Treatment Of Posterior Eye Diseases Research Articles

The topical ocular delivery of rapamycin to posterior eye tissues and the suppression of retinal inflammatory disease

Treatment of posterior eye diseases with intravitreal injections of drugs, while effective, is invasive and associated with side effects such as retinal detachment and endophthalmitis. In this work, we have formulated a model compound, rapamycin (RAP), in nanoparticle-based eye drops and evaluated the delivery of RAP to the posterior eye tissues in a healthy rabbit. We have also studied the formulation in experimental autoimmune uveitis (EAU) mouse model with retinal inflammation. Aqueous RAP eye drops were prepared using N-palmitoyl-N-monomethyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycolchitosan (Molecular Envelope Technology – MET) containing 0.23 ± 0.001% w/v RAP with viscosity, osmolarity, and pH within the ocular comfort range, and the formulation (MET-RAP) was stable in terms of drug content at both refrigeration and room temperature for one month. The MET-RAP eye drops delivered RAP to the choroid-retina with a Cmax of 145 ± 49 ng/g (tmax = 1 h). The topical application of the MET-RAP eye drops to the EAU mouse model resulted in significant disease suppression compared to controls, with activity similar to dexamethasone eye drops. The MET-RAP eye drops also resulted in a reduction of RORγt and an increase in both Foxp3 expression and IL-10 secretion, indicating a mechanism involving the inhibition of Th17 cells and the up-regulation of T-reg cells. The MET-RAP formulation delivers RAP to the posterior eye segments, and the formulation is active in EAU.

Prospective for Diagnosis and Treatment of Diabetic Retinopathy.

Diabetic retinopathy is a posterior eye disorder in which damage occurs to the light sensitive retina due to diabetes mellitus. This disorder specifically affects people aged between 18-64 with type ІІ diabetes. This disease progresses through different pathophysiological pathways, which include oxidative stress, inflammation, stimulation of the growth factor in the eye's vasculature, isoforms of protein kinase C, and also the activation of the hexosamine pathway. It starts as micro aneurysms and advances in complicated stage, which results in retinal detachment. Treatment of posterior eye diseases has complications due to the structural design of the eye and physiological barriers present. The current treatment approach involves the use of intravitreal anti- VEGFs, corticosteroids implants, laser and surgery; these treatment methods have drawbacks attributed to them despite their benefits. The development of a robust delivery system with minimal or no invasion to tackle the issues of diabetic retinopathy will be of considerable benefit to patients having diabetic retinopathy; the dependency on ophthalmologists for multiple injections will significantly reduce and provide a promising approach in drug delivery. In this review article, the authors provided information related to existing treatment methods available for diabetic retinopathy, the most significant among which is nanotechnology approach through which local delivery via the ocular route to posterior eye can be achieved. It also possesses the various carriers studied for the non-invasive approach for retinal delivery of medicaments. Non-invasive approach for delivery of drugs can be considered as potential for the treatment of diabetic retinopathy.

Ultrasound and Microbubbles for the Treatment of Ocular Diseases: From Preclinical Research towards Clinical Application.

The unique anatomy of the eye and the presence of various biological barriers make efficacious ocular drug delivery challenging, particularly in the treatment of posterior eye diseases. This review focuses on the combination of ultrasound and microbubbles (USMB) as a minimally invasive method to improve the efficacy and targeting of ocular drug delivery. An extensive overview is given of the in vitro and in vivo studies investigating the mechanical effects of ultrasound-driven microbubbles aiming to: (i) temporarily disrupt the blood–retina barrier in order to enhance the delivery of systemically administered drugs into the eye, (ii) induce intracellular uptake of anticancer drugs and macromolecules and (iii) achieve targeted delivery of genes, for the treatment of ocular malignancies and degenerative diseases. Finally, the safety and tolerability aspects of USMB, essential for the translation of USMB to the clinic, are discussed.

Nanoparticle-Hydrogel Composite Drug Delivery System for Potential Ocular Applications.

Intravitreal injections are clinically established procedures in the treatment of posterior eye diseases, such as wet age-related macular degeneration (wet AMD) which requires monthly intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) protein drugs that can lead to complications due to frequent dosing. In this study, we designed a composite drug delivery system (DDS) consisting of drug-loaded poly (lactide–co–glycolide) (PLGA) nanoparticles and a chemically crosslinked hyaluronan hydrogel to reduce the dosing frequency. The morphology, size, composition, and drug loading efficiency of the prepared nanoparticles were characterized. The properties of the modified hyaluronan polymers used were also examined. The degree of swelling/degradation and controlled release ability of the hyaluronan hydrogel and the composite DDS were identified using bovine serum albumin (BSA) as a model drug. The results show that this system can retain 75% of its wet weight without losing its integrity and release the model drug at the rate of 0.4 μg/day for more than two months under physiological conditions. In addition, the nanoparticulate formulation of the system can further improve bioavailability of the drugs by penetrating deep into the retinal layers. In conclusion, the proposed composite DDS is easily prepared with biocompatible materials and is promising for providing the sustained release of the protein drugs as a better treatment for ocular neovascular diseases like wet AMD.

Design of a navigational catheter system for the targeted delivery of therapeutics within the suprachoroidal space

Diseases of the posterior segment of the eye are common causes of blindness and can be difficult to treat due to their location. Recently, there has been increased interest in the use of the suprachoroidal space to deliver therapeutics to the posterior segment. This space is accessible through a trans-scleral approach and blunt dissection of the adjacent scleral and choroidal tissues. However, despite recent commercial interest, there are few tools designed specifically to provide targeted delivery of therapeutics to a localised region within the suprachoroidal space. Therefore, we designed and prototyped a novel navigational catheter system for the targeted delivery of payloads within the suprachoroidal space. The system consists of a customised catheter tip designed to minimise blunt dissection stresses on neighbouring tissues, a mechanism for controlled catheter navigation, and a method for targeted delivery of large payloads. A customised in vitro model of the eye was also designed to visually demonstrate the capability of the catheter system to controllably navigate within the suprachoroidal space and deliver a targeted payload. This system can enable the delivery of large therapeutic payloads to the eye for the treatment of posterior eye diseases, thereby impacting the development and availability of vision-saving treatments.

Potential of Lipoprotein-Based Nanoparticulate Formulations for the Treatment of Eye Diseases.

Lipoproteins are naturally occurring nanoparticles and their main physiological function is the promotion of lipid metabolism. They can be prepared in vitro for use as drug carriers, and these reconstituted lipoproteins show similar biological activity to their natural counterparts. Some lipoproteins can cross the blood-retinal barrier and are involved in intraocular lipid metabolism. Drug-loaded lipoproteins can be delivered to the retina for the treatment of posterior eye diseases. In this review, we have discussed the therapeutic applications of lipoproteins for eye diseases and introduced the emerging animal models used for the evaluation of their therapeutic effects.

Controlled release technology for anti-angiogenesis treatment of posterior eye diseases: Current status and challenges.

Antiangiogenic therapeutics, such as corticosteroids, VEGF targeting antibodies and aptamers have been demonstrated effective in controlling retinal and choroidal neovascularization related vision loss. However, to manage the chronic conditions, it requires long term and frequent intravitreal injections of these drugs, resulting in poor patient compliance and suboptimal treatment. In addition, emerging drugs such as tyrosine kinase inhibitors and siRNAs received much expectations, but the late stage clinical trials encountered various obstacles. Controlled release technology could improve the existing treatment regimen by extending therapeutic duration, reducing risks and burdens caused by frequent injections, and enabling new drugs to overcome the hurdles of translation. Here, we give qualitative and quantitative discussions about the principle mechanisms of polymeric reservoir, polymeric matrix and hydrogel systems. We also reveal the design rationales of the existing drug delivery and release systems in preclinical and clinical stages. Lastly, the animal models of ocular angiogenesis diseases are critically reviewed, which could help to facilitate the translation of controlled release technologies from bench to bedside.

Evaluation of the Toxicity of Intravitreally Injected PLGA Microspheres and Rods in Monkeys and Rabbits: Effects of Depot Size on Inflammatory Response.

Poly(lactic-co-glycolic) acid (PLGA) inserts have been successfully developed for the treatment of posterior eye disease as a means of reducing injection frequency of intravitreally administered therapeutics. PLGA microspheres are also of interest for the delivery of intravitreal drugs, since they offer the advantage of being easily injected without surgical procedures or large injectors. In the current study, the toxicity of PLGA microspheres and rods was investigated in nonhuman primates (NHPs) and rabbits. An in vitro assessment of cytokine responses to PLGA in peripheral blood mononuclear cells (PBMCs) and macrophages was also performed. Intravitreal administration of 3, 10, or 12.5 mg/eye of PLGA microspheres in NHPs resulted in a severe immune response characterized by a foreign body response. Follow-up studies in the rabbit confirmed this finding for PLGA microspheres ranging in size from 20 to 100 μm. In contrast, administration of PLGA rod implants with a similar PLGA mass did not elicit a significant immune response. In vitro assays in PBMCs and macrophages confirmed proinflammatory cytokine release upon treatment with PLGA microspheres but not PLGA rods. These data demonstrate a lack of tolerability of PLGA microspheres upon intravitreal injection, and suggest that the size, shape, and/or surface area of PLGA depots are critical attributes in determining ocular toxicity.

Controlled and sustained release of a corticosteroid drug from block copolymers synthetized by ATRP

During last decades, implantable drug delivery systems (DDS) have been developed to optimize therapeutic properties of drugs and ensure their release in a specific site. Acrylic polymers have obtained growing interest in biomedical applications for their biocompatibility and chemical properties that make them extremely versatile. In this work, we focused on the realization of polymeric systems for controlled and sustained release of betamethasone 17,21‐dipropionate (BDP), a corticosteroid drug, in the treatment of the posterior eye diseases (PED). The investigated DDS were made of opportunely designed methacrylic block copolymers. Different series of methylmethacrylate/2‐hydroxyethylmethacrylate (MMA/HEMA) block copolymers, with various monomeric compositions (20‐60 mol% HEMA), were synthetized by Atom Transfer Radical Polymerization to find the best hydrophilic/hydrophobic ratio, able to ensure optimal kinetic release. Copolymers were characterized by nuclear magnectic resonance, size exclusion chromatography, and differential scanning calorimetry. Monitoring of drug release from films loaded with BDP was carried out by HPLC analysis. In particular, PMMA‐b‐PHEMA with 47 mol% of HEMA showed the best release profile to achieve the therapeutic reference dose, used in the treatment of PED (1‐3 µg/day), up to four months. Additionally, intraocular inserts with different shapes were prepared using silicon molds made by means of a 3D printer. POLYM. ENG. SCI., 57:570–578, 2017. © 2017 Society of Plastics Engineers

Poly(ortho ester) nanoparticles targeted for chronic intraocular diseases: ocular safety and localization after intravitreal injection

Treatment of posterior eye diseases is more challenging than the anterior segment ailments due to a series of anatomical barriers and physiological constraints confronted by drug delivery to the back of the eye. In recent years, concerted efforts in drug delivery have been made to prolong the residence time of drugs injected in the vitreous humor of the eye. Our previous studies demonstrated that poly(ortho ester) (POE) nanoparticles were biodegradable/biocompatible and were capable of long-term sustained release. The objective of the present study was to investigate the safety and localization of POE nanoparticles in New Zealand white rabbits and C57BL/6 mice after intravitreal administration for the treatment of chronic posterior ocular diseases. Two concentration levels of POE nanoparticles solution were chosen for intravitreal injection: 1.5 mg/ml and 10 mg/ml. Our results demonstrate that POE nanoparticles were distributed throughout the vitreous cavity by optical coherence tomography (OCT) examination 14 days post-intravitreal injection. Intraocular pressure was not changed from baseline. Inflammatory or adverse effects were undetectable by slit lamp biomicroscopy. Furthermore, we demonstrate that POE nanoparticles have negligible toxicity assessed at the cellular level evidenced by a lack of glia activation or apoptosis estimation after intravitreal injection. Collectively, POE nanoparticles are a novel and nontoxic as an ocular drug delivery system for the treatment of posterior ocular diseases.

Targeted delivery of brain-derived neurotrophic factor for the treatment of blindness and deafness.

Neurodegenerative causes of blindness and deafness possess a major challenge in their clinical management as proper treatment guidelines have not yet been found. Brain-derived neurotrophic factor (BDNF) has been established as a promising therapy against neurodegenerative disorders including hearing and visual loss. Unfortunately, the blood–retinal barrier and blood–cochlear barrier, which have a comparable structure to the blood–brain barrier prevent molecules of larger sizes (such as BDNF) from exiting the circulation and reaching the targeted cells. Anatomical features of the eye and ear allow use of local administration, bypassing histo-hematic barriers. This paper focuses on highlighting a variety of strategies proposed for the local administration of the BDNF, like direct delivery, viral gene therapy, and cell-based therapy, which have been shown to successfully improve development, survival, and function of spiral and retinal ganglion cells. The similarities and controversies for BDNF treatment of posterior eye diseases and inner ear diseases have been analyzed and compared. In this review, we also focus on the possibility of translation of this knowledge into clinical practice. And finally, we suggest that using nanoparticulate drug-delivery systems may substantially contribute to the development of clinically viable techniques for BDNF delivery into the cochlea or posterior eye segment, which, ultimately, can lead to a long-term or permanent rescue of auditory and optic neurons from degeneration.

Nanotherapy for posterior eye diseases

It is assumed that more than 50% of the most enfeebling ocular diseases have their origin in the posterior segment. Furthermore, most of these diseases lead to partial or complete blindness, if left untreated. After cancer, blindness is the second most dreaded disease world over. However, treatment of posterior eye diseases is more challenging than the anterior segment ailments due to a series of anatomical barriers and physiological constraints confronted for delivery to this segment. In this regard, nanostructured drug delivery systems are proposed to defy ocular barriers, target retina, and act as permeation enhancers in addition to providing a controlled release. Since an important step towards developing effective treatment strategies is to understand the course or a route a drug molecule needs to follow to reach the target site, the first part of the present review discusses various pathways available for effective delivery to and clearance from the posterior eye. Promise held by nanocarrier systems, viz. liposomes, nanoparticles, and nanoemulsion, for effective delivery and selective targeting is also discussed with illustrative examples, tables, and flowcharts. However, the applicability of these nanocarrier systems as self-administration ocular drops is still an unrealized dream which is in itself a huge technological challenge.

Drug and gene delivery to the back of the eye: from bench to bedside.

The ARVO 2012 Summer Eye Research Conference (SERC 2012) on “Drug and Gene Delivery to the Back of the Eye: From Bench to Bedside” was held June 15 and 16, 2012, at the University of Colorado Anschutz Medical Campus in Aurora, Colorado. The SERC provided a diverse group of approximately 150 scientists and physicians representing industry and academia from 14 countries with a unique opportunity to explore the latest approaches to drug and gene delivery to the posterior segment of the eye. Unlike the 2009 SERC meeting, which focused on novel drug delivery platforms while elucidating the anatomic barriers to reach the posterior segment,1 the most recent meeting explored strategies for bypassing ocular barriers using novel materials, nanoparticulate delivery systems, and gene therapy. It brought together experts in both ophthalmology and tangentially related areas to discuss the application and inherent technical challenges for translating experimental results from the laboratory bench to dependable medical therapies at the bedside and, where possible, it exemplified findings in ocular models with methods and results gleaned from disciplines outside of ophthalmology. The present review of the SERC provides investigators with tools to navigate these nascent approaches by exploring strategies from key laboratory investigations, drug development specialists, and clinical trials. The 2-day conference comprised the following six sessions: (1) barriers to drug delivery and transporter-guided drug design; (2) drug/gene delivery systems and cell therapies for the eye; (3) pharmacokinetics (PK), pharmacodynamics, and alternative routes of drug delivery; (4) nanotechnology for diagnosis and treatment of posterior eye disease; (5) translation of gene delivery for posterior eye disease; and (6) clinical trials. Rather than being a deliberate summary of each presentation, this review describes the common themes expressed during the six sessions.

Development, characterizations and biocompatibility evaluations of intravitreal lipid implants.

The treatment of posterior eye diseases is always challenging mainly due to inaccessibility of the region. Many drugs are currently delivered by repeated intraocular injections. The purpose of this study was to investigate the potential applications of natural triglycerides as alternative carriers to synthetic polymers in terms of drug release profile and also biocompatibility for intraocular use. In vitro/in vivo evaluations of intravitreal implants fabricated from the physiological lipid, glyceride tripalmitate containing clindamycin phosphate as a model drug was performed. The micro-implants with average diameter of 0.4 mm were fabricated via a hot melt extrusion method. The extrudates were analyzed using scanning electron microscopy, differential scanning calorimetry, and in vitro drug dissolution studies. For biocompatibility, the implants were implanted into rabbit eyes. Clinical investigations including fundus observations, electroretinography as well as histological evaluations were performed. In vitro tests guaranteed usefulness of the production method for preparing the homogenous mixture of the drug and lipid without affecting thermal and crystalinity characteristics of the components. In vitro releases indicated a bi-phasic pattern for lower lipid ratios, which were completed by the end of day three. With higher lipid ratios, more controlled release profiles were achieved until about ten days for a lipid ratio of 95%. Clinical observations did not show any abnormalities up to two months after implantation into the rabbit eye. These results suggest that although the implant could not adequately retard release of the present drug model yet, due to good physical characteristics and in vivo biocompatibility, it can represent a suitable device for loading wide ranges of therapeutics in treatment of many kinds of retinochoroidal disorders.

A polymeric device for controlled transscleral multi-drug delivery to the posterior segment of the eye

The design of drug delivery systems that can deliver multiple drugs to the posterior segment of the eye is a challenging task in retinal disease treatments. We report a polymeric device for multi-drug transscleral delivery at independently controlled release rates. The device comprises a microfabricated reservoir, controlled-release cover and three different fluorescent formulations, which were made of photopolymeized tri(ethyleneglycol)dimethacrylate (TEGDM) and poly(ethyleneglycol)dimethacrylate (PEGDM). The release rate of each fluorescent is controlled by varying the PEGDM/TEGDM ratio in its formulation and the cover. The release kinetics appeared to be related to the swelling ratio of the PEGDM/TEGDM polymers. When the devices were implanted onto rat sclerae, fluorescence was observable in the ocular tissues during 4weeks’ implantation and distributed locally around the implantation site. Our polymeric system, which can administer multiple compounds with distinct kinetics, provides prolonged action and less invasive transscleral administration, and is expected to provide new tools for the treatment of posterior eye diseases with new therapeutic modalities.

Progress in sustained-release drug delivery system for treatment of posterior segment eye diseases

There is an urgent requirement to find effective therapeutic procedures for the treatment of refractory eye diseases of posterior segment such as posterior uveitis, proliferative vitreoretinopathy, and macular edema associated with diabetes and retinal vein occlusion. Due to systemic side effect developed from systemic drug administration and the low efficiency of topical drug administration, implantable drug devices for the treatment of posterior segment diseases have been explored. In recent years, three different intraocular implantable devices (ganciclovir, fluocinolone acetonide and dexamethasone) have been approved by FDA and showed exciting clinical efficacy. However, these devices have surgical complications and the drug-related side effects. Recently, transscleral drug delivery to the posterior segment has been investigated. Transscleral drug delivery has advantages of large scleral surface area, better safety profile, easily drug administration and could evolve into an effective route with the use of novel biomaterials and the study of drug delivery methods.

Chitosan Electrodeposition for Microrobotic Drug Delivery

A method to functionalize steerable magnetic microdevices through the co-electrodeposition of drug loaded chitosan hydrogels is presented. The characteristics of the polymer matrix have been investigated in terms of fabrication, morphology, drug release and response to different environmental conditions. Modifications of the matrix behavior could be achieved by simple chemical post processing. The system is able to load and deliver 40-80 μg cm(-2) of a model drug (Brilliant Green) in a sustained manner with different profiles. Chitosan allows a pH responsive behavior with faster and more efficient release under slightly acidic conditions as can be present in tumor or inflamed tissue. A prototype of a microrobot functionalized with the hydrogel is presented and proposed for the treatment of posterior eye diseases.

A pharmacokinetic study of a combination of beta adrenoreceptor antagonists – In the isolated perfused ovine eye

The treatment of posterior eye diseases, such as diabetic retinopathy and age-related macular degeneration, is of growing interest as the number of people affected by these conditions continues to rise. This study utilises the methods of cassette dosing and the perfused ovine eye model – to reduce animal usage and therefore animal time – to show that for a series of beta adrenoreceptor antagonists, lipophilicity is a key physicochemical property that governs drug distribution within the eye. Following intravitreal injection, lipophilic beta adrenoreceptor antagonists penetrate to the posterior eye, where they bind to the choroid and reside in the retina at greater concentrations than more hydrophilic beta adrenoreceptor antagonists, which preferentially penetrate to the anterior eye.

Ocular Pharmacokinetic Study Using T1 Mapping and Gd-Chelate- Labeled Polymers

Recent advances in drug discovery have led to the development of a number of therapeutic macromolecules for treatment of posterior eye diseases. We aimed to investigate the clearance of macromolecular contrast probes (polymers conjugated with Gd-chelate) in the vitreous after intravitreal injections with the recently developed ms-DSEPI-T12 MRI and to examine the degradation of disulfide-containing biodegradable polymers in the vitreous humor in vivo. Intravitreal injections of model contrast agents poly[N-(2-hydroxypropyl)methacrylamide]-GG-1,6-hexanediamine-(Gd-DO3A), biodegradable (Gd-DTPA)-cystine copolymers, and MultiHance were performed in rabbits; their distribution and elimination from the vitreous after injections were determined by MRI. Times for macromolecular contrast agents to decrease to half their initial concentrations in the vitreous ranged from 0.4-1.3 days post-injection. Non-biodegradable polymers demonstrated slower vitreal clearance than those of disulfide-biodegradable polymers. Biodegradable polymers had similar clearance as MultiHance. Usefulness of T(1) mapping and ms-DSEPI-T12 MRI to study ocular pharmacokinetics was demonstrated. Results suggest an enzymatic degradation mechanism for the disulfide linkage in polymers in the vitreous leading to breakup of polymers in vitreous humor over time.

Drug Delivery to the Posterior Segment of the Eye

Drug delivery into the posterior segment of the eye is complicated by the presence of the blood-ocular barrier. Strategies for delivering drugs to the posterior segment include systemic administration, modification of the blood-eye barrier, and local drug delivery. Recently, new topical treatments have emerged for the treatment of posterior eye disease. Iontophoretic, juxtascleral, and intravitreal routes can be used to achieve therapeutic levels in the posterior segment. Extended-release intravitreal drug delivery systems can achieve sustained therapeutic levels with the goal of providing a prolonged clinical benefit.