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Pharmaceutics
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Drug Delivery in Ophthalmology
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Drug Delivery in Ophthalmology

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Delivery and Controlled Release".

Deadline for manuscript submissions: closed (10 November 2022) | Viewed by 25240

Special Issue Editor

Prof. Dr. Yvan Arsenijevic

E-Mail Website
Guest Editor
Unit of Retinal Degeneration and Regeneration, Department of Ophthalmology, University of Lausanne, Hôpital Ophtalmique Jules-Gonin, Fondation Asile des aveugles, 1004 Lausanne, Switzerland
Interests: retinal degeneration; epigenetics; disease mechanisms; disease models; retina organoids; gene therapy; ophthalmology

Special Issue Information

Dear Colleagues,

The eye is an interesting organ for drug delivery development owing to its accessibility and monitoring feasibility to record physiological activity versus morphological features. The progress in our comprehension of disease mechanisms has made it possible to identify multiple targets to potentially develop new treatments for retinal degeneration affecting the photoreceptor cells or the retinal ganglion cells in the cases of inherited retinal dystrophies and glaucoma, respectively. However, small molecules often have a very short half-life in the eye, rendering chronic treatments problematic. Concerning genetic diseases, gene transfer has brought great success with the proof-of-concept that a gene augmentation strategy can restore some visual functions over the course of months or even years. Many clinical trials are ongoing, but few data are available about the patients or from a methodological point of view.

This Special Issue on ocular drug delivery aims to present different reviews on the successes, hurdles, and potential solutions with drug delivery into the eye using small molecules such as nanodrugs, nonviral and viral drug delivery, as well as antisense oligonucleotides. Promising techniques to avoid subretinal injections and even intraocular injections will be discussed. The goal of this Issue is to present the state-of-the-art of the field to help each researcher choose the adequate tool for the disease they aim to target. Some of these procedures may also be transposable to other organs.

Prof. Dr. Yvan Arsenijevic
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceutics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • retina
  • nanoparticles
  • non-viral gene therapy
  • viral vectors
  • gene editing

Published Papers (8 papers)

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Research

Jump to: Review

18 pages, 3128 KiB  
Article
Non-Invasive Iontophoretic Delivery of Cytochrome c to the Posterior Segment and Determination of Its Ocular Biodistribution
by Laura Gisela González Iglesias, Siwar Messaoudi and Yogeshvar N. Kalia
Pharmaceutics 2022, 14(9), 1832; https://doi.org/10.3390/pharmaceutics14091832 - 31 Aug 2022
Cited by 2 | Viewed by 1262
Abstract
The intact porcine eye globe model was used to demonstrate that transscleral iontophoresis could deliver a small protein, cytochrome c (Cyt c), to the posterior segment and to investigate post-iontophoretic biodistribution in the different ocular compartments. The effects of Cyt c concentration (1, [...] Read more.
The intact porcine eye globe model was used to demonstrate that transscleral iontophoresis could deliver a small protein, cytochrome c (Cyt c), to the posterior segment and to investigate post-iontophoretic biodistribution in the different ocular compartments. The effects of Cyt c concentration (1, 5, and 10 mg/mL), current density (3.5 and 5.5 mA/cm2), and duration of the current application (10 min and 1, 2, and 4 h) were evaluated. The data confirmed that transscleral iontophoresis enhanced the intraocular delivery of Cyt c under all conditions as compared to passive controls (same setup but without the current application). Increasing the Cyt c concentration resulted in a proportional enhancement in the Cyt c delivery. Increasing the current density from 3.5 to 5.5 mA/cm2 increased iontophoretic delivery at a Cyt c concentration of 10 mg/mL but did not appear to do so at 5 mg/mL; this was attributed in part to the effect of melanin binding. Short duration iontophoresis (10 min, 3.5 mA/cm2) of a 10 mg/mL Cyt c solution created a depot in the sclera. When this was followed by a 4 h incubation period, post-iontophoretic Cyt c diffusion from the sclera resulted in a different biodistribution, and Cyt c could be quantified in the posterior segment. Full article
(This article belongs to the Special Issue Drug Delivery in Ophthalmology)
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12 pages, 5031 KiB  
Article
The Role of Cryotherapy in Vitreous Concentrations of Topotecan Delivered by Episcleral Hydrogel Implant
by Martina Kodetova, Radka Hobzova, Jakub Sirc, Jiri Uhlik, Katerina Dunovska, Karel Svojgr, Ana-Irina Cocarta, Andrea Felsoova, Ondrej Slanar, Martin Sima, Igor Kozak and Pavel Pochop
Pharmaceutics 2022, 14(5), 903; https://doi.org/10.3390/pharmaceutics14050903 - 20 Apr 2022
Cited by 4 | Viewed by 2072
Abstract
Transscleral diffusion delivery of chemotherapy is a promising way to reach the vitreal seeds of retinoblastoma, the most common intraocular malignancy in childhood. In this in vivo study, the delivery of topotecan via lens-shaped, bi-layered hydrogel implants was combined with transconjunctival cryotherapy to [...] Read more.
Transscleral diffusion delivery of chemotherapy is a promising way to reach the vitreal seeds of retinoblastoma, the most common intraocular malignancy in childhood. In this in vivo study, the delivery of topotecan via lens-shaped, bi-layered hydrogel implants was combined with transconjunctival cryotherapy to assess whether cryotherapy leads to higher concentrations of topotecan in the vitreous. The study included 18 New Zealand albino rabbits; nine rabbits received a topotecan-loaded implant episclerally and another nine rabbits received transconjunctival cryotherapy superotemporally 2 weeks before implant administration. Median vitreous total topotecan exposures (area under the curve, AUC) were 455 ng·h/mL for the cryotherapy group and 281 ng·h/mL for the non-cryotherapy group, and were significantly higher in the cryotherapy group, similar to maximum levels. Median plasma AUC were 50 ng·h/mL and 34 ng·h/mL for the cryotherapy and non-cryotherapy groups, respectively, with no statistically significant differences between them. In both groups, AUC values in the vitreous were significantly higher than in plasma, with plasma exposure at only approximately 11–12% of the level of vitreous exposure. The results confirmed the important role of the choroidal vessels in the pharmacokinetics of topotecan during transscleral administration and showed a positive effect of cryotherapy on intravitreal penetration, resulting in a significantly higher total exposure in the vitreous. Full article
(This article belongs to the Special Issue Drug Delivery in Ophthalmology)
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18 pages, 8928 KiB  
Article
AAV-CRISPR/Cas9 Gene Editing Preserves Long-Term Vision in the P23H Rat Model of Autosomal Dominant Retinitis Pigmentosa
by Saba Shahin, Hui Xu, Bin Lu, Augustus Mercado, Melissa K. Jones, Benjamin Bakondi and Shaomei Wang
Pharmaceutics 2022, 14(4), 824; https://doi.org/10.3390/pharmaceutics14040824 - 09 Apr 2022
Cited by 5 | Viewed by 2746
Abstract
Retinitis pigmentosa (RP) consists of a group of inherited, retinal degenerative disorders and is characterized by progressive loss of rod photoreceptors and eventual degeneration of cones in advanced stages, resulting in vision loss or blindness. Gene therapy has been effective in treating autosomal [...] Read more.
Retinitis pigmentosa (RP) consists of a group of inherited, retinal degenerative disorders and is characterized by progressive loss of rod photoreceptors and eventual degeneration of cones in advanced stages, resulting in vision loss or blindness. Gene therapy has been effective in treating autosomal recessive RP (arRP). However, limited options are available for patients with autosomal dominant RP (adRP). In vivo gene editing may be a therapeutic option to treat adRP. We previously rescued vision in neonatal adRP rats by the selective ablation of the Rhodopsin S334ter transgene following electroporation of a CRISPR/Cas9 vector. However, the translational feasibility and long-term safety and efficacy of ablation therapy is unclear. To this end, we show that AAV delivery of a CRISPR/Cas9 construct disrupted the Rhodopsin P23H transgene in postnatal rats, which rescued long-term vision and retinal morphology. Full article
(This article belongs to the Special Issue Drug Delivery in Ophthalmology)
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15 pages, 2590 KiB  
Article
Topical Pirfenidone-Loaded Liposomes Ophthalmic Formulation Reduces Haze Development after Corneal Alkali Burn in Mice
by Carlos Daniel Diaz-Palomera, Isaac Alejandro Vidal-Paredes, Jose Navarro-Partida, Margarita Cid-Hernandez, Luis Carlos Rosales-Rivera, Ricardo De la Rosa-Bibiano, Hugo Christian Monroy-Ramirez, Arturo Santos and Juan Armendariz-Borunda
Pharmaceutics 2022, 14(2), 316; https://doi.org/10.3390/pharmaceutics14020316 - 28 Jan 2022
Cited by 7 | Viewed by 2851
Abstract
Corneal chemical burns (CCBs) frequently result in corneal fibrosis or haze, an opacity of the cornea that obstructs vision and induces corneal blindness. Diverse strategies have been employed to prevent or reduce CCB-related corneal haze. In this study, we evaluated the physicochemical characteristics [...] Read more.
Corneal chemical burns (CCBs) frequently result in corneal fibrosis or haze, an opacity of the cornea that obstructs vision and induces corneal blindness. Diverse strategies have been employed to prevent or reduce CCB-related corneal haze. In this study, we evaluated the physicochemical characteristics and biologic effects of a topical pirfenidone (PFD)-loaded liposomal formulation (PL) on a corneal alkali burn mice model. We found that PL was appropriate for ocular application due to its physiologic tear pH, osmolarity and viscosity suitable for topical ophthalmic use. Regarding its therapeutic activity, PL-treated mice had significantly reduced haze size and density, corneal edema, corneal thickness, and corneal inflammatory infiltration, in contrast to PFD in aqueous solution (p < 0.01). Importantly, the antifibrotic activity of PL (reduction of corneal haze) was associated with modulation of transforming growth factor (TGF)-β and Interleukin (IL)-1β genes. PL suppressed TGF-β expression and restored normal IL-1β expression in corneal tissue more efficiently in contrast to PFD in aqueous solution. In conclusion, PFD showed essential anti-inflammatory and anti-fibrotic effects in the treatment of alkali burns. Noteworthy, a new formulation of PFD-loaded liposomes remarkably improved these effects, standing out as a promising treatment for corneal haze. Full article
(This article belongs to the Special Issue Drug Delivery in Ophthalmology)
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Review

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32 pages, 2308 KiB  
Review
Ocular Drug Delivery: Advancements and Innovations
by Bo Tian, Evan Bilsbury, Sean Doherty, Sean Teebagy, Emma Wood, Wenqi Su, Guangping Gao and Haijiang Lin
Pharmaceutics 2022, 14(9), 1931; https://doi.org/10.3390/pharmaceutics14091931 - 13 Sep 2022
Cited by 15 | Viewed by 3287
Abstract
Ocular drug delivery has been significantly advanced for not only pharmaceutical compounds, such as steroids, nonsteroidal anti-inflammatory drugs, immune modulators, antibiotics, and so forth, but also for the rapidly progressed gene therapy products. For conventional non-gene therapy drugs, appropriate surgical approaches and releasing [...] Read more.
Ocular drug delivery has been significantly advanced for not only pharmaceutical compounds, such as steroids, nonsteroidal anti-inflammatory drugs, immune modulators, antibiotics, and so forth, but also for the rapidly progressed gene therapy products. For conventional non-gene therapy drugs, appropriate surgical approaches and releasing systems are the main deliberation to achieve adequate treatment outcomes, whereas the scope of “drug delivery” for gene therapy drugs further expands to transgene construct optimization, vector selection, and vector engineering. The eye is the particularly well-suited organ as the gene therapy target, owing to multiple advantages. In this review, we will delve into three main aspects of ocular drug delivery for both conventional drugs and adeno-associated virus (AAV)-based gene therapy products: (1) the development of AAV vector systems for ocular gene therapy, (2) the innovative carriers of medication, and (3) administration routes progression. Full article
(This article belongs to the Special Issue Drug Delivery in Ophthalmology)
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38 pages, 1674 KiB  
Review
Lentiviral Vectors for Ocular Gene Therapy
by Yvan Arsenijevic, Adeline Berger, Florian Udry and Corinne Kostic
Pharmaceutics 2022, 14(8), 1605; https://doi.org/10.3390/pharmaceutics14081605 - 31 Jul 2022
Cited by 11 | Viewed by 3247
Abstract
This review offers the basics of lentiviral vector technologies, their advantages and pitfalls, and an overview of their use in the field of ophthalmology. First, the description of the global challenges encountered to develop safe and efficient lentiviral recombinant vectors for clinical application [...] Read more.
This review offers the basics of lentiviral vector technologies, their advantages and pitfalls, and an overview of their use in the field of ophthalmology. First, the description of the global challenges encountered to develop safe and efficient lentiviral recombinant vectors for clinical application is provided. The risks and the measures taken to minimize secondary effects as well as new strategies using these vectors are also discussed. This review then focuses on lentiviral vectors specifically designed for ocular therapy and goes over preclinical and clinical studies describing their safety and efficacy. A therapeutic approach using lentiviral vector-mediated gene therapy is currently being developed for many ocular diseases, e.g., aged-related macular degeneration, retinopathy of prematurity, inherited retinal dystrophies (Leber congenital amaurosis type 2, Stargardt disease, Usher syndrome), glaucoma, and corneal fibrosis or engraftment rejection. In summary, this review shows how lentiviral vectors offer an interesting alternative for gene therapy in all ocular compartments. Full article
(This article belongs to the Special Issue Drug Delivery in Ophthalmology)
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20 pages, 2279 KiB  
Review
Ocular Barriers and Their Influence on Gene Therapy Products Delivery
by Bastien Leclercq, Dan Mejlachowicz and Francine Behar-Cohen
Pharmaceutics 2022, 14(5), 998; https://doi.org/10.3390/pharmaceutics14050998 - 06 May 2022
Cited by 14 | Viewed by 2917
Abstract
The eye is formed by tissues and cavities that contain liquids whose compositions are highly regulated to ensure their optical properties and their immune and metabolic functions. The integrity of the ocular barriers, composed of different elements that work in a coordinated fashion, [...] Read more.
The eye is formed by tissues and cavities that contain liquids whose compositions are highly regulated to ensure their optical properties and their immune and metabolic functions. The integrity of the ocular barriers, composed of different elements that work in a coordinated fashion, is essential to maintain the ocular homeostasis. Specialized junctions between the cells of different tissues have specific features which guarantee sealing properties and selectively control the passage of drugs from the circulation or the outside into the tissues and within the different ocular compartments. Tissues structure also constitute selective obstacles and pathways for various molecules. Specific transporters control the passage of water, ions, and macromolecules, whilst efflux pumps reject and eliminate toxins, metabolites, or drugs. Ocular barriers, thus, limit the bioavailability of gene therapy products in ocular tissues and cells depending on the route chosen for their administration. On the other hand, ocular barriers allow a real local treatment, with limited systemic side-effects. Understanding the different barriers that limit the accessibility of different types of gene therapy products to the different target cells is a prerequisite for the development of efficient gene delivery systems. This review summarizes actual knowledge on the different ocular barriers that limit the penetration and distribution of gene therapy products using different routes of administration, and it provides a general overview of various methods used to bypass the ocular barriers. Full article
(This article belongs to the Special Issue Drug Delivery in Ophthalmology)
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44 pages, 2654 KiB  
Review
Lipid Nanoparticles as a Promising Drug Delivery Carrier for Topical Ocular Therapy—An Overview on Recent Advances
by Shery Jacob, Anroop B. Nair, Jigar Shah, Sumeet Gupta, Sai H. S. Boddu, Nagaraja Sreeharsha, Alex Joseph, Pottathil Shinu and Mohamed A. Morsy
Pharmaceutics 2022, 14(3), 533; https://doi.org/10.3390/pharmaceutics14030533 - 27 Feb 2022
Cited by 50 | Viewed by 5760
Abstract
Due to complicated anatomical and physical properties, targeted drug delivery to ocular tissues continues to be a key challenge for formulation scientists. Various attempts are currently being made to improve the in vivo performance of therapeutic molecules by encapsulating them in various nanocarrier [...] Read more.
Due to complicated anatomical and physical properties, targeted drug delivery to ocular tissues continues to be a key challenge for formulation scientists. Various attempts are currently being made to improve the in vivo performance of therapeutic molecules by encapsulating them in various nanocarrier systems or devices and administering them via invasive/non-invasive or minimally invasive drug administration methods. Biocompatible and biodegradable lipid nanoparticles have emerged as a potential alternative to conventional ocular drug delivery systems to overcome various ocular barriers. Lipid-based nanocarrier systems led to major technological advancements and therapeutic advantages during the last few decades of ocular therapy, such as high precorneal residence time, sustained drug release profile, minimum dosing frequency, decreased drug toxicity, targeted site delivery, and, therefore, an improvement in ocular bioavailability. In addition, such formulations can be given as fine dispersion in patient-friendly droppable preparation without causing blurred vision and ocular sensitivity reactions. The unique advantages of lipid nanoparticles, namely, solid lipid nanoparticles, nanostructured lipid carriers, nanoemulsions, and liposomes in intraocular targeted administration of various therapeutic drugs are extensively discussed. Ongoing and completed clinical trials of various liposome-based formulations and various characterization techniques designed for nanoemulsion in ocular delivery are tabulated. This review also describes diverse solid lipid nanoparticle preparation methods, procedures, advantages, and limitations. Functionalization approaches to overcome the drawbacks of lipid nanoparticles, as well as the exploration of new functional additives with the potential to improve the penetration of macromolecular pharmaceuticals, would quickly progress the challenging field of ocular drug delivery systems. Full article
(This article belongs to the Special Issue Drug Delivery in Ophthalmology)
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