugs to the posterior eye is challenging, owing to anatomical and physiological constrains of the eye. There is an increasing need for managing rapidly progressing posterior eye diseases, such as age-related macular degeneration, diabetic retinopathy and retinitis pigmentosa. Drug delivery to the posterior segment of the eye is therefore compounded by the increasing number of new therapeutic entities (e.g. oligonucleotides, aptamers and antibodies) and the need for chronic therapy. Currently, the intravitreal route is widely used to deliver therapeutic entities to the retina. However, frequent administration of drugs via this route can lead to retinal detachment, endophthalmitis and increased intraocular pressure. Various controlled delivery systems, such as biodegradable and non-biodegradable implants, liposomes and nanoparticles, have been developed to overcome such adverse effects, with some success. The periocular route is a promising alternative, owing to the large surface area and the relatively high permeability of the sclera. Yet, the blood-retinal barrier and efflux transporters hamper the transport of therapeutic entities to the retina. As such, the efficient delivery of drugs to the posterior eye remains a major challenge facing the pharmaceutical scientist. In this review, we discuss the barriers of the posterior eye drug delivery and the various drug-delivery strategies used to overcome these barriers.
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22
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Omri S, Omri B, Savoldelli M, Jonet L, Thillaye-Goldenberg B, Thuret G, Gain P, Jeanny JC, Crisanti P, Behar-Cohen F. The outer limiting membrane (OLM) revisited: clinical implications. Clin Ophthalmol 2010; 4:183-95. [PMID: 20463783 PMCID: PMC2861922 DOI: 10.2147/opth.s5901] [Citation(s) in RCA: 75] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Purpose The outer limiting membrane (OLM) is considered to play a role in maintaining the structure of the retina through mechanical strength. However, the observation of junction proteins located at the OLM and its barrier permeability properties may suggest that the OLM may be part of the retinal barrier. Material and methods Normal and diabetic rat, monkey, and human retinas were used to analyze junction proteins at the OLM. Proteome analyses were performed using immunohistochemistry on sections and flat-mounted retinas and western blotting on protein extracts obtained from laser microdissection of the photoreceptor layers. Semi-thin and ultrastructure analyses were also reported. Results In the rat retina, in the subapical region zonula occludens-1 (ZO-1), junction adhesion molecule (JAM), an atypical protein kinase C, is present and the OLM shows dense labeling of occludin, JAM, and ZO-1. The presence of occludin has been confirmed using western blot analysis of the microdissected OLM region. In diabetic rats, occludin expression is decreased and glial cells junctions are dissociated. In the monkey retina, occludin, JAM, and ZO-1 are also found in the OLM. Junction proteins have a specific distribution around cone photoreceptors and Müller glia. Ultrastructural analyses suggest that structures like tight junctions may exist between retinal glial Müller cells and photoreceptors. Conclusions In the OLM, heterotypic junctions contain proteins from both adherent and tight junctions. Their structure suggests that tight junctions may exist in the OLM. Occludin is present in the OLM of the rat and monkey retina and it is decreased in diabetes. The OLM should be considered as part of the retinal barrier that can be disrupted in pathological conditions contributing to fluid accumulation in the macula.
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Affiliation(s)
- S Omri
- INSERM, U872 Physiopathology of ocular diseases: Therapeutic innovations, Paris, France
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23
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El Sanharawi M, Kowalczuk L, Touchard E, Omri S, de Kozak Y, Behar-Cohen F. Protein delivery for retinal diseases: from basic considerations to clinical applications. Prog Retin Eye Res 2010; 29:443-65. [PMID: 20398784 DOI: 10.1016/j.preteyeres.2010.04.001] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Because the eye is protected by ocular barriers but is also easily accessible, direct intravitreous injections of therapeutic proteins allow for specific and targeted treatment of retinal diseases. Low doses of proteins are required in this confined environment and a long time of residency in the vitreous is expected, making the eye the ideal organ for local proteic therapies. Monthly intravitreous injection of Ranibizumab, an anti-VEGF Fab has become the standard of care for patients presenting wet AMD. It has brought the proof of concept that administering proteins into the physiologically low proteic concentration vitreous can be performed safely. Other antibodies, Fab, peptides and growth factors have been shown to exert beneficial effects on animal models when administered within the therapeutic and safe window. To extend the use of such biomolecules in the ophthalmology practice, optimization of treatment regimens and efficacy is required. Basic knowledge remains to be increased on how different proteins/peptides penetrate into the eye and the ocular tissues, distribute in the vitreous, penetrate into the retinal layers and/or cells, are eliminated from the eye or metabolized. This should serve as a basis for designing novel drug delivery systems. The later should be non-or minimally invasive and should allow for a controlled, scalable and sustained release of the therapeutic proteins in the ocular media. This paper reviews the actual knowledge regarding protein delivery for eye diseases and describes novel non-viral gene therapy technologies particularly adapted for this purpose.
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Affiliation(s)
- M El Sanharawi
- Inserm, UMRS 872, Centre de Recherche des Cordeliers, Paris, France
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24
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Molokhia SA, Jeong EK, Higuchi WI, Li SK. Transscleral iontophoretic and intravitreal delivery of a macromolecule: study of ocular distribution in vivo and postmortem with MRI. Exp Eye Res 2009; 88:418-25. [PMID: 19000673 PMCID: PMC2723719 DOI: 10.1016/j.exer.2008.10.010] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2008] [Revised: 09/23/2008] [Accepted: 10/11/2008] [Indexed: 11/27/2022]
Abstract
The distribution and clearance of macromolecules in ocular delivery are not well understood. It has been hypothesized that iontophoresis can enhance transscleral delivery of macromolecules. The objective of this study was to investigate the ocular distribution of a macromolecule after transscleral iontophoretic delivery and intravitreal injection in vivo using nuclear magnetic resonance imaging (MRI) and to compare these results. Experiments of constant current transscleral iontophoresis of 4mA or intravitreal injection were performed on New Zealand white rabbits in vivo. Iontophoresis experiments were also performed on rabbits postmortem. Galbumin (Gd-labeled albumin) was the model permeant surrogate to clinical therapeutic agents. MRI was used to monitor the distribution of the molecule in the eye after ocular iontophoresis and intravitreal injection. In addition, the conjunctiva, sclera, choroid, and retina were extracted in the transscleral iontophoresis study to determine the amounts of Galbumin in these tissues using Inductively Coupled Plasma Optical Emission Spectroscopy (ICP-OES). The results show that iontophoresis enhanced the ocular delivery of Galbumin. The macromolecule was mainly delivered into the conjunctiva and sclera in microgram quantities and then diffused towards the posterior section in the upper hemisphere of the eye in vivo. Both in vivo and postmortem studies show that the iontophoretic delivery of Galbumin into the vitreous was below the detection limit. In the intravitreal injection study, the diffusion coefficient of Galbumin in the vitreous humor was estimated to be close to that of free aqueous diffusion.
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Affiliation(s)
- Sarah A. Molokhia
- Department of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, University of Utah, UT 84112, USA
| | - Eun-Kee Jeong
- Department of Radiology and Utah Center for Advanced Imaging Research, University of Utah, Salt Lake City, UT 84108, USA
| | - William I. Higuchi
- Department of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, University of Utah, UT 84112, USA
| | - S. Kevin Li
- Division of Pharmaceutical Sciences, College of Pharmacy, University of Cincinnati, 3225 Eden Ave, HPB 136, Cincinnati, OH 45267, USA
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25
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Abstract
Anatomy and physiology of the eye makes it a highly protected organ. Designing an effective therapy for ocular diseases, especially for the posterior segment, has been considered as a formidable task. Limitations of topical and intravitreal route of administration have challenged scientists to find alternative mode of administration like periocular routes. Transporter targeted drug delivery has generated a great deal of interest in the field because of its potential to overcome many barriers associated with current therapy. Application of nanotechnology has been very promising in the treatment of a gamut of diseases. In this review, we have briefly discussed several ocular drug delivery systems such as microemulsions, nanosuspensions, nanoparticles, liposomes, niosomes, dendrimers, implants, and hydrogels. Potential for ocular gene therapy has also been described in this article. In near future, a great deal of attention will be paid to develop non-invasive sustained drug release for both anterior and posterior segment eye disorders. A better understanding of nature of ocular diseases, barriers and factors affecting in vivo performance, would greatly drive the development of new delivery systems. Current momentum in the invention of new drug delivery systems hold a promise towards much improved therapies for the treatment of vision threatening disorders.
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26
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Abstract
Research into treatment modalities affecting vision is rapidly progressing due to the high incidence of diseases such as diabetic macular edema, proliferative vitreoretinopathy, wet and dry age-related macular degeneration and cytomegalovirus retinitis. The unique anatomy and physiology of eye offers many challenges to developing effective retinal drug delivery systems. Historically, drugs have been administered to the eye as liquid drops instilled in the cul-de-sac. However retinal drug delivery is a challenging area. The transport of molecules between the vitreous/retina and systemic circulation is restricted by the blood-retinal barrier, which is made up of retinal pigment epithelium and endothelial cells of the retinal blood vessels. An increase in the understanding of drug absorption mechanisms into the retina from local and systemic administration has led to the development of various drug delivery systems, such as biodegradable and non-biodegradable implants, microspheres, nanoparticles and liposomes, gels and transporter-targeted prodrugs. Such diversity in approaches is an indication that there is still a need for an optimized noninvasive or minimally invasive drug delivery system to the eye. A number of large molecular weight compounds (i.e., oligonucleotides, RNA aptamers, peptides and monoclonal antibodies) have been and continue to be introduced as new therapeutic entities. However, for high molecular weight polar compounds the mechanism of epithelial transport is primarily through the tight junctions in the retinal pigment epithelium, as these agents undergo limited transcellular diffusion. Delivery and administration of these new drugs in a safe and effective manner is still a major challenge facing pharmaceutical scientists. In this review article, the authors discuss various drug delivery strategies, devices and challenges associated with drug delivery to the retina.
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Affiliation(s)
- Kumar G Janoria
- University of Missouri-Kansas City, Department of Pharmaceutical Sciences, School of Pharmacy, 5005 Rockhill Road, Kansas City, MO 64110, USA
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27
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Chen CY, Hooper C, Chiu D, Chamberlain M, Karia N, Heriot WJ. Management of submacular hemorrhage with intravitreal injection of tissue plasminogen activator and expansile gas. Retina 2007; 27:321-8. [PMID: 17460587 DOI: 10.1097/01.iae.0000237586.48231.75] [Citation(s) in RCA: 82] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE To evaluate the clinical outcome of intravitreal tissue plasminogen activator (tPA) and expansile gas injection as a minimally invasive treatment for submacular hemorrhage (SMH). METHODS This study was a retrospective clinical case series examining 104 eyes that received an intravitreal injection of 30-100 mcg of tPA and expansile gas (SF6 or C3F8) for SMH. The main outcomes evaluated were visual acuities (VA), anatomic displacement of submacular blood, and surgical complications. RESULTS : A total of 85, 77, and 81 eyes were available at 1 week, 3 months, and 12 months follow up, respectively. Postoperatively, > or = 2 Snellen lines improvement were achieved in 43/85 eyes (51%) at 1 week, 49/77 eyes (63%) at 3 months, and 52/81 eyes (64%) at 12 months. Postoperative VA improvement was significantly associated with preoperative VA, submacular blood displacement, and the underlying cause of SMH. Diagnostic postoperative angiogram and clinical examination were possible at 8.2 +/- 7.4 weeks and 9.5 +/- 7.4 weeks, respectively. The observed complications included breakthrough vitreous hemorrhage in 8 eyes (8%) and retinal detachment in 3 eyes (3%). CONCLUSIONS In this retrospective series, intravitreal injection of tPA and expansile gas was shown to be a safe and effective technique that can improve VA in most eyes with SMH and assist in the diagnosis of the underlying cause.
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Affiliation(s)
- Christine Y Chen
- Ocular Genetics Unit, Eye Research Australia, University of Melbourne, East Melbourne, Victoria, Australia.
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28
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Ranta VP, Urtti A. Transscleral drug delivery to the posterior eye: prospects of pharmacokinetic modeling. Adv Drug Deliv Rev 2006; 58:1164-81. [PMID: 17069929 DOI: 10.1016/j.addr.2006.07.025] [Citation(s) in RCA: 108] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2006] [Accepted: 07/31/2006] [Indexed: 01/12/2023]
Abstract
Basic biological research has provided new approaches to treat severe diseases of the retina and choroid, such as age related macular degeneration. Although it is possible to deliver drugs from a subconjunctival drug depot to the retina and choroid, the barriers and kinetics of this route of drug administration are not well known. In this review we investigate the pharmacokinetic aspects of transscleral drug delivery into the posterior eye with emphasis on pharmacokinetic modeling. The existing simulation models related to the transscleral drug delivery are reviewed and future directions for the model development are discussed. In addition, a new simulation model for the transscleral drug delivery based on permeability data is introduced. This compartmental model contains several ocular tissues (sclera, choroid, retinal pigment epithelium and vitreous) and it takes into account the clearance of the drug via choroidal circulation. The model is used to simulate the vitreous delivery of macromolecules based on the available data on FITC-dextran 70 kDa.
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Affiliation(s)
- Veli-Pekka Ranta
- Department of Pharmaceutics, University of Kuopio, FIN-70211 Kuopio, Finland.
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29
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Abstract
Drug delivery to the eye is hampered by anatomical factors, including the corneal epithelium, the blood-aqueous barrier and the blood-retinal barrier. This review aims to outline the major routes of ocular drug delivery, including systemic, topical, periocular and intravitreal. The pharmacokinetics, the disadvantages and the clinical relevance of these drug delivery routes have been emphasised. Recent advances in surgical techniques, therapeutic approaches and material sciences have produced exciting new therapies for ocular diseases. The role of ophthalmic drug formulation in targeting the desired ocular tissue and enhancing drug delivery by the chosen route whilst minimising side effects is also discussed.
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Affiliation(s)
- Deepta Ghate
- Emory University Eye Center, 1365B, Clifton Road, Atlanta, GA 30322, USA
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30
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Fluid Physiology of the Subretinal Space. Retina 2006. [DOI: 10.1016/b978-0-323-02598-0.50119-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register]
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31
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Mechanisms of Normal Retinal Adhesion. Retina 2006. [DOI: 10.1016/b978-0-323-02598-0.50118-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register]
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32
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Cruysberg LPJ, Nuijts RMMA, Gilbert JA, Geroski DH, Hendrikse F, Edelhauser HF. In vitro sustained human transscleral drug delivery of fluorescein-labeled dexamethasone and methotrexate with fibrin sealant. Curr Eye Res 2005; 30:653-60. [PMID: 16109645 DOI: 10.1080/02713680590968600] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
PURPOSE To study the use of fibrin sealant as a drug delivery system for the sustained transscleral delivery of dexamethasone and methotrexate. METHODS Scleral sections excised from moist-chamber-stored human globes were mounted in a perfusion chamber. Dexamethasone-fluorescein or methotrexate-fluorescein in either fibrin sealant or balanced salt solution (BSS) was applied to the episcleral surface. BSS was perfused to the choroidal side, fluorescence was measured in perfusate fractions, and an apparent scleral permeability P(A) was calculated for each solute-vehicle combination. RESULTS P(A) for both compounds was significantly lower with fibrin sealant delivery compared to delivery in BSS (p < 0.001). However, the fibrin sealant vehicle provided a more sustained release of both drugs through 24 hr. CONCLUSIONS Incorporating dexamethasone and methotrexate into a fibrin sealant provided a more gradual drug delivery and a more uniform delivery compared to dissolving these drugs in BSS. Fibrin sealant could be useful for transscleral delivery for posterior segment disease.
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Affiliation(s)
- Lars P J Cruysberg
- Department of Ophthalmology, University Hospital of Maastricht, The Netherlands
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Abstract
The leading causes of blindness are retinal and choroidal diseases manifesting abnormal vessel permeability and growth. Scientists have sought to understand the mechanisms underlying these pathologic conditions with the hope of developing directed and effective pharmacologic therapies. Research has yielded important new mechanistic data, making possible the development of new drugs. One of the most important targets to have emerged is a secreted protein named vascular endothelial growth factor. This review will summarize the current state of our knowledge regarding this growth factor and outline some important questions that remain to be answered.
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Reid SNM, Farber DB. Glial transcytosis of a photoreceptor-secreted signaling protein, retinoschisin. Glia 2005; 49:397-406. [PMID: 15538749 DOI: 10.1002/glia.20131] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
In vitro studies have clearly shown that signaling/guidance proteins can diffuse to their targets. However, it is unclear whether they can travel by diffusion in vivo, or if they are distributed in the tissue by an active mechanism. Retinoschisin, a signaling molecule related to neuropilins, is synthesized and secreted by photoreceptor cells in the outer retina; then it interacts with inner retinal cells contributing to synaptic organization and optic nerve fiber integrity. We developed an assay to examine how retinoschisin, which is secreted a distance away, reaches its inner retinal targets. We found that retinoschisin is preferentially taken up and carried into the inner retina from the retinal outer border (the photoreceptor side) by Müller cells (the main glial cells of the vertebrate retina). This transcytosis is disrupted by DL-alpha-aminoadipic acid, a Müller cell/glia-specific toxin. Our results suggest that glial uptake/transcytosis can provide an effective and precise alternative for distributing signaling molecules in the nervous system.
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Affiliation(s)
- Silvia N M Reid
- Jules Stein Eye Institute, UCLA School of Medicine Center for the Health Sciences, 100 Stein Plaza, Los Angeles, CA 90095-7008, USA.
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Abstract
Despite numerous scientific efforts, delivery of therapeutic amounts of a drug to the retina remains a challenge. This challenge is compounded if chronic therapy is desired. The inability or inefficiency of topical and systemic routes for retinal delivery of existing drugs is now widely accepted. Although the intravitreal route offers high local concentrations in the vitreous and, hence, retina, these advantages are offset by side effects, such as cataracts, endophthalmitis and retinal detachment, following repeated intravitreal injections, or intravitreal placement of sustained-release implants. As discussed in this review, periocular routes, including subconjunctival, sub-tenon, retrobulbar, peribulbar and posterior juxtascleral routes, potentially offer a more promising alternative for enhanced drug delivery to the retina compared with topical and systemic routes. Periocular routes exploit the permeability of sclera for retinal drug delivery, and they are particularly useful for administering sustained-release systems of potent drugs. This review discusses the various periocular routes with respect to their anatomical location, pharmacokinetics, safety and mechanisms of drug delivery. In the coming years, several innovations in absorption enhancement, drug delivery systems and drug administration devices are anticipated for improving retinal drug delivery via periocular routes.
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Affiliation(s)
| | - Makena Hammond
- Department of Pharmaceutical Sciences and
- School of Engineering, Science, and Technology, Virginia State University, USA Petersburg, Virginia, USA
| | - Uday B Kompella
- Department of Pharmaceutical Sciences and
- Department of Ophthalmology, University of Nebraska Medical Centre, Omaha, NE 68198-5840, USA
- School of Engineering, Science, and Technology, Virginia State University, USA Petersburg, Virginia, USA
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Pitkänen L, Pelkonen J, Ruponen M, Rönkkö S, Urtti A. Neural retina limits the nonviral gene transfer to retinal pigment epithelium in an in vitro bovine eye model. AAPS JOURNAL 2004; 6:e25. [PMID: 15760110 PMCID: PMC2751250 DOI: 10.1208/aapsj060325] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
We investigated the permeation of liposomal and polymeric gene delivery systems through neural retina into retinal pigment epithelium (RPE) and determined the roles of various factors in permeation and subsequent uptake of the delivery systems by RPE. Anterior parts and vitreous of fresh bovine eyes were removed. Retina was left intact or peeled away. Complexes of ethidium monoazide (EMA)-labeled plasmid DNA and cationic carriers (polyethyleneimine, poly-L-lysine, DOTAP liposomes) were pipetted on the retina or RPE. Two hours later the neural retina was removed, if present, and the RPE cells were detached. Contaminants were removed by sucrose centrifugation, and the RPE cells were analyzed for DNA uptake by flow cytometry. Cellular uptake of FITC-dextrans (molecular weight [mw] 20,000, 500,000 and 2,000,000), FITC-poly-L-lysine (mw 20,000), FITC-labeled oligonucleotide (15-mer), and naked EMA-labeled plasmid DNA was determined after pipetting the solutions on the RPE or neural retina. Location of the fluorescent materials in the retina was visualized with fluorescence microscopy. Neural retina decreased the cellular uptake of DNA complexes by an order of magnitude, the uptake of FITC-dextrans slightly, whereas delivery of polycationic FITC-poly-L-lysine to RPE was almost completely inhibited. Neural retina decreased the cellular uptake of FITC-oligonucleotides, while the uptake of uncomplexed plasmid was always negligible. Conclusions from FACS and fluorescence microscopy were similar: delivery of polymeric and liposomal DNA complexes into RPE are limited by the neural retina. This is due to the size and positive charge of the complexes.
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Affiliation(s)
- Leena Pitkänen
- University of Kuopio, Department of Pharmaceutics, Kuopio, Finland.
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Lai YKY, Shen WY, Brankov M, Lai CM, Constable IJ, Rakoczy PE. Potential long-term inhibition of ocular neovascularisation by recombinant adeno-associated virus-mediated secretion gene therapy. Gene Ther 2002; 9:804-13. [PMID: 12040462 DOI: 10.1038/sj.gt.3301695] [Citation(s) in RCA: 87] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2001] [Accepted: 02/08/2002] [Indexed: 11/09/2022]
Abstract
Neovascularisation (NV) within the eye often results in visual loss. Vascular endothelial growth factor (VEGF) has been implicated in the development of ocular NV. Previous studies have shown that VEGF antagonists successfully suppressed retinal and choroidal NV in animal models. However, the systemic approach and transient nature of the delivery systems used in these studies hinder therapeutic application. To achieve stable and localised ocular anti-angiogenic therapy, we explored the use of recombinant adeno-associated virus (rAAV)-mediated secretion gene therapy (SGT). In this study, we generated a rAAV vector encoding soluble VEGF receptor 1, sFlt-1 (AAV-CMV.sflt) and determined its ability to inhibit cautery-induced corneal NV and laser-induced choroidal NV. Delivery of AAV-CMV.sflt into the anterior chamber resulted in transgene expression in the iris pigment epithelium and corneal endothelium, which reduced the development of corneal NV in the stroma of cauterised rats by 36% compared with cauterised control groups (P = 0.009). Subretinal delivery of AAV-CMV.sflt near the equator of the eye also suppressed choroidal NV at the laser lesions around the optic nerve by 19% (P = 0.002), indicating that there was diffusion of the secreted anti-angiogenic protein across the retina. Both results suggest that the long-term suppression of ocular NV is possible through the use of stable rAAV-mediated SGT.
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Affiliation(s)
- Y K Y Lai
- Department of Molecular Ophthalmology, Lions Eye Institute, Nedlands, Western Australia, Australia
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Short and long term effect of intravitreal tissue plasminogen activator in eyes with submacular hemorrhage. SPEKTRUM DER AUGENHEILKUNDE 2000. [DOI: 10.1007/bf03162829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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Abstract
This paper reviews the anatomic and physiologic conditions which predispose to fluid accumulation within the retina. Retinal edema has its inception in disease that causes a breakdown of the blood-retinal barrier in retinal capillaries and/or the retinal pigment epithelium (RPE). Edema develops not only because protein and fluid enter the extracellular space, but because the external limiting membrane and the convoluted extracellular pathway within the retina limit the clearance of albumin and other large osmotically-active molecules. These molecules bind water to cause edema. Recognition of edema clinically is complicated by the facts that angiographic markers (fluorescein and ICG) do not match albumin in size, and that clinical leakage does not always correlate closely with tissue swelling or functional loss. Active water transport across the RPE is efficient at removing subretinal water, but the flow resistance of the retina limits RPE access to the water of retinal edema. Consideration of the pathophysiology of retinal edema may aid in the development of better strategies for managing retinal edema.
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Sekiryu T, Yamauchi T, Enaida H, Hara Y, Furuta M. Retina Tomography After Vitrectomy for Macular Edema of Central Retinal Vein Occlusion. Ophthalmic Surg Lasers Imaging Retina 2000. [DOI: 10.3928/1542-8877-20000501-07] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Abstract
The author has done pretty much what he wanted to do throughout his professional life. Little harm resulted. A few findings may survive.
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Affiliation(s)
- D M Maurice
- Columbia University, Department of Ophthalmology, 630 W. 168 Street, New York, NY 10032, USA
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Chapter 9 Structure, composition and function of the retinal interphotoreceptor matrix. ACTA ACUST UNITED AC 1991. [DOI: 10.1016/0278-4327(91)90014-s] [Citation(s) in RCA: 40] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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Abstract
Experimental work shows that subretinal fluid is removed both by active transport across the retinal pigment epithelium (RPE) and by passive hydrostatic and oncotic forces that work most effectively when the RPE barrier has been damaged. The retina will stay attached whether or not the RPE is intact--but retinal function requires the RPE barrier and thus active transport is the primary mechanism of subretinal fluid control. RPE fluid transport is normally limited by the retina (which resists water flow from the vitreous) but can be quite powerful when a reservoir of subretinal fluid is present. Clinical serous detachments are unlikely to form solely as a result of small RPE defects or leaks, since the active and passive transport systems for removing subretinal fluid are both so strong. It is suggested that the primary pathology in most serous retinopathy is a diffuse metabolic or vascular abnormality of RPE fluid transport, and that RPE defects or leaks are necessary but only secondary components of the disease. Several hypotheses for removing subretinal fluid therapeutically are considered in terms of their physiology. The subretinal space between the photoreceptors and the retinal pigment epithelium (RPE) is the remnant of the embryonic optic vesicle. In the developed eye the subretinal space is of minimal size, but no tissue junctions form across it and it can re-open under pathological conditions of retinal detachment. In a sense, the title of this paper is misleading since normally there should be no subretinal fluid to control. However, ocular mechanisms are necessary to prevent an accumulation of fluid, and to remove it under conditions of stress or disease.
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Affiliation(s)
- M F Marmor
- Department of Ophthalmology, Stanford University School of Medicine, California 94305
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Foulds WS. Is your vitreous really necessary? The role of the vitreous in the eye with particular reference to retinal attachment, detachment and the mode of action of vitreous substitutes. Eye (Lond) 1987; 1 ( Pt 6):641-64. [PMID: 3331605 DOI: 10.1038/eye.1987.107] [Citation(s) in RCA: 50] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Affiliation(s)
- W S Foulds
- Tennent Institute of Ophthalmology, University of Glasgow, Western Infirmary
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