Essay: Animal models in diabetic retinopathy

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Animal-based research has played a key role in understanding infectious diseases, neuroscience, physiology, and toxicology.110 It became essential in DR, as well, allowing the enhanced understanding of the cellular and molecular aspects of the pathogenesis of DR, and thus for developing new and better treatments.111 During the last two decades, several animal species, such as zebrafish, mice, rats, cats, dogs, pigs and non-human primates, have been used as models on these studies. DR animal models basically present hyperglycemia, which can be induced: (1) with chemicals (e.g., streptozotocin, STZ) or surgical pancreatectomy; (2) spontaneously, by selective breeding or genetic manipulation;111,112 or (3) using viruses (e.g., coxsackie B virus, encephalomyocarditis virus and Kilham rat virus) to initiate pancreatic β cell destruction.113 These animal models show pathologic events similar to those in patients with diabetes and DR, namely some pathologic features regarding structural abnormalities or the dissociation of neurovascular units of the retina, such as pericyte loss, and increased vascular permeability.112
Most of the animal models of DR are based on rodents, mostly rats and mice (Table 1).111,112 Various rodent models are available and have been used in this topic, thus a proper selection of a certain animal model should be carried out, according to the purpose of the study in order to improve the potency of DR research. Although these animal models provide a remarkable tool to investigate the pathogenesis of DR, they only allow the study of the early stages of the disease. Actually, the major criticism regarding the use of rodents as a model DR is that they reproduce most aspects of the early stages of DR, but have not the late, neovascular stage of the disease found in PDR patients, probably owing to the short lifespan of the animals and thus the shorter duration of diabetes.111 Therefore, researchers choose to use rodent models of PDR to study neovascularization, even though some of these models are not characterized by hyperglycemia. Overexpression of VEGF (human VEGF165 gene) in photoreceptors or exposure to hyperoxia during the early developmental periods, are generally used to induce retinal neovascularization.111,112
Although animal experiments have contributed much to the understanding of mechanisms of disease, their value in predicting the effectiveness of treatment strategies still remains controversial.114 A former study revealed that only about one third of highly cited animal research articles were translated to the level of human randomized trials,115 and as little as 8% of drugs passed Phase I successfully.116 Translational failure may be explained by methodological flaws in animal studies, leading to inadequate data and incorrect conclusions, and also by disease specificities or by the limited ability of animal models to mimic the extremely complex process of a human disease.114,117
3. Emerging therapeutic targets in diabetic retinopathy
As aforementioned, the current pharmacologic therapies for the treatment of DR and DME are primarily based on the anti-angiogenic action of anti-VEGF drugs and the anti-inflammatory actions of steroids. 118 Emerging therapies are under investigation and target various molecules and mechanisms involved in the cascade of events leading to or aggravated by angiogenesis and inflammation. 119,120 These include various growth factors and hormones, signal transduction pathways, oxidative stress, endoplasmic reticulum stress, and neurodegeneration. 120,121 All these pathways may ultimately culminate in BRB breakdown, which in turn aggravates cellular damage stimulating inflammation. To evaluate potential therapeutic targets, different in vitro and animal models of diabetes or retinopathy of prematurity (ROP) were used. In ROP, retinal neovascularization is a key pathogenic feature resembling PDR; the oxygen-induced retinopathy (OIR) model has been used to mimic ROP.
VEGF and other growth factors
It is well established that VEGF plays a major role in the pathological vascular permeability and angiogenesis observed in DR. In fact, intravitreal anti-VEGF drugs are currently the most effective therapy for advanced stages of DR, as described above. 120 However, due to systemic side-effects, and since VEGF has neuroprotective actions in the retina, alternative or additional therapeutic targets are needed.
Within the cascade of VEGF signaling, neuropilin-1 (NRP-1), a coreceptor for VEGF, was demonstrated to potentiate neovascularization in the OIR model, by the ability to bind VEGF and semaphorin 3A (SEMA3A). 122 The authors suggested that NRP-1 and SEMA3A, which are increased in the vitreous of PDR patients, contribute to the deleterious effects of VEGF. Neutralization of NRP-1 or semaphorin 3A, with intravitreal administration of soluble recombinant NRP-1 or virally delivered interference RNA against Sema3A, respectively, was shown to result in vasoprotective effects. 122,123 VEGF also activates the Src family of tyrosine kinases, namely Src, which associates with VEGF receptor 2 (VEGFR2), and mediates vascular permeability induced by VEGF. Similarly, targeting this pathway was shown to protect retinal vasculature, since topical administration of TG100801, which inhibited VEGFR2/Src kinase, was sufficient to abolish vascular leakage induced by VEGF in the mouse retina. 124 In fact, since different receptor tyrosine kinases stimulate angiogenesis in response to angiogenic ligands like VEGF and platelet-derived growth factor (PDGF), the inhibition of multiple tyrosine kinases has been evaluated as a strategy to halt angiogenesis. 118 In addition, the neutralization of selective angiogenic growth factor pathways, others than VEGF, has been studied. Examples of these pathways, as promising targets for inhibition of retinal neovascularization, are placental growth factor 125, PDGF 126, transforming growth factor- β 127, and connective tissue growth factor (CTGF, CCN2). 128 Alternatively, the activation of antiangiogenic growth factors’ signaling may be an attractive strategy as is the case of pigment epithelium-derived growth factor (PEDF). 129 The angiopoietin (Ang)/Tie2 pathway has been regarded as an interesting target owing to its role in maintaining vascular integrity. Ang-1 and -2 are endogenous ligands for the vascular endothelial receptor tyrosine kinase Tie2. The activation of Tie2 by Ang-1 stimulates phosphorylation and downstream signaling, which results in blood vessel stabilization, whereas Ang-2 competes with Ang-1 for Tie2 binding and reduces Tie2 phosphorylation. A small-molecule (AKB-9778), inhibitor of vascular endothelial-protein tyrosine phosphatase, a negative regulator of Tie2, was shown to induced phosphorylation of Tie2 and reduce retinal neovascularization and vessel leakage in mice. 130 A phase 2 clinical trial with AKB-9778 is currently ongoing. Erythropoietin is a major regulator of erythropoiesis and exert a plethora of effects in the retina including neuroprotection and vasoprotection. Thereby, it has gained relevance as potential therapeutic factor for retinal degenerative diseases. However, in DR, although studies in animal models reported protective effects in early stages, preventing structural vascular and neural damage, it might enhance the effects of VEGF in late stages and contribute to neovascularization. 120
Hormones and secreted peptides
In addition to growth factor, several hormones and secreted peptides have recently been reported to open new therapeutic pharmacological possibilities for the treatment of DR.
The kinin-kallikrein system has been associated with retinal vascular permeability in eyes with DME, suggesting that kallikrein inhibitors may provide new therapeutic options for DME. In fact, kallikrein was found to contribute to retinal vascular permeability via bradykinin receptor in a mechanism independent of VEGF in mice. 131
The endothelin system, was also associated with diabetic micrangiopathy since it contributes to the imbalance between endothelium-derived vasodilator and vasoconstrictor signaling. Increased levels of endothelin-1 were found in diabetic patients, which favors vasoconstriction. In diabetic mice, the blockade of endothelin-A receptor by administration of atrasentan was able to attenuate retinal capillary degeneration and pericyte loss. 132
The pituitary adenylate cyclase-activating polypeptide (PACAP) has been shown to exert a retinal protective role in different pathologies. Particularly, in diabetic rats, intravitreal administration of PACAP was shown to induce protective effects by increasing anti- and decreasing proapoptotic factors. 133
The β-adrenergic system has also been evaluated as a potential new therapeutic target for neovascular retinal diseases. In this regard, β-adrenergic system modulation may result either in reduction or in exacerbation of vascular changes. In OIR model, the blockade of β-adrenergic receptors has been reported to inhibit retinal neovascularization, while the activation of β-adrenergic receptors was shown to exert antiangiogenic effects in STZ-induced diabetic rats. 134
The hormone somatostatin, which is reduced in the diabetic retina, has been shown to exert angiostatic and antipermeability actions in the retina. Since topical administration of somatostatin was found to prevent retinal neurodegeneration in diabetic rats, it has been proposed as a new target for treatment of DR and a clinical trial is currently ongoing. 135
The vasohibin family includes novel endogenous regulators of angiogenesis. Particularly, vasohibin-1, is a negative feedback regulator of angiogenesis produced by endothelial cells. To test its vasoprotective effect, in mice, intravitreal recombinant vasohibin was found to suppress retinal neovascularization. 136
Vasoinhibins are a family of peptides derived from the hormone prolactin, which have been found to inhibit blood vessel growth, vasopermeability, and vasodilation. Regarding retinal vasculature, in vitro, vasoinhibins were found to reduce VEGF-induced vasopermeability in rat retinal capillary endothelial cells; in vivo, vasoinhibins blocked vasopermeability in rat retinas induced by diabetes or VEGF. 137
Dipeptidyl peptidase IV (DPP-IV) inhibitors have been widely used to treat diabetes through the increase of insulin release and glycemic control. Recently, the DPP-IV inhibitor sitagliptin was reported to prevent the increase in BRB permeability, and exert anti-inflammatory and neuroprotective effects in the retina of diabetic rats. This effect, however, was found to be independent of glycemic normalization, suggesting additional potential therapeutic targets associated with dipeptidyl peptidase IV. 138
Hyperglycemia, oxidative stress, and endoplasmic reticulum stress
Several drugs were developed targeting the main pathways triggered by hyperglycemia in the eye as well as in other tissues. These include mainly advanced glycation end-product inhibitors and aldose reductase inhibitors. 119 An emergent target may be the G protein-coupled receptor-91 (GPR91) which is a receptor for succinate. Due to accumulation of succinate under hyperglycemia, as well as in the hypoxic retina, the activation of GPR91 contributes to vessel growth by regulating the production of angiogenic factors. GPR91 inhibition may provide a new therapeutic target for the treatment of pathological retinal angiogenesis. 139
An important player in the pathogenesis of DR is the increased oxidative stress. Although numerous antioxidants have been tested as a way to counterbalance the oxidative environment, significant benefits for diabetic patients have not been reported. 121 Therefore, the identification of specific sources of oxidative stress are needed. In this regard, arginase has emerged as a new target. 140 Excessive arginase activity, as in diabetes, reduces the L-arginine available for nitric oxide synthase, causing it to produce superoxide, increasing oxidative stress.
The thioredoxin-interacting protein (TXNIP) is able to inhibit thioredoxin activity and reduce the cellular antioxidant capacity. In the context of DR, TXNIP expression was found to be increased by high glucose and diabetes in retinal endothelial cells and diabetic retinas; contributing to inflammation and neuronal apoptosis. Blockade of TXNIP by siRNA reverted these effects in diabetic rats, highlighting this pathway as a possible therapeutic target. 141
Also of therapeutic interest is the NF-E2-related factor 2 (Nrf2), a key stress-response transcription factor with protective actions. Nrf2 deficiency suppresses retinal revascularization and increases pathologic neovascularization in mice. Accordingly, Nrf2 activation was reported to promote reparative angiogenesis and suppressed pathologic neovascularization. 142
An important role in the regulation of pathological angiogenesis was associated with the unfolded protein response in the context of endoplasmic reticulum (ER) stress. This pathway may open novel possibilities for the treatment of DR. Potential targets in this context include mainly ER transmembrane proteins: protein kinase RNA-like ER kinase, inositol-requiring protein 1α, and activating transcription factor 6. 143
Inflammation
Inflammation has long been implicated in the pathogenesis of DR and the intravitreal administration of anti-inflammatory steroids is currently widely used in clinical practice. Since this treatment is associated with important side-effects, new and specific anti-inflammatory targets are needed. An example are the blockade of pro-inflammatory cytokines like IL-1β or TNF, investigated with promising results in animal models. 120
An emerging approach is the modulation of suppressor of cytokine signaling 3 (SOCS3). In fact, using a model of OIR mice, neovascularization was reduced by inhibition of retinoic-acid-receptor-related orphan receptor alpha (RORα); an effect associated with SOCS3. 144
The chemokine platelet factor-4 variant might be a promising target since in diabetic rats it was found to be as potent as bevacizumab (anti-VEGF drug) inhibiting diabetes-induced BRB breakdown. 145
Major signal transduction pathways
Several signal transduction pathways are involved in the pathogenesis of DR. One of this pathways extensively studied is the protein kinase C (PKC). Inhibitors of PKC have been evaluated in clinical trials with promising results. 118,119
Other signaling pathways recently implicated in the disease, with potential for new therapeutic possibilities, include Rho 146, Wnt 147, and c-Jun. 148
Additionally, several microRNAs were implicated in the pathogenesis of DR. These microRNAs represent a powerful class of modulators of gene expression, and may open new gain- or loss-of-function strategies to effectively treat this disease. 149
4. Ocular therapy
4.1. Sustained release technology
As aforementioned, intravitreal injections are widely used in ocular therapy. Actually, they enable a simple, direct application of a drug to the site of the disease. Given the treatment burden, an elegant alternative and effective drug delivery system would be a huge step forward in ocular therapy. So that sustained release technology became a rapidly expanding and primary field, in such a way that “(…) the future of medical ophthalmology (…) is sustained-release drug delivery”.150 The new technologies are designed aiming not only to reduce the need for frequent intraocular injections, as well as to reduce or even eliminate eye drops. They also smooth dosing spikes, enabling consistent delivery within the therapeutic range for all kinds of ophthalmic drugs over time, ranging from hours to months.151 Table 2 briefly describes some of the current sustained release ophthalmic drug systems,152-157 illustrated in Figure 9.
Figure 9. Location of currently used/in development implants for drug delivery to posterior segment of the eye. Free floating implants (A): Ozurdex™ (A1) is a rod-shaped implant (0.46 mm in diameter and 6 mm in length) inserted into the eye through the pars plana using a 22-gauge (22G) injector; Iluvien™ (A2) is a cylindrical implant (0.37 x 3.5 mm) inserted into the eye through the pars plana using a 25G applicator. Subconjunctival implant (B): Durasert™ is biodegradable translucent cylindrical implant (0.4 x 3-4 mm) injected into subconjunctival space with a 25G needle. Scleral-fixated implants (C): Vitrasert® (C1) is surgically implanted into the vitreous through the pars plana and attached to the sclera by a suture (drug core’s dimensions: 2.5 x 1 mm); Retisert® (C2) is implanted in the eye via a pars plana incision and fixated to the scleral by a suture (drug core’s dimensions: 3 x 2 mm); I-vation™ (C3) is a helical device (0.4 x 0.21 mm) that is implanted through a pars plana sclerotomy; Renexus® (ECT) (C4) contains modified human cells that secrete CNTF, i.e., this device does not primarily store the drug, but rather produces it in situ. The immunoisolatory membrane surrounding the encapsulated cells allows ingress of oxygen and nutrients and egress of therapeutic factors, but blocks the entry of immune system components.158 Intravitreal injection (D): Verisome® (D1) is injected into the eye as a liquid, via a 30G needle, that coalesces into a single spherule; Tethadur™ (D2) is an injectable, nanostructured, porous BioSilicon™ material that is a suspension of a powdery material and a solution of a biologic drug. XXX
The most frequently used routes to target the posterior segment of the eye are topical, systemic, intravitreal, subconjunctival, and scleral.157,159-161 Among these, the scleral and intravitreal routes are considered the most suitable for the location of drug delivery implants for ocular posterior segment diseases, since they offer direct drug delivery to the target site with minimal systemic diffusion.157
The sclera is used to anchor implants that extend through the retina into the vitreous humour. Scleral implants became very popular since they offer reliable release and reduced interference, while the normal eye function is maintained.157 However, whenever non-biodegradable (e.g., Retisert and Vitrasert, see Table 2 for details), implants need to be surgically inserted and removed, that makes this approach relatively expensive and reduces patient acceptance. To overcome this problem, attempts were made in order to develop non-biodegradable implants that can be refilled without further surgical procedures.157
Intravitreal injections are generally performed in the clinic under local anesthetic. The direct administration of a drug or implant into the vitreous humour is made using a 27- or 30-gauge needle, via pars plana, a relatively avascular zone in the eye approximately 3 mm posterior from the limbus.160,161 Nonetheless, this is an invasive procedure, since penetration of all layers of the ocular globe is needed. Accordingly, many post-procedure complications, such as endophthalmitis, retinal detachment, iritis, uveitis, intraocular haemorrhage, cataract, and hypotony, are likely to occur.160 As repeated injections are commonly required, the number of complications tends to increase. Also this procedure requires hospitalization, a specially trained physician for administration, which increases the overall cost, in addition to the high cost of the medicine per se.161 All this scenario makes a trend towards the development of alternative methods of a controlled drug delivery in the long-term..
4.2. Micro/nanoscale biomedical devices
Biomedical implantable devices, which include the medical bionic devices, have been engineered based on a combined study of biology and electronics, aiming to help in restoration of various functions of organs and in increasing the life expectancy of the patients.162 This market is expected to grow at a cumulative annual growth rate (CAGR) of 9.20% till 2018 and to reach $32.3 billion by 2018. Vision bionics are one of the products that dominate the bionics market.163 These devices are roughly classified in two classes, depending upon the site of implantation: (1) the retinal prostheses, used for retinal and optic nerve stimulation to reverse blindness; and (2) the retino-cortical prostheses, used for CNS stimulation towards a better vision, compromised due to optic nerve damage.164-167
The Argus® II Retinal Prosthesis System (Second Sight Medical Products Inc., Sylmar, CA), also known as Bionic Eye, was the first retinal prosthetic device to obtain regulatory approval in both Europe (March 2011) and the USA (February 2013).168 This device aims to restore a basic level of vision to adult patients with profound vision loss from outer retinal dystrophies, such as severe to profound retinitis pigmentosa.168,169 A tiny video camera attached to a pair of glasses captures a scene. The video is then sent to a small patient-worn computer (i.e., the video processing unit – VPU) where it is processed and transformed into instructions that are sent back to the glasses via a cable. Finally, these instructions are transmitted wirelessly to an antenna in the internal retinal implant (Figure 10A).170 Further retinal prostheses models were thoroughly reviewed recently.171
Bio-retina (Nano Retina Inc., Herzeliya Pituach, Israel) entered clinical trials, in 2013. This device acts as a bionic retina designed to restore sight to those suffering from retinal degenerative diseases, involving photoreceptor degeneration, such as AMD and DR. It consists on a nanoelectrode and photosensor array resulting in a tiny device, whose less than 30 min-implantation procedure requires local anesthesia, a small incision in the sclera and positioning onto the damaged retina (Figure 10B). The nanoelectrodes interface with the bipolar cells and transmit the signal back to the RGCs, replacing the function of damaged photoreceptors and, thereby, restoring vision.172
Figure 10. Vision bionic devices. The Argus® II Retinal Prosthesis System (A) is composed by an epiretinal prosthesis surgically implanted in and on the eye (upper panel) which receives the signal transformed by the VPU from the images captured by the miniature video camera. The Bio-retina (B) is composed by ordinary-looking glasses (1) with a laser apparatus (2) that delivers power, up to 3 mW, to the photovoltaic cell on the eye implant (3 x 4 mm) (3). The photodetectors on a (24 x 24 pixel) grid send electric pulses that stimulate the neuronal cells, which transmit the image to the brain. Currently, the device is able to generate only grayscale images. XXX
4.3. Nanoparticle-based systems
Nanoparticles (NP)s) are defined as nanometer-sized particles, in the range of 0.1–100 nm in the three dimensions.173 NPs may have potential application for several clinical purposes, such as gene therapy, drug delivery (treatment and/or prevention of diseases), and imaging.173,174 These materials are even able to combine both therapy and diagnostic imaging functions, delivering therapeutic drugs and diagnostic imaging agents simultaneously within the same dose. This remarkable property makes them promising candidates to the so-called “theranostics”, a clinical and technological fairly young field that is developing incredibly fast.175
As drug delivery systems, NPs can provide: (1) sustained delivery; (2) targeted delivery to specific cells or tissues; (3) improved delivery of both water-insoluble drugs and large biomolecule drugs, and (4) reduced side effects, minimizing toxicological reactions.174 Importantly, NPs can bypass biological barriers, especially blood-neural barriers including the blood–brain barrier (BBB) and BRB,176 which makes them exquisitely suitable for ocular diseases. Their physicochemical properties, namely size, surface charge, and shape, are the main determinants for the therapeutic effects in biological systems.176 The size of the NPs suitable for systemic administration for therapeutic purposes might be in the range between 2 and 200 nm. Too small NPs (<5 nm) are vulnerable to renal excretion and clearance from target tissues.176 It was previously reported that 20 nm-gold NPs could pass through the BRB, whereas 100 nm gold NPs were not observed in any of the retinal layers, when administered intravenously.177 The surface charge determines cellular uptake, biodistribution, and interaction with other biological environments. Generally, positively charged NPs are known to be more easily internalized than neutral and negatively charged NPs.176 Finally, shape also affects biodistribution, as well as the adhesion pattern.176 Furthermore, all these properties are adjustable, resulting in a diverse spectrum of NPs with specific characteristics and performance, which allows researchers to find the appropriate design of NPs according to their purposes of application. As described above, intravitreal implants provide sustained drug release for six to eight months, but there can be unexpected issues, such as the need for surgical removal of the implants. These difficulties can be overcome by using NPs as a drug delivery system.173 The number of intravitreal injections may be decreased by using NPs.178 Actually, the use of nanotechnology is being investigated for several ophthalmic applications in the treatment of posterior segment eye disorders.179 NPs have been receiving attention as one of the novel drug delivery systems that overcome the barriers of the eye including the cornea, conjunctiva, and BRB. In particular, retinopathy might be the main target of NP-based medicine in ophthalmology, because it is hard for specific drugs to reach the retina with the appropriate concentration, due to restricted permeability caused by the BRB.177 Nevertheless, toxicity of NPs on neuronal cells is still questionable. Figure 11 illustrates how some NPs’ properties affect their toxicity. Size, dose, dosing time, chemical composition (core and coating), surface charge (zeta potential), and water solubility are factors that contribute to neuronal toxicity of NPs. Therefore, NPs must be thoroughly characterized before their application.177 The mechanism of neuronal toxicity includes the formation of ROS,180 and the alteration of the gene expression pattern.181 Besides neuronal cells, microglial cells are also affected by NPs. In fact, microglial cells are able to phagocytose NPs, increasing the production of intracellular ROS and reactive nitrogen species,182 as well as to increase significantly the inducible nitric oxide synthase expression and the secretion levels of TNF, IL-1β, and IL-6,183 when exposed to NPs. The types of NPs-based systems that have been investigated for the posterior segment of the eye are schematically illustrated in Figure 12 and described hereafter. Figure 11. Factors affecting toxicity of NPs on neuronal cells. Image reprinted and adapted with permission from MDPI.177 Figure 12. Examples of NPs-based systems. (A) nanoliposomes (lipid bilayer enclosing an aqueous core) (small unilamellar vesicle, SUV), (B) nanomicelles (inner hydrophobic core and outer hydrophilic shell), (C) nanoemulsions (lipid monolayer enclosing a liquid lipid core), (D) nanoparticles, (E) cyclodextrins (β-cyclodextrin)184, (F) dendrimers (PAMAM), and (G) quantum dots. Typical size is pointed out below each representative illustration. Red symbols represent the incorporated/bound drug molecules. Nanoliposomes (Figure 12A) are small artificial vesicles containing a single or multiple bilayered lipidic membrane, formed from natural or synthetic non-toxic phospholipids and cholesterol, surrounding an aqueous core or compartment. Liposome properties vary substantially with lipid composition, fluidity of the bilayers, size, surface charge and the method of preparation.185 The liposomes allow the non-covalent encapsulation of both hydrophilic drugs in the core and lipophilic drugs in the bilayer,179 making them well suited for a dual-delivery therapeutic.186 Ionic drug loading can be obtained by using cationic or anionic lipids.179 Concerning posterior eye delivery, an extended list of encapsulated drugs is known.161 Nevertheless, their application is limited, due to the short shelf life, limited drug loading, and difficulty in sterilization.161 Currently, there are more than 11 formulations approved for clinical use, and several in clinical and preclinical development.186 Particularly for the treatment of retinal diseases, two products are already in the market. Visudyne® (Novartis Pharmaceuticals, USA) was approved by the FDA, in 2000. This is a liposomal formulation incorporating verteporfin, which is administered intravenously, in diseases such as choroidal neovascularization due to AMD, serous central corioretinopathy and choroidal hemangioma. Verteporfin accumulates in the blood vessels of the choroid and, when stimulated by non-thermal red light with a wavelength of 693 nm, in the presence of oxygen, produces highly reactive short-lived singlet oxygen and other reactive oxygen radicals, resulting in local damage to the endothelium and blockage of the vessels. Photrex® (Miravant Medical Technologies, USA) has completed Phase III clinical studies and is awaiting FDA approval. This formulation contains rostaporfin, another liposomal photosensitizer, and is indicated also for the treatment of AMD. The frequency of the required treatments is significantly lower than that of Visudyne®.161 Recently, liposome-NP assemblies, composed of liposomes and metallic NPs encapsulated in the aqueous core, embedded in the lipid bilayer or decorated onto the surface, have emerged as promising multifunctional therapeutic constructs.186 Niosomes are also lamellar (bilayer) structures, composed of nonionic surfactant molecules surrounding an aqueous compartment.187 These structures are preferred over other vesicular systems in ocular delivery because: they are chemically stable; raw materials are easily available and less expensive; unlike phospholipids, handling of surfactants does not require special precautions and conditions, which make them more attractive for industrial manufacturing; they are biodegradable, biocompatible, and non-immunogenic.173,188 Nanomicelles (Figure 12B) consist of amphiphilic molecules that self-assemble in aqueous media to form organized structures where the polar head groups are in contact with the surrounding solvent, and the hydrophobic single-tail regions are oriented towards the nanomicelle centre. The self-assembly occur at concentrations greater than the critical micelle concentration (CMC).189 Nanomicelles are similar to liposomes: whereas liposomes are composed of lipid bilayers, nanomicelles are made of monolayers.179 In ocular drug delivery, nanomicelles offer unique advantages due to their nanoscale size and high permeation through ocular epithelia with minimal or no irritation. Nanomicelles can be formed with either surfactants (e.g., anionic surfactants such as sodium dodecyl sulfate (SDS), cationic surfactant: dodecyltrimethylammonium bromide (DTAB), and nonionic surfactants such as n-dodecyl tetra (ethylene oxide) (C12E4)) or polymeric systems.190 Polymeric nanomicelles are among the most promising delivery systems in nanomedicine. They have a distinct core-shell structure in which an inner core (hydrophobic) is enclosed by a shell (hydrophilic). The hydrophobic segments are mostly a polyester (polycaprolactone, poly (D,L-lactide)), a polyether (polypropylene oxide), or a poly aminoacid (poly(β-benzyl-L-aspartate)). Poly (ethylene glycol) (PEG) and derivatives are usually used as the hydrophilic block.190 Previously, nonionic surfactants nanomicelles were found to reach the retina following topical application, mainly through the conjunctival/scleral pathway.191 Nanoemulsions (Figure 12C) can be defined as oil-in-water (o/w) emulsions in which droplets consisting of a lipid monolayer enclosing a liquid lipid core, with mean diameters between 100 and 500 nm, are formed. These structures are stabilized by the use of surfactants. The surfactants, along with the small size of nanoemulsions, provide increased membrane permeability, thus higher penetration in the deeper layers of the ocular structure and facilitated drug uptake. Hence, these systems offer a faster therapeutic action using smaller doses which means fewer ocular side effects and less applications per day, enhancing patient compliance.161 Nevertheless, nanoemulsions are unsuitable for long-term sustained drug release.192 Nanoparticles (NPs) (Figure 12D) can be produced from various materials (e.g., natural and synthetic polymers, metal oxides, silica, and noble metals).186 Polymeric NPs are colloidal particles which are able to encapsulate (dissolved or dispersed) bioactive or drug molecules, including chemotherapeutic agents, proteins, and nucleic acid, for biomedical application.161 Polymeric NPs have been engineered from natural polymers like albumin, gelatine, sodium alginate, and chitosan, or synthetic polymers, such as poly(lactic-co-glycolic acid) (PLGA), poly(lactic acid) (PLA), polyvinyl alcohol (PVA), poly(ethylene-co-vinyl acetate) (PEVA), polyimide, and poly(methyl methacrylate) (PMMA).173,174,179 These NPs have various sizes, shapes, and stabilities for drug delivery, allowing the encapsulation of either hydrophilic or hydrophobic therapeutic agents.186 Concerning delivery to the posterior segment of the eye, several polymeric NPs have been studied.161 More recently, stimuli-responsive polymeric NPs, able of responding to external stimulus by changing their physico-chemical properties, are emerging as a new challenge in nanomedicine.186 PLA NPs were reported to pass through the retinal layers, accumulating in RPE when injected into the vitreous of rabbits.193 Albumin NPs were also reported as a very efficient drug delivery system for ophthalmic diseases, like CMV retinitis.194 Other polymeric NPs, such as chitosan NPs, were primarily used to delivery in anterior segment diseases, with limited application in posterior segment diseases.179 Nanogels are hydrogels composed of a nanoscale network of hydrophilic polymers (e.g., N-isopropylacrylamide and 2-hydroxyl methacrylate-lactide-dextran macromer), directly loaded with the drug, both hydrophilic and hydrophobic drugs. The kinetics of drug release from the nanogels can be controlled by varying the degradation rate of the crosslinks and through external stimuli, such as pH and temperature.179 Previously described nanogels were found to be able to bypass the ocular biological barriers, and thus to be used as intraocular drug delivery carriers195 and deliver drugs to the retina.196 Other nanogels, based on cyclodextrins (CD) (Figure 12E), were found to be able to deliver drugs from the eye surface into its posterior segment.197 CDs are a family of cyclic oligosaccharides composed of six (αCD), seven (βCD), eight (γCD) or more α(14)-linked D-glucopyranose subunits. The molecule has a water soluble hydrophilic exterior, and an apolar cavity that provides a hydrophobic matrix198 capable of hosting a wide range of guest molecules, ranging from polar molecules to apolar molecules.199 Therefore, CDs are capable of forming inclusion complexes with many drugs, acting as true carriers by keeping hydrophobic drug molecules in solution and delivering them to the target site where they partition.173 Dendrimers (Figure 12F) are highly branched, star-like, typically water soluble, chemically tunable macromolecule systems with three components: a central core, an interior dendritic structure (the branches), and an exterior surface with the functional surface groups. Dendrimers are mainly prepared from polyamidoamine (PAMAM). Drugs can be either entrapped in the dendrimer network through hydrogen bonds, hydrophobic interactions, and ionic interactions or they can be conjugated through covalent bonds.179 Dendrimers are able to provide a sustained drug delivery in the posterior segment. Nonetheless, their cytotoxicity is a limitation, since it depends on the functional group.174 In previous studies using the intravitreal administration of PAMAM dendrimers in neuroinflammation animal models, dendrimers were selectively localized in activated microglia, suggesting that they are appropriate deliver drug systems to these cells and hence potentially useful in the the treatment of retinal neuroinflammation for a sustained period.200,201 A final note for a NP that has had a significant impact on research in many fields across the physical, chemical, and biological sciences: the quantum dots (QDs) (Figure 12G). QDs are semiconductor nanocrystals whose dimensions are in the range of 2–6 nm.202 They are composed of a heavy metal core (e.g., cadmium selenide), with an intermediate unreactive zinc sulfide shell and a customized outer coating of different bioactive molecules, tailored to a specific application. Their composition and very small size grant unique fluorescent and optical properties that cannot be achieved with traditional fluorophores: (1) minimal photobleaching and a much higher signal-to-noise ratio; (2) broad absorption spectra but very narrow emission spectra.203 Thus, the main application that is known for QDs, namely in ophthalmology, is as imaging agents to labeling, for instance, neurons, glia203,204 and endothelial cells in retinal capillaries.205 Another approach involving QDs that has been under development is the neuronal activation with optical stimulation of photoresponsive surfaces. Recently, it was reported the capability to deliver electrical stimulation to the retinal cells by silicon-based QDs into a model of retinal degeneration.206 Similarly to what is already known concerning the use of QDs, simultaneously, as targeting and drug delivery systems,207 the same is yearned for posterior segment eye diseases. Limitations As described above, NP-based drug delivery systems are potentially successful for posterior segment therapy. Nevertheless, these systems are not devoid of pitfalls and there are still many limitations to be solved. Actually, improvements need to be done in drug loading, release, biodistribution, toxicity, ocular irritation, and patient compliance.173,186 Closing remarks The anatomy, physiology and biochemistry of the eye render this organ particularly impervious to foreign substances and pharmacokinetically critical. Accordingly, ocular drug delivery is a challenging topic to the pharmaceutical scientific and industrial community.173 Concerning posterior segment ocular disorders, such as DME and DR, the most common current options are surgery and intravitreal anti-VEGF.161,177 The conventionally used dosage forms present poor ocular bioavailability.173 Thus, in order to deliver any drug in a significant amount to posterior segment of the eye, intraocular invasive procedures, including intravitreal injections, are needed. These methods require repeated and regular administrations, over a period of several months to years.161 In this way, research towards the improvement in ocular drug delivery approaches enabling less-invasive routes and less-frequent administrations, precise drug targeting within the eye, increased therapeutic efficacy, reduced side effects, and good patient compliance, became front burner.160 Nanotechnology is a current hot-topic due to its potential application in several fields, from chemistry and engineering to biology and medicine.179 Particularly, nanomedicine is expected to ameliorate human health, through superior diagnosis and therapy quality. Nanometer-scaled particles can be used for the treatment of posterior segment diseases. Indeed, these nanosystems seem to be a promising alternative over the classic systems174 since they are able to bypass the BRB or other barriers in the eye, and remain in the eye for longer periods, reducing treatment administrations.177 Despite the promising characteristics of these systems and the results achieved in preclinical tests and cell line studies, the majority of them are still under development. Besides, the cost of development and manufacture, the ability for scale up, and the need for approval by the regulatory authorities also retards their entrance in the pharmaceutical market.161 Nanosystems herein described are encouraging and promising tools for what nanotechnology can do for medicine, in general, and for the therapy of the posterior segment of the eye, such as DR, in particular.

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