scholarly journals Hollow Microcapsules as Periocular Drug Depot for Sustained Release of Anti-VEGF Protein

Pharmaceutics ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 330
Author(s):  
Krishna Radhakrishnan ◽  
Anita Vincent ◽  
Rini Rachel Joseph ◽  
Miguel Moreno ◽  
Andreas Dickescheid ◽  
...  
Keyword(s):  
Sustained Release ◽  
Ex Vivo ◽  
Current Treatment ◽  
Age Related Macular Degeneration ◽  
Layer By Layer ◽  
Anti Vegf ◽  
Age Related ◽  
Positively Charged ◽  
Vegf Protein

Diseases affecting the posterior segment of the eye such as age-related macular degeneration and diabetic retinopathy are leading causes of blindness all over the world. The current treatment regimen for such diseases involves repeated intravitreal injections of anti- Vascular Endothelial Growth Factor (VEGF) proteins. This method is highly invasive and can lead to severe complications. In an attempt to develop less invasive alternatives, we propose the use of a controlled release system consisting of anti-VEGF loaded hollow microcapsules that can be administered periocularly to form drug eluting depots on the episcleral surface. The microcapsules with either positive or negative surface charge were prepared by a layer by layer approach and showed pH responsive permeability switching. An ex vivo experiment using porcine sclera indicated positively charged microcapsules remained on the episcleral surface over four days while the negatively charged microcapsules were washed away. These positively charged microcapsules were then loaded with anti-VEGF protein ranibizumab using pH dependent permeability switching and protein release from the microcapsules were studied using an in vitro setup. An ex vivo experiment utilizing porcine sclera demonstrated sustained release of ranibizumab over seven days with zero-order kinetics.

scholarly journals Antioxidant Role of PRGF on RPE Cells after Blue Light Insult as a Therapy for Neurodegenerative Diseases

2020 ◽  
Vol 21 (3) ◽  
pp. 1021 ◽  
Author(s):  
Carlota Suárez-Barrio ◽  
Susana del Olmo-Aguado ◽  
Eva García-Pérez ◽  
María de la Fuente ◽  
Francisco Muruzabal ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Human Cell Line ◽  
Antioxidant Effect ◽  
Age Related Macular Degeneration ◽  
Strong Impact ◽  
Retinal Diseases ◽  
Age Related ◽  
Gene And Protein Expression

Oxidative stress has a strong impact on the development of retinal diseases such as age-related macular degeneration (AMD). Plasma rich in growth factors (PRGF) is a novel therapeutic approach in ophthalmological pathologies. The aim of this study was to analyze the antioxidant effect of PRGF in retinal epithelial cells (EPR) in in vitro and ex vivo retinal phototoxicity models. In vitro analyses were performed on ARPE19 human cell line. Viability and mitochondrial status were assessed in order to test the primary effects of PRGF. GSH level, and protein and gene expression of the main antioxidant pathway (Keap1, Nrf2, GCL, HO-1, and NQO1) were also studied. Ex vivo analyses were performed on rat RPE, and HO-1 and Nrf2 gene and protein expression were evaluated. The results show that PRGF reduces light insult by stimulating the cell response against oxidative damage and modulates the antioxidant pathway. We conclude that PRGF’s protective effect could prove useful as a new therapy for treating neurodegenerative disorders such as AMD.

scholarly journals New Therapies of Neovascular AMD – Beyond Anti VEGFs

2018 ◽  
Author(s):  
Praveen Yerramothu
Keyword(s):  
Tissue Factor ◽  
Treatment Options ◽  
Significant Risk ◽  
Current Treatment ◽  
Geographic Atrophy ◽  
Age Related Macular Degeneration ◽  
P450 Monooxygenase ◽  
New Therapies ◽  
Anti Vegf ◽  
Age Related

Neovascular age-related macular degeneration (nAMD) accounts for one of the leading causes of blindness among the aging population. The current treatment options for nAMD include intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF). However, standardised frequent administration of anti-VEGF injections only improves the vision in approximately 30%-40% of nAMD patients. Current therapies targeting nAMD pose a significant risk of retinal fibrosis and geographic atrophy (GA) development in nAMD patients. A need exists to develop new therapies to treat nAMD with effective and long-term anti-angiogenic effects. Recent research on nAMD has discovered novel therapeutic targets and angiogenic signalling mechanisms involved in its pathogenesis. For example, tissue factor, human intravenous immune globulin, interferon-β signalling, cyclooxygenase-2 (COX-2) and cytochrome P450 monooxygenase lipid metabolites have been identified as key players in the development of angiogenesis in AMD disease models. Furthermore, novel therapies such as NLRP3 inflammasome inhibition, targeted intraceptor nanoparticle therapy, inhibitors of integrins and tissue factor are currently being tested at the level of clinical trials to treat nAMD. The aim of this review is to discuss the scope for alternative therapies proposed to anti-VEGFs for the treatment of nAMD.

scholarly journals Fabrication and Characterisation of a Photo-Responsive, Injectable Nanosystem for Sustained Delivery of Macromolecules

2021 ◽  
Vol 22 (7) ◽  
pp. 3359
Author(s):  
Pakama Mahlumba ◽  
Pradeep Kumar ◽  
Lisa C. du du Toit ◽  
Madan S. Poka ◽  
Philemon Ubanako ◽  
...  
Keyword(s):  
Minimally Invasive ◽  
Sustained Release ◽  
Uv Spectroscopy ◽  
Particle Diameter ◽  
Age Related Macular Degeneration ◽  
Sustained Delivery ◽  
Age Related ◽  
Frequent Administration ◽  
Size And Morphology

The demand for biodegradable sustained release carriers with minimally invasive and less frequent administration properties for therapeutic proteins and peptides has increased over the years. The purpose of achieving sustained minimally invasive and site-specific delivery of macromolecules led to the investigation of a photo-responsive delivery system. This research explored a biodegradable prolamin, zein, modified with an azo dye (DHAB) to synthesize photo-responsive azoprolamin (AZP) nanospheres loaded with Immunoglobulin G (IgG). AZP nanospheres were incorporated in a hyaluronic acid (HA) hydrogel to develop a novel injectable photo-responsive nanosystem (HA-NSP) as a potential approach for the treatment of chorio-retinal diseases such as age-related macular degeneration (AMD) and diabetic retinopathy. AZP nanospheres were prepared via coacervation technique, dispersed in HA hydrogel and characterised via infrared spectroscopy (FTIR), X-ray diffraction (XRD) and thermogravimetric analysis (TGA). Size and morphology were studied via scanning electron microscopy (SEM) and dynamic light scattering (DLS), UV spectroscopy for photo-responsiveness. Rheological properties and injectability were investigated, as well as cytotoxicity effect on HRPE cell lines. Particle size obtained was <200 nm and photo-responsiveness to UV = 365 nm by decreasing particle diameter to 94 nm was confirmed by DLS. Encapsulation efficiency of the optimised nanospheres was 85% and IgG was released over 32 days up to 60%. Injectability of HA-NSP was confirmed with maximum force 10 N required and shear-thinning behaviour observed in rheology studies. In vitro cell cytotoxicity effect of both NSPs and HA-NSP showed non-cytotoxicity with relative cell viability of ≥80%. A biocompatible, biodegradable injectable photo-responsive nanosystem for sustained release of macromolecular IgG was successfully developed.

scholarly journals Neovascular Age-Related Macular Degeneration: Therapeutic Management and New-Upcoming Approaches

2020 ◽  
Vol 21 (21) ◽  
pp. 8242
Author(s):  
Federico Ricci ◽  
Francesco Bandello ◽  
Pierluigi Navarra ◽  
Giovanni Staurenghi ◽  
Michael Stumpp ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Repeated Administration ◽  
Current Treatment ◽  
Age Related Macular Degeneration ◽  
Significant Advance ◽  
Neovascular Amd ◽  
Significant Treatment ◽  
Anti Vegf ◽  
Age Related ◽  
Ankyrin Repeat Proteins

Age-related macular degeneration (AMD) constitutes a prevalent, chronic, and progressive retinal degenerative disease of the macula that affects elderly people and cause central vision impairment. Despite therapeutic advances in the management of neovascular AMD, none of the currently used treatments cures the disease or reverses its course. Medical treatment of neovascular AMD experienced a significant advance due to the introduction of vascular endothelial growth factor inhibitors (anti-VEGF), which dramatically changed the prognosis of the disease. However, although anti-VEGF therapy has become the standard treatment for neovascular AMD, many patients do not respond adequately to this therapy or experience a slow loss of efficacy of anti-VEGF agents after repeated administration. Additionally, current treatment with intravitreal anti-VEGF agents is associated with a significant treatment burden for patients, caregivers, and physicians. New approaches have been proposed for treating neovascular AMD. Among them, designed ankyrin repeat proteins (DARPins) seem to be as effective as monthly ranibizumab, but with greater durability, which may enhance patient compliance with needed injections.

scholarly journals Sunitinib-Loaded MPEG-PCL Micelles for the Treatment of Age-Related Macular Degeneration

2020 ◽  
Vol 88 (3) ◽  
pp. 30 ◽  
Author(s):  
Jarriaun Streets ◽  
Priyanka Bhatt ◽  
Deepak Bhatia ◽  
Vijaykumar Sutariya
Keyword(s):  
Macular Degeneration ◽  
Polymeric Micelles ◽  
Retinal Pigment Epithelial Cell ◽  
Retinal Pigment ◽  
Current Treatment ◽  
Age Related Macular Degeneration ◽  
Intravitreal Injections ◽  
Epithelial Cell Line ◽  
Anti Vegf ◽  
Age Related

Age-related macular degeneration (AMD) will be responsible for the vision impairment of more than five million late-aged adults in the next 30 years. Current treatment includes frequent intravitreal injections of anti-vascular endothelial growth factor (VEGF) agents. However, there are methods of drug delivery that can decrease the frequency of intravitreal injections by sustaining drug release. MPEG-PCL ((methoxypoly(ethylene glycol) poly(caprolactone)) has been reported as biocompatible and biodegradable. Polymeric micelles of MPEG-PCL can be useful in efficiently delivering anti-VEGF drugs such as sunitinib to the posterior segment of the eye. In this study, the novel micellar formulation exhibited an average dynamic light scattering (DLS) particle size of 134.2 ± 2.3 nm with a zeta potential of −0.159 ± 0.07 mV. TEM imaging further confirmed the nanoscopic size of the micelles. A sunitinib malate (SM)-MPEG-PCL formulation exhibited a sustained release profile for up to seven days with an overall release percentage of 95.56 ± 2.7%. In addition to their miniscule size, the SM-MPEG-PCL formulation showed minimal cytotoxicity onto the ARPE-19 human retinal pigment epithelial cell line, reporting a percent viability of more than 88% for all concentrations tested at time intervals of 24 h. The SM-MPEG-PCL micelles also exhibited exceptional performance during an anti-VEGF ELISA that decreased the overall VEGF protein expression in the cells across a 24–72 h period. Furthermore, it can be concluded that this type of polymeric vehicle is a promising solution to symptoms caused by AMD and improving the management of those suffering from AMD.

scholarly journals Ref-1/APE1 inhibition with novel small molecules blocks ocular neovascularization

2018 ◽  
Author(s):  
Sardar Pasha Sheik Pran Babu ◽  
Kamakshi Sishtla ◽  
Rania S. Sulaiman ◽  
Bomina Park ◽  
Trupti Shetty ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Ex Vivo ◽  
Age Related Macular Degeneration ◽  
Lesion Volume ◽  
Ocular Neovascularization ◽  
Age Related ◽  
Promising Therapeutic Approach ◽  
Dna Binding Assay

AbstractOcular neovascular diseases like wet age-related macular degeneration are a major cause of blindness. Novel therapies are greatly needed for these diseases. One appealing antiangiogenic target is reduction-oxidation factor 1-apurinic/apyrimidinic endonuclease 1 (Ref-1/APE1). This protein can act as a redox-sensitive transcriptional activator for NF-κB and other pro-angiogenic transcription factors. An existing inhibitor of Ref-1’s function, APX3330, previously showed antiangiogenic effects. Here, we developed improved APX3330 derivatives and assessed their antiangiogenic activity. We synthesized APX2009 and APX2014 and demonstrated enhanced inhibition of Ref-1 function in a DNA-binding assay compared to APX3330. Both compounds were antiproliferative against human retinal microvascular endothelial cells (HRECs; GI50 APX2009: 1.1 μM, APX2014: 110 nM) and macaque choroidal endothelial cells (Rf/6a GI50APX2009: 26 μM, APX2014: 5.0 μM). Both compounds significantly reduced the ability of HRECs and Rf/6a cells to form tubes at mid nanomolar concentrations compared to control, and both significantly inhibited HREC and Rf/6a cell migration in a scratch wound assay, reducing NF-κB activation and downstream targets.Ex vivo, both APX2009 and APX2014 inhibited choroidal sprouting at low micromolar and high nanomolar concentrations respectively. In the laser-induced choroidal neovascularization mouse model, intraperitoneal APX2009 treatment significantly decreased lesion volume by 4-fold compared to vehicle (p< 0.0001, ANOVA with Dunnett’s post hoc tests), without obvious intraocular or systemic toxicity. Thus, Ref-1 inhibition with APX2009 and APX2014 blocks ocular angiogenesisin vitroandex vivo, and APX2009 is an effective systemic therapy for CNVin vivo, establishing Ref-1 inhibition as a promising therapeutic approach for ocular neovascularization.

scholarly journals New Therapies of Neovascular AMD—Beyond Anti-VEGFs

Vision ◽  
2018 ◽  
Vol 2 (3) ◽  
pp. 31 ◽  
Author(s):  
Praveen Yerramothu
Keyword(s):  
Tissue Factor ◽  
Treatment Options ◽  
Significant Risk ◽  
Current Treatment ◽  
Geographic Atrophy ◽  
Age Related Macular Degeneration ◽  
P450 Monooxygenase ◽  
New Therapies ◽  
Anti Vegf ◽  
Age Related

Neovascular age-related macular degeneration (nAMD) is one of the leading causes of blindness among the aging population. The current treatment options for nAMD include intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF). However, standardized frequent administration of anti-VEGF injections only improves vision in approximately 30–40% of nAMD patients. Current therapies targeting nAMD pose a significant risk of retinal fibrosis and geographic atrophy (GA) development in nAMD patients. A need exists to develop new therapies to treat nAMD with effective and long-term anti-angiogenic effects. Recent research on nAMD has identified novel therapeutic targets and angiogenic signaling mechanisms involved in its pathogenesis. For example, tissue factor, human intravenous immune globulin, interferon-β signaling, cyclooxygenase-2 (COX-2) and cytochrome P450 monooxygenase lipid metabolites have been identified as key players in the development of angiogenesis in AMD disease models. Furthermore, novel therapies such as NACHT, LRR and PYD domains containing protein 3 (NLRP3) inflammasome inhibition, inhibitors of integrins and tissue factor are currently being tested at the level of clinical trials to treat nAMD. The aim of this review is to discuss the scope for alternative therapies proposed as anti-VEGFs for the treatment of nAMD.

Evaluation of Port Delivery System with ranibizumab for the treatment of neovascular age-related macular degeneration

2021 ◽  
Vol 12 (3) ◽  
pp. 191-200
Author(s):  
Annika J Patel ◽  
Dante J Pieramici ◽  
Nika Bagheri
Keyword(s):  
Macular Degeneration ◽  
Delivery System ◽  
Current Treatment ◽  
Age Related Macular Degeneration ◽  
Office Visits ◽  
Continuous Release ◽  
Anti Vegf ◽  
Age Related ◽  
Pars Plana

Current treatment of neovascular age-related macular degeneration involves periodic intravitreal injections of anti-VEGF medication, creating a burden to patients and physicians, resulting in nonadherence to recommended dosing schedules. The Port Delivery System with ranibizumab offers a long-term solution that involves implantation of a device into the pars plana and provides continuous release of anti-VEGF medication into the vitreous, thus requiring fewer office visits. The Port Delivery System has demonstrated comparable visual and anatomic outcomes to monthly injections and shows promise in alleviating the patient burden in the treatment of neovascular age-related macular degeneration, making possible better long-term real-world visual outcomes.

scholarly journals New molecular targets for the treatment of neovascular age-related macular degeneration

2017 ◽  
Vol 1 (3) ◽  
Author(s):  
Gian Marco Tosi ◽  
Marcella Barbarino ◽  
Maurizio Orlandini ◽  
Federico Galvagni
Keyword(s):  
Macular Degeneration ◽  
Vision Loss ◽  
Current Treatment ◽  
Age Related Macular Degeneration ◽  
Western World ◽  
Treatment Protocols ◽  
Anti Vegf ◽  
Age Related ◽  
Long Term Follow Up ◽  
New Treatments

Age-related macular degeneration (AMD) is a progressive chronic disease that currently represents the leading cause of irreversible vision loss in the western world. Experimental and clinical evidence has demonstrated that vascular endothelial growth factor A (VEGF-A) plays an important role in promoting the choroidal neovascularization that characterizes the wet form of AMD. Intravitreal injection of anti- VEGF-A agents is the current treatment of choice for neovascular AMD (nAMD). These agents have brought about dramatic changes in the treatment of nAMD, but most patients require frequently repeated injections and regular long-term follow-up, with a significant percentage of them showing resistance to anti-VEGF-A drugs. Thus, the identification of additional therapies that could improve the treatment protocols is needed. There are numerous areas of investigation into new treatments, with increasing efforts being made to study drugs that address various targets along the angiogenic signaling cascade, or other pathways related to the onset of nAMD. The aim of the present review is to summarize and discuss promising new therapies and targets that have the potential to improve outcomes and to lengthen treatment durability, especially in patients with recalcitrant or recurrent forms of nAMD.

scholarly journals High Density Display of an Anti-Angiogenic Peptide on Micelle Surfaces Enhances Their Inhibition of αvβ3 Integrin-Mediated Neovascularization In Vitro

Nanomaterials ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 581
Author(s):  
Rajini Nagaraj ◽  
Trevor Stack ◽  
Sijia Yi ◽  
Benjamin Mathew ◽  
Kenneth R Shull ◽  
...  
Keyword(s):  
Treatment Options ◽  
Surface Display ◽  
Antibody Therapy ◽  
Inhibitory Effect ◽  
Age Related Macular Degeneration ◽  
Αvβ3 Integrin ◽  
Inhibition Of Proliferation ◽  
Anti Vegf ◽  
Age Related

Diabetic retinopathy (DR), Retinopathy of Pre-maturity (ROP), and Age-related Macular Degeneration (AMD) are multifactorial manifestations associated with abnormal growth of blood vessels in the retina. These three diseases account for 5% of the total blindness and vision impairment in the US alone. The current treatment options involve heavily invasive techniques such as frequent intravitreal administration of anti-VEGF (vascular endothelial growth factor) antibodies, which pose serious risks of endophthalmitis, retinal detachment and a multitude of adverse effects stemming from the diverse physiological processes that involve VEGF. To overcome these limitations, this current study utilizes a micellar delivery vehicle (MC) decorated with an anti-angiogenic peptide (aANGP) that inhibits αvβ3 mediated neovascularization using primary endothelial cells (HUVEC). Stable incorporation of the peptide into the micelles (aANGP-MCs) for high valency surface display was achieved with a lipidated peptide construct. After 24 h of treatment, aANGP-MCs showed significantly higher inhibition of proliferation and migration compared to free from aANGP peptide. A tube formation assay clearly demonstrated a dose-dependent angiogenic inhibitory effect of aANGP-MCs with a maximum inhibition at 4 μg/mL, a 1000-fold lower concentration than that required for free from aANGP to display a biological effect. These results demonstrate valency-dependent enhancement in the therapeutic efficacy of a bioactive peptide following conjugation to nanoparticle surfaces and present a possible treatment alternative to anti-VEGF antibody therapy with decreased side effects and more versatile options for controlled delivery.

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