Current nanotechnology approaches for the treatment and management of diabetic retinopathy.

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Contents lists available at ScienceDirect

European Journal of Pharmaceutics and Biopharmaceutics journal homepage: www.elsevier.com/locate/ejpb

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Q1 Research paper

Current nanotechnology approaches for the treatment and management of diabetic retinopathy

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CEBIMED, Research Centre for Biomedicine, FP-ENAS, Fernando Pessoa University, Porto, Portugal Faculty of Health Sciences, Fernando Pessoa University (UFP-FCS), Porto, Portugal c Centre for Research and Technology of Agro-Environmental and Biological Sciences, CITAB, University of Trás-os-Montes e Alto Douro, UTAD, Vila Real, Portugal d Department of Biology and Environment, University of Trás-os-Montes e Alto Douro, UTAD, Vila Real, Portugal e Department of Physical Chemistry, Faculty of Pharmacy, University of Barcelona, Barcelona, Spain f Institute of Nanoscience and Nanotechnology, University of Barcelona, Barcelona, Spain g Faculty of Pharmacy, University of Coimbra (FFUC), Pólo das Ciências da Saúde, Coimbra, Portugal b

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Joana F. Fangueiro a,b, Amélia M. Silva c,d, Maria L. Garcia e,f, Eliana B. Souto g,⇑

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Article history: Received 1 November 2014 Accepted in revised form 15 December 2014 Available online xxxx

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Keywords: Diabetes mellitus Diabetic retinopathy Nanoparticles Nanotechnology Ocular drug delivery

a b s t r a c t Diabetic retinopathy (DR) is a consequence of diabetes mellitus at the ocular level, leading to vision loss, and contributing to the decrease of patient’s life quality. The biochemical and anatomic abnormalities that occur in DR are discussed in this review to better understand and manage the development of new therapeutic strategies. The use of new drug delivery systems based on nanoparticles (e.g. liposomes, dendrimers, cationic nanoemulsions, lipid and polymeric nanoparticles) is discussed along with the current traditional treatments, pointing out the advantages of the proposed nanomedicines to target this ocular disease. Despite the multifactorial nature of DR, which is not entirely understood, some strategies based on nanoparticles are being exploited for a more efficient drug delivery to the posterior segment of the eye. On the other hand, the use of some nanoparticles also seems to contribute to the development of DR symptoms (e.g. retinal neovascularization), which are also discussed in light of an efficient management of this ocular chronic disease. Ó 2014 Published by Elsevier B.V.

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Abbreviations: ACE, angiotensin-I converting enzyme; AGT, angiotensinogen; AGTR1, angiotensin II type 1 receptor; AGEs, advanced glycation end-products; AMD, age-related macular degeneration; AR2, aldose reductase; ARPE, arising retinal pigment epithelia; BRB, blood–retinal barrier; CAT, catalase; DME, diabetic macular edema; DR, diabetic retinopathy; EPO, erythropoietin; FDA, Food and Drug Administration; GH, growth hormone; GHIH, growth hormone-inhibiting hormone; GLUT1, glucose transporter 1; GPx, glutathione peroxidase; GSH, reduced glutathione; GR, glutathione reductase; IGF-1, insulin-like growth factor 1; IOP, intraocular pressure; IRMA, intra-retinal microvascular abnormalities; K5, plasminogen kringle 5; mRNA, messenger ribonucleic acid; PAMAM, polyamidoamine; PDGFs, plateletderived growth factors; PEDF, pigment epithelium derived factor; PEG-b-PCL, poly(ethylene glycol)-b-polycaprolactone; PLA, poly(lactic acid); PLGA, poly(lacticco-glycolic acid); PMMA, poly(methyl methacrylate); PVA, polyvinyl alcohol; PDR, proliferative diabetic retinopathy; PKC, protein kinase C; MnSOD, manganese superoxide dismutase; NADPH, nicotinamide adenine dinucleotide phosphate; NISA, non-peptide imidazolidine-2,4-dione; NLC, nanostructured lipid carriers; NPDR, non-proliferative diabetic retinopathy; NOS2A, NOS3, nitric oxide synthases; o/w, oil-in-water; RAGEs, receptor for AGEs; RNS, reactive nitrogen species; ROS, reactive oxygen species; RVO, retinal vein occlusion; SI, silicate; SLN, solid lipid nanoparticles; SRIF, somatotropin release-inhibiting factor; SSTR, somatostatin receptor; STZ, streptozotocin; SOD, superoxide dismutase; TGFbeta, transforming growth factor beta; TiO2, bare titanium dioxide; UDP, uridine diphosphate; VEGFs, vascular endothelial growth factors; w/o, water-in-oil. ⇑ Corresponding author. Faculty of Pharmacy, University of Coimbra (FFUC), Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal. Tel.: +351 239 488 400; fax: +351 239 488 503. E-mail address: [email protected] (E.B. Souto).

1. Introduction

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Diabetes mellitus is a chronic disease that affects billions of people all over the world, and results from the body’s inability to either produce or use insulin. This disease is mainly associated with high levels of glucose in the blood, i.e. hyperglycemia. It can be classified into two chronic forms, namely: (i) Type 1, which is diagnosed earlier usually in children and youth and is characterized by the deficiency in the production of insulin. In this case, there is a destruction of islet beta cells mostly attributed to auto-immune etiology; (ii) Type 2, which has higher incidence (90–95% of the cases) and it is characterized by the reduced production of insulin and/or by insulin resistance, affecting mainly muscle, liver and adipose tissue, resulting in inappropriate levels of circulating glucose. There is a third form of diabetes, the gestational diabetes, which is observed during pregnancy in a small number of women caused by interference of placental hormones interference with insulin receptor resulting in inappropriate elevated glucose levels [1]. The inability of the body to use glucose resulting from the deficiency of the hormone responsible for its use (i.e. insulin), leads to constant hyperglycemia which results in many chronic effects, such as macro- and microvascular complications associated with

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http://dx.doi.org/10.1016/j.ejpb.2014.12.023 0939-6411/Ó 2014 Published by Elsevier B.V.

Please cite this article in press as: J.F. Fangueiro et al., Current nanotechnology approaches for the treatment and management of diabetic retinopathy, Eur. J. Pharm. Biopharm. (2014), http://dx.doi.org/10.1016/j.ejpb.2014.12.023

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heart disease, stroke and peripheral arterial diseases. The constant hyperglycemia causes damage in the small blood vessels, which affects the ocular, nervous and renal system. That is why it is of utmost relevance to control diabetes and its consequences, to prevent retinopathy, neuropathy and nephropathy complications [1]. Diabetic retinopathy (DR) is one of the major consequences of diabetes and it is characterized by microvascular complications having a significant impact on patient’s life quality, in particular, in visual acuity, eventually leading to blindness [2]. Diabetic patients, both Types 1 and 2, are regularly screened for retinopathy with an initial dilated and comprehensive eye examination by an ophthalmologist. Even patients with a very rigorous control of diabetes, are not free from developing DR [3]. In order to prevent and reverse diabetic side effects, such as retinopathy, several strategies have been used to prevent the chronic disease with modern and innovative systems based on nanoparticles which are addressed in this review. Nanoparticles may be applied for several clinical purposes. When applying this concept in medicine, it is called nanomedicine. In drug delivery, nanoparticles (1–1000 nm) are used for the treatment and/or prevention of diseases, with the final goal to spam patient’s life-time. Regarding these goals, nanoparticles offer numerous advantages, compared to treatments with drugs alone or even with classic delivery systems. The majority of the drugs show problems including (i) low solubility in solvents; (ii) high toxicity; (iii) need of high doses to exhibit therapeutic effect; (iv) aggregation; (v) enzymatic and chemical degradation and (vi) reduced half-time. Thus, the loading of drugs into nanoparticles could overcome these limitations and additionally provide (i) sustained delivery; (ii) targeted delivery to specific cells or tissues; (iii) improved delivery of both water-insoluble drugs and large biomolecule drugs, and (iv) reduced side effects minimizing toxicological reactions [4,5]. This paper reviews the diabetes-induced mechanisms involved in the course of DR, a knowledge that is fundamental in the design of new therapeutic strategies. The contribution of nanomedicine to treat and manage DR and its microvascular changes is also discussed.

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2. Diabetic retinopathy

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2.1. Concepts

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DR is potentially caused by sustained hyperglycemia and the consequences occurring in the minor vascular retinal vessels [6]. DR is also characterized by the abnormal growth of new blood vessels resulting from a hypoxic retina, in order to improve the supply of oxygen [7]. According to the international classification system, DR is divided into two broad categories, namely, the non-proliferative DR (NPDR) and the proliferative DR (PDR) [8]. NPDR is further subdivided into mild, moderate, and severe. This classification system considers the number and severity of anatomical abnormalities, which include: (i) microaneurysms; (ii) hemorrhages; (iii) venous beading, and (iv) intra-retinal microvascular abnormalities (IRMA), when attributing to the eyes a particular level of severity [9]. The international classification of DR is summarized in Table 1. An ophthalmologist could detect the DR by the analysis of these symptoms, in parallel with additional examinations, such as visual acuity test, dilated eye examination and tonometry, which measures the intraocular pressure (IOP) [2]. Retina is the anatomical structure of the eye affected in the DR. Physiologically it is the light-sensitive tissue located at the back of the eye, it is characterized by a thin transparent structure composed by several layers comprising the light-sensitive structures. It is enriched in polyunsaturated fatty acids and is metabol-

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Table 1 International clinical DR disease severity scale, adapted from [8]. Proposed disease severity level

Dilated ophthalmoscopy findings

No apparent retinopathy Mild nonproliferative DR Moderate nonproliferative DR

No abnormalities

Severe nonproliferative DR

No signs of PDR, with any of the following: – More than 20 intra-retinal hemorrhages in each of four quadrants – Definite venous beading in two or more quadrants – Prominent intra-retinal microvascular anomalies in one or more quadrants

PDR

One or more of the following: – Neovascularization – Vitreous or pre-retinal hemorrhage

Microaneurysms only More than just microaneurysms, but less than severe NPDR

ically very active having high glucose oxidation and oxygen uptake [10]. The schematic structure of the human eye and the ocular globe is shown in Fig. 1. The cells figuring in retina are divided into three major groups, namely, (i) the neuronal component, which includes photoreceptors, interneurons, and ganglion cells, responsible for retinal visual function which converts light into electrical signals; (ii) the glial components, Muller cells, astrocytes and resident macrophages (microglia), which are responsible for retina support (e.g., nutritional, regulatory); and (iii) the vascular components, which consist of the central retinal artery, supplying the inner and outer retina by diffusion from choroidal circulation. The retinal vessels are responsible for the maintenance of blood– retinal barrier (BRB) and are composed of endothelial cells with tight junctions between them [7,11]. Pericytes or mural cells are another type of contractible cells surrounding the capillaries endothelial cells. The main function of these cells is the regulation of retinal capillary perfusion and its loss is associated with DR. Diabetes will affect both neuronal and vascular components of the retina and will influence some cells and extracellular proteins [2,12].

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2.2. Pathophysiology

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The major symptom in diabetes is hyperglycemia, which causes both acute and reversible changes in cellular metabolism and long-term irreversible changes in stable macromolecules. The metabolism of the cells starts to response to the hyperglycemic environment even before disease pathology is detectable [6,13]. In an advanced stage, the ischemia is the major factor responsible for the growth of abnormal retinal blood vessels (neovascularization) which grow in an attempt to supply oxygen to the hypoxic retina [2]. In addition, the loss of some retinal cells is also detected in DR patients [13]. In addition to hyperglycemia, there are other factors that contribute to the development of DR, such as hyperlipidemia and hypertension [14–17]. Despite the acknowledgment hyperglycemia consequences at the ocular level, the mechanisms causing the vascular disruption in retinopathy are not well known, and, not surprisingly, several pathways have been pointed out as being implicated. However, it is crucial to understandthe mechanism of capillary loss due to biochemical mechanisms to clarify the disease pathogenesis. Thus, good glycemic control is a very important strategy to inhibit/prevent the development of DR in addition to early intervention to prevent the progression of retinopathy in diabetes [2]. However, the challenging in maintaining good glycemic levels for this chronic disease could be a hard task, since other factors also contribute to the development of DR, including pregnancy, age and hypertension [1]. In order to find a

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Fig. 1. Schematic illustration of the human eye and its main physiological structures. Retina is the ocular structure affected by the development of DR and is located in the posterior segment of the eye. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

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better and more efficient therapeutic option, it is essential to ascertain intracellular and molecular mechanisms that lead to the development and prevalence of DR. During the curse of DR, the sustained hyperglycemic milieu in diabetes leads to a breakdown of the BRB. The tight junctions of the endothelial cells figuring in the BRB become loose, enabling entry of certain macromolecules and leading to the capillary thickness resulting in structural rigidity of the blood vessels [1]. Diabetic macular edema (DME) occurs following this breakdown of BRB increasing vascular permeability of retinal capillaries, leading to thickening of the macular area. DME appears as a primary signal of DR and causes blurred vision with consequent disturbing of the architecture of the retina [7]. The function of endothelial cells is the maintenance of the BRB, by multiplication from the inner part of the wall, and is strongly affected in DR patients in which this growth is initially exacerbated. When these cells suffer any damage or pathological multiplication, vascular permeability is altered resulting in capillaries blockage, appearance of small hemorrhages and yellow deposits (hard exudates) [1,2]. Other cells affected by hyperglycemia are the pericytes. The damage caused in these cells in diabetic patients, leads to a change in retinal hemodynamics, including abnormal auto-regulation of retinal blood flow [18]. Loss of these cells occurs in DR, leading to microaneurysm formation and acellular capillaries. Thus, endothelial cells and pericytes of retinal microvasculature suffer apoptosis, and this contributes to the development of acellular capillaries and pericyte ghosts [19]. In DR there is an increased leucostasis, which seems to play an important role in the pathogenesis of the disease [20]. The leucocytes have a tendency to adhere to the vascular endothelium affecting its function resulting in retinal perfusion, angiogenesis and vascular permeability [21]. Also, their capacity to generate superoxide radicals and proteolytic enzymes leads to endothelial cell damage and vascular leakage in the retinal microcirculation [20,21]. These are the major complications observed in NPDR, being the capillary occlusion more evident and the development of abnormal capillaries without blood flow, and finally ischemia. The evolution to pre-PDR is determined by the development of neovascularization, resulting from the retinal ischemia and hypoxia [22]. Neovascularization, also called angiogenesis, is a significant phenomenon involved in PDR, and is a consequence of an imbalance of the growth factors which contributes to the development of other several diseases including macular edema and retinal inflammatory diseases [13]. The activation of endothelial cells located within normal vessels leads to the initiation of angiogenesis process [23]. The new capillary formation involves several

steps, being the first creation of new endothelial cells tubes, which are stabilized and spatially oriented. However, these new vessels formed will be functionally and anatomically incompetent, mainly due to the constant hyperglycemia which affects the retinal blood flow [24]. Other complications associated with oxidative stress at retinal level are implied in the DR. The oxidative stress is developed by some biochemical changes contributing to the functional and structural alterations in the retinal microvasculature. Thus, oxidative stress is responsible for the formation of reactive oxygen species (ROS) and mitochondrial dysfunction [25]. Consequently, mitochondrial changes and formation of acellular retinal capillaries are prevented by an overexpression of the enzyme responsible for scavenging mitochondrial superoxide, the superoxide dismutase (SOD), which is high in DR leading to dysfunctional mitochondria prior to apoptosis [11,26]. Despite the current scientific developments, the mechanisms through which hyperglycemia results in retinal pathology, remain inconclusive. It is noteworthy that DR has a multifactorial nature and it is known that some of the major implied pathways contribute to the development of this pathology. The main biochemical pathways that influence DR are: (i) polyol pathway; (ii) protein kinase C (PKC) activation; (iii) advanced glycation end-products (AGEs) pathway provoked by their accumulation; (iv) activation of the hexosamine pathway; (v) oxidative stress, and (vi) expression of growth factor, such as vascular endothelial growth factors (VEGFs) [1,11,27–30]. Due to hyperglycemia, excess of intracellular glucose is converted into other molecules, activating specific pathways. The polyol pathway begins by the conversion (reduction) of glucose to sorbitol, mediated by aldose reductase using nicotinamide adenine dinucleotide phosphate (NADPH) as a cofactor. The reactions are depicted in Fig. 2. The need of NADPH in the initial conversion of glucose to sorbitol leads to a deficiency for its availability for the activity of glutathione reductase (GR) that maintains the adequate levels of reduced glutathione (GSH), an important cellular antioxidant. The depletion of GSH may lead to increased levels of ROS leading to oxidative stress [31,32]. The PKC pathway is associated with DR since its PKC activity is increased in diabetes. Activation of some isoforms of PKC has been shown to increase vascular permeability, change blood flow (decreasing blood flow by increasing endothelin-1 levels) and development of neovascularization [33]. Additionally, PKC induces the expression of endothelin-1 and growth factors, such as platelet-derived growth factors (PDGFs) and VEGFs, and VEGFs contribute largely for the development of retinal neovascularizaQ4 tion [34,35]. In hyperglycemic conditions, glucose and other carbohydrates react with amino-acids, proteins, lipids and nucleic acids, which


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results in AGEs formation. These glycation products usually accumulate in the basement membranes of retinal cells, making the anchoring of pericytes difficult and thus contributing for its loss and microvascular alterations in retinal capillaries [28,36]. The hexosamine pathway is activated when there is an excess of intracellular glucose that cannot be drained by glycolysis. The overproduction of fructose-6-phosphate (Fig. 3) is converted to glucosamine 6-phosphate by glutamine-fructose-6-phosphate amidotransferase which is the first step for the accumulation of glucosamines. Glucosamine 6-phosphate is rapidly metabolized leading to the formation of uridine diphosphate (UDP)-N-acetylglucosamine and UDP-N-acetylgalactosamine, serving as substrates for glycosylation which seems to be responsible for alterations on protein function, that can reduce cell protection and at the end induce cell apoptosis, namely on retinal neurons and endothelial cells [37]. Thus, understanding the significant biochemical mechanisms, which contributes to DR pathogenesis, is useful toward the development of new drug delivery systems and strategies to prevent and manage this ocular chronic disease. A summary illustration is depicted in Fig. 4 to highlight the most important pathways and factors leading to retinal neovascularization, the primary and most important problem in DR.

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3. Nanotechnology applied to ocular delivery

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The use of nanotechnology-based approaches for ocular delivery is an interesting challenge due to the several limitations that this route represents from the pharmaceutical point of view. The delivery of several drugs is limited by the anatomy and physiology of the human eye. Thus, nanoparticles seem to be a promising alternative over the classic systems, which are generally related to a very low bioavailability (5–10%) of the administered drugs [38]. Regarding the anatomy of the human eye, this is an isolated organ divided into anterior and posterior segments. The topical delivery of drugs by using eye-drops is limited to treat diseases affecting the anterior segment of the eye. The delivery of drugs into the posterior segment of the eye is possible by topical administration (i) through conjunctiva/sclera; (ii) from the cornea and aqueous humor. Other routes including intravitreal injection and implants are more invasive. Additionally, it is possible to reach the posterior segment through the systemic circulation after topical, parenteral, oral, or other administration routes that deliver the drug directly into the blood circulation [39]. The most studied nanomedicines for posterior segment of the eye are summarized in Fig. 5.

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Fig. 2. The polyol pathway is started by the conversion of glucose to sorbitol mediated by the enzyme aldose reductase, using NADPH as a hydrogen donor. Sorbitol is further converted into fructose by sorbitol dehydrogenase using NAD+ as cofactor.

Fig. 3. The overproduction of fructose-6-phosphate resulting from the high levels of glucose leads to the glucosamines accumulation.

Polymeric nanoparticles can be composed of several polymers, such as poly(lactic-co-glycolic acid) (PLGA), poly(lactic acid) (PLA), chitosan, polyvinyl alcohol (PVA) and poly(methyl methacrylate) (PMMA). These materials are approved by Food and Drug Administration (FDA) due to their biodegradability and biocompatibility [40]. Lipid nanoparticles, such as solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC) and liposomes, have been proposed for ocular delivery [41–46]. Their composition is mainly based on physiological lipids, such as phospholipids, ceramides, glycerides, being recognized as biocompatible and without or with minimal toxicity [4,38]. To further enhance the ocular bioavailability of drugs loaded in such nanoparticles, and to avoid the mucosal irritation and ocular rejection, the use of polyethylene glycols coating the surface of nanoparticles is considered a suitable alternative to deliver drugs into the posterior segment of the eye [40]. Dendrimers derive from polymers, such as polyamidoamine (PAMAM), which are usually water soluble [47]. These systems are useful due to their tunable chemistry and surface modification. Drugs can be entrapped in the dendrimer network composed of the functional groups. The most common material used for the production of dendrimers is PAMAM [48,49]. Although these systems seem to promote a sustained drug delivery in the posterior segment of the eye, their cytotoxicity is a limitation, since it depends on the functional group [49]. Cationic nanoemulsions are being exploited for ocular drug delivery due to the capacity to electrostatically interact with human ocular mucosa, as this latter is of anionic nature [38]. They are usually produced by high-energy emulsification methods and

Fig. 4. Schematic illustration of the main biochemical abnormalities in DR. The four pathways and some physiological changes in retinal cells, vessels and retinal blood flow, favoring retinal neovascularization.


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DR is an ocular disease that should be managed by an ophthalmologist and/or endocrinologist, and it should be directed toward both systemic and ocular aspects of the disease [54]. The current treatment strategies need to include the management of the hyperglycemia values, blood pressure and serum lipids [6,54]. The traditional and current strategies used in the management of DR involve laser surgery, vitrectomy, and the pharmacological therapy. For a better management, it is the usual combination of several strategies, since there is no cure for DR, but these strategies could delay and attenuate some of the major symptoms, avoiding the earlier blindness. The management of NPDR and early PDR are common in the pharmacological treatment, and sometimes associated with surgical treatment. In PDR, there is no option unless the surgery by laser, and according to the specific problems in the retina, it could include focal laser, scatter laser or vitrectomy.

down the leakage of blood from the microaneurysms and fluid in the eye. The laser beam absorption causes a local rise in temperature inducing protein denaturation and coagulative necrosis. Only one session is usually required [7]. The main adverse effects associated with this and other laser surgery imply the visual field constriction, night blindness, color vision changes, and accidental laser burn of the macula [55]. Scatter laser, or pan-retinal photocoagulation, is also applied on PDR, and it is used to ablate ischemic areas of the peripheral retina and thus, reducing the induction of angiogenic growth factors. The main goal is to induce the regression of neovascularization without vitreous hemorrhage or fibrovascular proliferation. Although photocoagulation is applied once, this treatment could require more sessions, usually two or more. The same adverse effects mentioned above for the photocoagulation treatment are also applied in pan-retinal photocoagulation [55]. Vitrectomy is applied to prevent blindness and/or severe visual loss in advanced cases of DR, specifically those with tractional retinal detachment or severe non-clearing vitreous hemorrhage [56]. This procedure is used to remove blood from the vitreous body. A possible side effect of this procedure is the acceleration of cataract formation, which can lead to the development of endophthalmitis and retinal detachment [57,58]. The choice of the treatment is adapted for the type of DR, and the surgery is mainly used in an advanced stage followed by the risk of blindness. Laser photocoagulation, pan-retinal photocoagulation and/or vitrectomy will continue to have a relevant role in the management of DR, to improve the patient’s quality life, and to reduce the cost of the therapy. Despite the benefits that surgery could offer to diabetic patients, this is not a first choice for NPDR and early PDR treatment, since adverse side effects of these procedures are present and the other DR symptoms still remain. Several innovative pharmacological therapies, particularly based on nanoparticles, are being considered.

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Focal laser, or laser photocoagulation, is usually applied in PDR, and it is based on a focused laser beam of a discrete wavelength onto specified parts of the retina. Its application can stop or slow

Several pharmacological therapies are available to manage the DR. According to the type of DR and the acknowledgement of the mechanisms responsible for the development and progression of

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can load several types of drugs since they can be oil-in-water (o/w) or water-in-oil (w/o) [50,51]. These systems have been successfully taken by Novagali Pharma, which has launched a marketed formulation NovasorbÒ. The major challenge in formulating was the selection of a cationic agent with an acceptable safety profile that would ensure a sufficient ocular surface retention time [51,52]. The anatomical barriers limit the penetration of drugs from the front to the posterior segments of the eye (vitreous humor, retina and choroid). The tight junctions that compose the corneal epithelium, corneal endothelium, retinal endothelial cells and retinal pigmented epithelium limit the diffusion of drugs and the BRB limits the drug delivery by systemic circulation [53]. Nanoparticles may improve the bioavailability of some drugs in the posterior segment of the eye decreasing the frequency of injections and adverse side effects. In addition, it is fundamental to improve patient compliance, particularly in chronic diseases.

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4. Classical vs nanotechnological strategies for the treatment and management of DR

Fig. 5. Schematic illustration of the most common nanoparticles used to reach the posterior segment of the eye.


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the disease, there are several approaches being considered. This section discusses the traditional therapies already applied in the management of DR and the new therapies involving nanoparticles. 4.2.1. Corticosteroids Corticosteroids are a class of drugs with high anti-inflammatory activity. These drugs also provide the ability to reduce vascular permeability and reduce the blood–retinal barriers breakdown, to down-regulate VEGF expression and/or production, and the capacity to inhibit matrix metalloproteinases [7,59]. The administration of corticosteroids in the management of DR includes the peribulbar, sub-tenon and intravitreal injections [55,60]. The main corticosteroids used in the management of DR will be discussed in this section. 4.2.1.1. Triamcinolone acetonide. Triamcinolone acetonide is the most common corticosteroid used in the management of DR by intravitreal injection, since it is the most efficient approach to deliver the drug to the posterior segment of the eye. The common dose is 4.0 mg/0.1 mL, however higher doses of 20–25 mg/0.2 mL have also been reported [60]. The management of DR with this drug has gained interest in the past years with improvement of visual acuity [61]. Since the 1970s, triamcinolone acetonide is being used for intravitreal injection to achieve a higher intraocular concentration in the post-segment of the eye. Firstly proposed in an animal model, triamcinolone acetonide was used as a pharmacological adjuvant to prevent the formation of proliferative scar tissue in order to improve outcomes following retinal detachment surgery [62]. The current marketed formulation of this drug is KenalogÒ40 (Bristol-Myers-Squibb, Princeton, NJ) [63–65]. In a study carried out by Bressler and co-workers [66], 840 eyes with macular edema were chosen to receive laser photocoagulation, injections of triamcinolone at 1 mg or 4 mg. The authors obtained fundus photographs at baseline as well as at one-, twoand three-year follow-up. At two-year follow-up, retinopathy progression has been documented in 31% of 330 eyes treated with photocoagulation; 29% of 256 eyes treated with 1 mg doses of triamcinolone; and 21% of 254 eyes treated with 4 mg doses of triamcinolone. Also, Gillies and co-workers reported the effect of intravitreal triamcinolone injections (4 mg/0.1 mL) in a double-masked, placebo-controlled, randomized clinical trial over 2 years [67]. Improvement of visual acuity was found in 56% of the patient eyes treated with intravitreal injection of triamcinolone compared with 26% of the eyes treated with the placebo. Despite the relative success of triamcinolone acetonide injections, its use also causes an increase in IOP (68%) and glaucoma medication was required in 44% of the patients, being a cataract surgery required in 54% of the patients. Additionally, other complications, such as trabeculectomy and endophthalmitis, were observed in the treated group. Additionally, a study conducted by Robinson and co-workers showed the main ocular barriers to the trans-scleral delivery of triamcinolone acetonide [68]. The results suggested that the conjunctival lymphatics/blood vessels may be an important barrier to the delivery of triamcinolone acetonide to the vitreous in this rabbit model. The barrier location and clearance abilities of the ocular tissues are important to consider when developing a successful trans-scleral drug delivery system. Araújo and co-workers encapsulated triamcinolone acetonide in NLC with adequate physicochemical properties for ocular delivery for anti-angiogenic purposes [42]. Additional studies revealed that these nanoparticles were able to provide a prolonged drug release followed by one-order kinetics, and permeability studies confirmed that triamcinolone acetonide was able to diffuse across rabbit sclera in sustained profile, following zero-order kinetics [41].

A different type of particles composed of PLA was tested for trans-scleral delivery [69]. Two nanosized particles were produced, nano (551 nm) and micro (2090 nm) loading triamcinolone acetonide. Beside the satisfactory parameters of both particles, only the microparticles were able to provide a sustained effective level of the drug in the retina. Other study reporting the encapsulation of triamcinolone acetonide for retinal purposes has been published by Suen and Chau [70]. The authors loaded the drug into nanoparticles synthesized by the functionalization of folate and poly(ethylene glycol)-b-polycaprolactone (folate-PEG-b-PCL). These nanoparticles were taken up by arising retinal pigment epithelia (ARPE)-19 cells (human RPE cell line) via receptor-mediated endocytosis. Results seem promising, since a high encapsulation efficiency was achieved (>97%) and enhanced uptake and controlled release were observed resulting in prolonged antiangiogenic gene expression of RPE cells. Additionally, the downregulation of VEGF and up-regulation of pigment epithelium derived factor (PEDF) were observed for 3 weeks.

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4.2.1.2. Dexamethasone. Dexamethasone is another corticosteroid with ocular therapeutic benefits, well-known for its anti-inflammatory effects in the treatment of acute and chronic posterior segment eye diseases such as uveitis [71]. Among the corticosteroids, dexamethasone is one of the most potent, with an anti-inflammatory activity that is sixfold greater than that of triamcinolone and 30-fold greater than cortisol [72]. The typical dose for the treatment with dexamethasone is instillation of 0.1% dexamethasone during 3–4 times per day. However, continuous application for extended periods of time could result in cases of glaucoma followed by optic nerve damage, defects in visual acuity and fields of vision, and posterior sub-capsular cataract formation and thinning of the cornea or sclera [52]. There are market formulations currently being used with dexamethasone, namely PosurdexÒ and OzurdexÒ both from Allergan, Irvine, CA. PosurdexÒ is still in phase III clinical trials and was developed to address the challenges of intravitreal corticosteroid therapy. Kuppermann and co-workers suggest that this new drug delivery system is well tolerated and provides benefits in the treatment of persistent macular edema [73]. The incision of the implant is simple and well tolerated. One single dose seems to have potential to treat macular edema. OzurdexÒ was initially approved by the FDA in 2009 as the first drug therapy for the treatment of macular edema following retinal vein occlusion (RVO), received FDA approval for the treatment of non-infectious ocular inflammation, or uveitis, affecting the posterior segment of the eye in 2010. In 2014, the FDA approved OzurdexÒ as the first intravitreal implant corticosteroid indicated for the treatment of DME in adult patients [74]. Clinical studies demonstrated that OzurdexÒ provides a sustained-release of dexamethasone with potentially reduced adverse effects [75]. Clinical studies have shown that this dexamethasone implant is a promising new treatment option for patients with persistent macular edema resulting from retinal vein occlusion, DR, and uveitis or Irvine-Gass syndrome. There are some studies concerning the loading of dexamethasone in polymeric nanoparticles. Gómez-Gaete and co-workers used PLGA as a polymer and preliminary results revealed a controlled release of dexamethasone from the nanoparticles [76]. Another study reported by da Silva and co-workers loaded dexamethasone into biodegradable polyurethane containing clay nanoparticles [77]. The nanoparticles demonstrated to have similar mechanical properties with ocular soft tissues, which reduce their potential irritancy and toxicity. Dexamethasone was incorporated in 6.0 wt% in the polyurethane implants. In vitro and in vivo results in ARPE-19 cells show a good tolerance of the nanoparticles and additionally suggested that these degradable polyurethane and nanocomposites may act as temporary supports for transplanted

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RPE cells as an initial attempt of replacing dysfunctional RPE for macular reconstitution of age-related macular degeneration patients. 4.2.1.3. Fluocinolone acetonide. Fluocinolone acetonide is one of the most potent corticosteroids applied in postsegment eye complications [78]. Usually, it is used to manage DME, one of the most complications of DR. There is a marketed formulation of this drug in an implant presentation, RetisertÒ [79]. This is a non-biodegradable implant designed to release 0.59 lg/day of fluocinolone acetonide in the postsegment of the eye [80]. RetisertÒ was approved for the treatment of chronic, noninfectious, posterior uveitis [81]. Preclinical studies have demonstrated that the implant is well tolerated, with no measurable systemic drug absorptions [82]. However, in a study concerning DME patients, results from clinical trials [83] indicate a significant reduction in ocular edema, however after 2 years a high percentage of the patients (80–90%) showed cataracts and required surgery due to enhanced ocular pressure. IluvienÒ (pSivida Corp. Watertown, MA) is another formulation with this corticosteroid, an injectable, non-erodible, implant used for the treatment of chronic DME. A study made by Sanford [84] in patients with DME, previously treated with macular laser photocoagulation, showed that this intravitreal implant 0.2 lg/day was significantly more efficient than sham injection in improving visual acuity. The treatment showed to have more benefits in the subgroup of patients whose DME duration was P3 years. However, adverse effects occurred, namely cataracts, in 82% of IluvienÒ treated patients and 51% of sham injection recipients, and increase in IOP, in 37% (IluvienÒ treated) and 12% (sham injection recipients) of the patients. There are no reports describing the loading of fluocinolone acetonide in nanoparticles, however some studies have demonstrated that the formulation of this drug in polymeric implants is a promising approach for intraocular long-term delivery [78,85,86]. 4.2.2. Anti-angiogenic factors VEGF is a 35–45 kDa homodimeric protein, highly conserved that exists in several isoforms. VEGF is an endothelial-cell-specific angiogenic factor and a vascular permeability factor whose production is increased by hypoxia, thus VEGFs have gained much attention for the treatment of DR. Monoclonal antibodies, used to neutralize VEGFs, are currently being administered via intravitreal injection for the treatment of ocular diseases, such as PDR, age-related macular degeneration (AMD) and choroidal neovascularization. VEGFs have the ability to increase the permeability of blood–tissue barriers and in DR are overexpressed due to hypoxia that occurs in the retinal cells, which is a major stimulus for the development of retinal neovascularization (Fig. 6). The expression of VEGFs seems to increase in patients as they progress from NPDR to PDR [87,88]. Some of the complications occurring in PDR, e.g. reduced retinal blood flow and posterior hypoxia followed by loss of capillary pericytes and endothelial cells, are associated with an increase in the synthesis and secretion of VEGF [12,55]. 4.2.2.1. Bevacizumab. Bevacizumab is a recombinant humanized antibody, showing activity against all isoforms of VEGF-A [89]. This monoclonal antibody demonstrated to be an efficient treatment for DR, DME and iris neovascularization [90–92]. The marketed formulation of this drug belongs to Genentech, namely AvastinÒ (Genentech, California, US). Several studies [93–97] regarding the use of 1.25 mg of bevacizumab for DME therapy demonstrated beneficial effects, although several injections were required. Clinical studies with AvastinÒ [98] reported that a single intravitreal 1.5 mg injection reduced the leakage in persistent new vessels associated with PDR patients. A recent study [99] also published

7

similar results, with additional improvement of the visual acuity in patients unresponsive to pan-retinal photocoagulation. Studies involving the use of bevacizumab loaded into nanoparticles are being carried out, with the aim to improve the drug’s bioavailability and exploit alternative administration pathways. One of the major problems encountered when loading these drugs into nanoparticles is related to the limited physicochemical stability of the monoclonal antibodies during the production process, and also during their release and in vivo performance. The selection of a particular type of nanoparticles will reflect its in vitro long-term stability and in vivo therapeutic efficacy. Polymeric nanoparticles are interesting systems that seem to dominate the field of ophthalmic drug delivery. Reasons for that are the adequate physicochemical properties of polymeric nanoparticles, biocompatibility, non-toxicity and diversity [100,101]. Varshochian and co-workers developed PLGA nanoparticles to encapsulate the bevacizumab [100]. PLGA is considered to be safe and has been extensively used in drug delivery [102]. The authors proved that PLGA nanoparticles were able to protect protein inactivation and aggregation in the presence of albumin. In vivo and ex vivo release of bevacizumab followed a sustained profile and seemed to be effective in the protection of the antibody integrity [100]. Other study describing the same type of nanoparticles was published by Li and co-workers [103], who proved the ability of PLGA nanoparticles to load bevacizumab and to promote a prolonged release by adjusting the drug/polymer ratio. Lu and co-workers studied the effects of an intravitreal injection of bevacizumab-chitosan nanoparticles in pathological morphology of the retina and the expression of VEGF protein and VEGF messenger ribonucleic acid (mRNA) in the retina of diabetic rats [104]. The results showed that chitosan nanoparticles were able to provide a sustained release of bevacizumab and this alternative was useful to inhibit the choroidal neovascularization. Additionally, the expression of VEGF was effectively inhibited and the nanoparticles containing the anti-VEGF agent and provided a prolonged action.

615

4.2.2.2. Ranibizumab. Ranibizumab is a fragment of bevacizumab with specificity for all isoforms of human VEGF-A [89], which is already being studied for DR and DME as an anti-VEGF agent. It was shown that intravitreal ranibizumab applications reduced the progression of these pathologies and their severity [105]. The marketed formulation is LucentisÒ (Genentech, California, US) and is being used for the treatment of AMD and DME, in patients with DR. LucentisÒ was approved for the treatment of AMD in 2006, receiving later approval for DME in 2012 (Genentech, California, US). Clinical studies revealed that intravitreal ranibizumab (0.5 or 0.3 mg) rapidly and sustainably improved vision, reducing the risk of further vision loss. Additionally, improvement of the macular edema in patients with DME was achieved. There are no reports describing the loading of ranibizumab in nanoparticles for ocular drug delivery.

651

4.2.2.3. Pegaptanib. Pegaptanib is an aptamer that binds to all isoforms of VEGF-A [84]. Pegaptanib has a marketed formulation named MacugenÒ (Pfizer/Eyetech Pharmaceuticals, New York, USA) accepted since 2004 by the FDA for the treatment of AMD. Clinical studies with intravitreal Pegaptanib showed a regression of neovascularization suggesting a direct effect upon retinal neovascularization in patients with DR [106,107]. A phase II study in patients with DME involving MacugenÒ (0.3, 1.0 or 3.0 mg) found that this drug specifically blocks the 165 amino-acid isoform of VEGF (V165), resulting in a better visual acuity, reducing the central retinal thickness, and reducing the need for additional therapy with photocoagulation when compared with sham injections [108]. Gonzalez and co-workers showed that intravitreal injection

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616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 635 636 637 638 639 640 641 642 643 644 645 646 647 648 649 650

652 653 654 655 656 657 658 659 660 661 662 663 664 665

667 668 669 670 671 672 673 674 675 676 677 678

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Fig. 6. Schematic illustration of VEFGs action in the development of angiogenesis, a leading cause of DR. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.) 679 680 681 682 683 684 685 686 687 688 689 690 691 692 693 694 695 696 697 698 699 700 701 702 703 704 705 706 707 708 709 710 711 712 713 714 715

of Pegaptanib produced short-term marked and rapid regression in diabetic retinal neovascularization [109]. To our knowledge there are no reports describing the loading of Pegaptanib for ocular drug delivery. Nanoparticles loading Pegaptanib could be useful to avoid intravitreal injections and increase patient’s compliance. 4.2.2.4. VEGF Trap eye. VEGF Trap eye, also known as aflibercept, is a recombinant fusion protein consisting of the binding domains of VEGF receptors 1 (VEGFR1; 2nd binding domain) and 2 (VEGFR2; 3rd binding domain) and Fc fragment of a human IgG1 backbone, being widely studied for DR applications. Similar to ranibizumab and bevacizumab, aflibercept, the VEGF Trap eye binds to all isomers of the VEGF-A family [110]. Currently named as EyleaÒ (Regeneron Pharmaceuticals, Inc., New York, USA; and Bayer Healthcare Pharmaceuticals, Berlin, Germany), aflibercept was firstly approved for DME and AMD treatment in 2011 by FDA. Aflibercept has shown a higher affinity for VEGF-A along with a longer duration of action as compared to other anti-VEGF antibodies, since the receptor sequences of aflibercept provide powerful binding to VEGF, creating a one-month intravitreal binding activity exceeding both ranibizumab and bevacizumab [111]. Preliminary studies reveal the benefits of this treatment in improvement visual acuity in patients with DME [112,113]. To our knowledge, there are no reports describing the loading of aflibercept for ocular drug delivery. 4.2.3. Protein C Kinase inhibitors The sustained hyperglycemia, in diabetes, induces increased levels of diacylglycerol and activation of PKC. These features lead to biochemical and metabolic abnormalities, mainly due to the increased production of extracellular matrix and cytokines, induction of cytosolic phospholipase A2 activation, and inhibition of Na+–K+-ATPase, that enhance contractility, permeability, and vascular cell proliferation [33]. PKC isoforms, b and d, play an important role in modulating the expression and production of VEGF affecting growth and permeability of retinal endothelium [6,114]. Ruboxistaurin, a selective inhibitor of PKC-b, is being studied for the management of DR and DME. The oral administration of this drug reveals promising results in the improvement of visual acuity,

reduction of vision loss, need for laser treatment, and macular edema progression [115–118]. It has also been reported that ruboxistaurin is able to delay the progression of DME [119] and inhibit the effect of VEGF on retinal permeability and endothelial cell growth [27]. In addition, the prevention and reversion of microvascular complications in animal models of diabetes by ruboxistaurin were reported by Ishii and co-workers [120] and other authors also reported its ability to block neovascularization associated with retinal ischemia [121]. The commercial formulation of ruboxistaurin, designated ArxxantÒ, synonym LY333531 (Eli Lilly and Company, Indiana, USA) is not yet approved by FDA for the treatment of DR due to the requirement of more evidences that this drug could safely use for this chronic disease. There are no updated studies describing the loading of PKC inhibitors for ocular drug delivery.

716

4.2.4. Growth hormone inhibitors The effect of growth hormone (GH) in the pathogenesis of DR was firstly supported by clinical observation of regression of severe PDR in 1953 [122]. Somatostatin, also known as growth hormoneinhibiting hormone (GHIH) or somatotropin release-inhibiting factor (SRIF), is a hormone that regulates the endocrine system. The use of synthetic analogues of somatostatin as therapeutic agents for DR is being exploited. Their role in the management of DR is directly linked with the inhibition of angiogenesis through somatostatin receptors present in endothelial cells. Also, there is an inhibition of post-receptor signaling events of peptide growth factors such as insulin-like growth factor 1 (IGF-1) and VEGF [123]. Octreotide, a somatostatin analogue, acts as GH inhibitor and is being used for the management of DR. Results have described this drug as safe and effective, acting by blocking the local and systemic production of GH and IGF-1 associated with angiogenesis and endothelial cell proliferation [123–125]. The use of octreotide and other somatostatin analogues seems to regulate angiogenic responses to the retinal hypoxic environment through a modulation of retinal levels of VEGF and its receptors [125]. The first clinical studies with octreotide for treating DR reported oscillating results in clinical trials for DR [126]. However, later studies provided evidences about the role of octreotide in DR,

731


717 718 719 720 721 722 723 724 725 726 727 728 729 730

732 733 734 735 736 737 738 739 740 741 742 743 744 745 746 747 748 749 750 751 752 753

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788 789 790 791 792 793 794 795 796 797 798 799 800

retarding the progression of advanced retinopathy and delaying the need for laser surgery [127,128]. The mechanism of action of octreotide could be associated with paracrine effect. Thus, the therapeutic effects of octreotide are hypothesized to be mediated by somatostatin receptor (SSTR) activation directly on the ocular target tissue. Besides, this paracrine effect potentially involves several SSTR subtypes, selective for octreotide, which mediate GH inhibition. At least, it seems that the peptide octreotide is not able to cross the blood–brain barrier, limiting the amount of drug reaching the retinal target tissue. Furthermore, this could result in a higher dose requirement of octreotide to be efficient in DR [129]. Due to the limitations mentioned above, the loading of this peptide in nanoparticles could be a suitable alternative to reach the retina in adequate concentrations, bringing benefits for the management of DR. There is a variety of nanoparticles associated with this peptide, namely gold nanoparticles [130], conjugates with amphiphilic molecules for imaging purposes [131], polymeric nanoparticles [132–135], polymeric hydrogels [136], polymeric microspheres [137], NLC [138], nanocapsules [139], liposomes [140]. Despite reporting the loading of octreotide into new therapeutic/imaging delivery systems, these studies do not focus on the formulation of nanoparticles for ocular delivery, in particular, for the management of DR. Recently, a novel class of SSTR agonists with nanomolar potency at SSTR2 and varying potency at SSTR3, a highly active non-peptide imidazolidine-2,4-dione (NISA) has been described and tested on DR. The effects of subtype selectivity and lipophilicity on the somatostatinergic ocular antiangiogenic function have been investigated in in vitro and in vivo ocular model systems showing that the antiangiogenic effect of NISA and octreotide was mediated via SSTR2 receptor and, although the downstream mechanisms seem less efficient than dose of GH, one should consider the direct Q5 ocular administration of these drugs to treat DR [129].

4.2.5. Advanced glycation end products inhibitors In a hyperglycemic environment, carbohydrates (e.g. glucose, fructose) interact with proteins forming covalent adducts by a non-enzymatic reaction to form AGEs [36,141]. AGEs are proposed as a contributing mechanism in the pathogenesis of diabetic clinical complications accelerating their synthesis and tissue deposition, both extracellularly and intracellularly [36]. These complications lead to the microvascular alterations in DR [2]. The use of AGEs inhibitors such as aminoguanidine has been investigated to prevent some of the diabetic vascular abnormalities [142–145]. The results suggest the inhibition of the accumulation of AGEs in the retinal capillaries with the use of aminoguanidine associated with acellular capillaries and pericyte loss [28,142,146].

9

Other AGE producing inhibitor is carnosine, a naturally occurring dipeptide, which seems to have potential vasoprotective effect on retinal capillaries by oral administration [147]. The main limitation for the therapeutic use of carnosine is its rapid hydrolysis mostly by plasma carnosinase [148]. Thus, new types of nanoparticles have been developed to provide high stability to this drug, e.g. functionalizing avidin- and streptavidin-gold nanoparticles with the carnosine-biotin conjugate [148]. Examples of studies reporting the formulation of AGEs in nanocarriers include magnetic nanoparticles [149], iron oxide nanoparticles [150] and silver nanoparticles [151]. A study carried out by Singha and co-workers [152] reported the prevention of glycation of a-crystallin (the major component of the eye lens) by conjugation with gold nanoparticles, suggesting a possible role of these particles against protein glycation reaction in ocular pathologies. Other study published by Yang and co-workers [153] reported the use of silica-based cerium (III) chloride nanoparticles in the inhibition of AGEs formation and reduction of oxidative stress. Results seem to be promisors, suggesting these particles as a novel agent for the prevention of cataractogenesis. Moreover, these nanoparticles could be an alternative against the use of AGEs production inhibitors, such as aminoguanidine and carnosine.

801

4.2.6. Antioxidants Hyperglycemia-induced oxidative stress is considered an important connection between high glucose levels and other metabolic abnormalities relevant in the development of DR complications. It results from the overproduction of ROS and reactive nitrogen species (RNS) and/or from the inability to suppress ROS/ RNS by antioxidant defense system and thus creating an imbalance between production and destruction [154]. The major ROS generated are the free radicals superoxide (O2 ), hydroxyl (OH), peroxyl (RO2), hydroperoxyl (HRO2 ) and the non-radical hydrogen peroxide (H2O2) [155]. And the major RNS are nitric oxide (_NO), considered vasoprotective, however, NO reacts easily with superoxide producing the highly reactive molecule ONOO (peroxynitrite), and subsequently triggering a cascade of harmfulness [155]. The formation of these ROS/RNS can be mediated by both enzymatic and non-enzymatic mechanisms (Fig. 7). The main damage caused by ROS is at mitochondrial level, namely in the DNA and membrane proteins, leading to imbalances in the electron transport chain, but also can affect lipids and proteins at other organelles. Excess of ROS results in the mitochondrial release of cytochrome C, mitochondrial membrane damage and ultimately induces cellular apoptosis [156]. It seems that overexpression of manganese superoxide dismutase (MnSOD) is enabled to protect the increasing oxidative stress result from the DR [11].

824

Fig. 7. The oxidative stress is triggered by the constant hyperglycemia in the retinal vessels. The four pathways are influenced, since it generates ROS and AGEs contributing to the inefficient activity of enzymatic antioxidant enzymes such as GSH, catalase, SOD and GSH reductase. This imbalance leads to the existence of retinal oxidative stress.


802 803 804 805 806 807 808 809 810 811 812 813 814 815 816 817 818 819 820 821 822 823

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Table 2 Examples of some of the most important antioxidants used in nano- and microencapsulation, their antioxidant mechanism and the variety of nanocarriers that are currently being studied. Antioxidant

Mechanism

Nanocarrier

References

Vitamin C/ascorbic acid

Free radical scavenging Stimulates the inhibition of retinal GSH reductase, and SOD activities

Polymeric nanoparticles

[169–172]

Liposomes SLN/NLC Dendrimers

[173,174] [175–177] [178]

Liposomes Polymeric nanoparticles Nanoemulsions SLN/NLC Nanocapsules

[179] [180–184] [185,186] [187,188] [189]

Liposomes Polymeric nanoparticles SLN/NLC Gelatin nanoparticles Nanoemulsions Self-emulsifying drug delivery systems (SEDDS)

[190] [191–193] [194–197] [198] [199,200] [201,202]

Nanoemulsions SLN/NLC Polymeric nanoparticles Nanocapsules

[203] [203,204] [205] [206]

Inhibition of VEGFs production

Microcapsules and nanocapsules Liposomes Polymeric nanoparticles Nanoemulsions SLN/NLC

[207,208] [209–211] [212–214] [215,216] [217–219]

Reduction of retinal oxidative stress Activation of antioxidant enzymatic activity Free radical scavenging

Polymeric nanoparticles SLN/NLC Microcapsules

[220,221] [222,223] [224]

Vitamin E/a-tocopherol

Prevention of lipid peroxidation

Reduction of retinal cell loss Resveratrol

Free radical scavenging Reduction of retinal oxidative stress

Reduction of retinal cell loss

a-Lipoic acid

Curcumin

Reduction of retinal oxidative stress

Epigallocatechin gallate (EGCG)

848 849 850 851 852 853 854 855 856 857 858 859 860 861 862 863 864 865 866 867 868 869 870 871 872 873 874 875 876 877 878 879 880

Inhibition of cell apoptosis Reduction of retinal oxidative stress Reduction of GSH and PGx levels Reduction of VEGFs expression

Additionally, it has been reported that MnSOD decreases hyperglycemia in streptozotocin (STZ)-induced diabetic rats [29,157]. Thus, the use of antioxidants could be a useful approach to manage DR and to avoid some of its complications. The antioxidants are molecules present in the human diet, such as vitamins A, C, E, some flavonoids and carotenoids, which sometimes are insufficient to prevent the oxidative stress. Vitamins E (tocopherols) and C (ascorbic acid) are potent antioxidants that prevent lipid peroxidation [158]. Their main functions are the (i) free radical scavenging and (ii) inhibition of retinal GR and SOD activity [30]. For DR management, a short-term high-dose vitamin E therapy could help to normalize retinal hemodynamics [159,160]. Also, resveratrol provides protection against oxidative stress in retinal pigment epithelial cells [161,162]. The use of a-tocopherol showed to be efficient in the prevention of diabetes-induced abnormal retinal blood flow [163]. Despite the evidences that antioxidants could have protective effects, some studies provide no association of the intake of antioxidants with improvement of DR [164–166]. These studies have some limitations and do not translate the real situation, such as medication, severity of the disease, gene and environmental factors [167]. Despite that, it is evident that oxidative stress and the formation of ROS have an important role in the development of DR and the use of antioxidants could be a good strategy to overcome these biochemical features. The profile of these substances could be improved by the use of nanoparticles since antioxidants are highly susceptible to oxidation presenting limited absorption profiles, and thus low bioavailability [168]. Table 2 describes the antioxidant mechanism of the most common antioxidants molecules investigated. The description of their loading in nanoparticles is also provided, however the available examples are mainly employed for oral delivery, to be introduced in the diet.

The use of gold nanoparticles showed to control the activity of some enzymes, such as GR, SOD, glutathione peroxidase (GPx) and catalase (CAT) in diabetic mice [225], also demonstrating some antioxidant activity in hyperglycemic rats. Gold nanoparticles were reported to inhibit lipid peroxidation and ROS generation, promoting a control over hyperglycemia. Thus, gold nanoparticles could represent a potential therapeutic treatment for DR management [225] as well as natural antioxidants, such as vitamins and polyphenols (either alone or encapsulated).

881

4.2.7. Gene delivery The management and treatment of DR are limited due to the multifactorial origin of this disease. Thus, gene delivery has gained much attention due to the exploration of genetic features that affects oxidation of retinal cells and the activation of the four main biochemical pathways (polyol, AGEs, hexosamine and PKC) [226]. Some of the genes involved in these pathways have been treated as potential candidate genes for the management of DR. These genes include [227] angiotensin-I converting enzyme (ACE), angiotensin II type 1 receptor (AGTR1), angiotensinogen (AGT), VEGF, aldose reductase (AR2), receptor for AGEs (RAGEs), glucose transporter 1 (GLUT1), inducible and constitutive nitric oxide synthases (NOS2A, NOS3), transforming growth factor beta (TGFbeta), endothelin isoforms, and its cellular receptors [228–232]. Xu and co-workers [233] studied and developed a gene-based intraocular erythropoietin (EPO) therapy for DR. The results are shown to be safe, feasible and exert long-term protective effects in DR patients. Studies involving nanoparticle-mediated gene delivery have been published by Park and co-workers [234], using PLGA to load a plasmid, namely plasminogen kringle 5 (K5), a natural angiogenic inhibitor. Retinal neovascularization was evaluated in rats with oxygen-induced retinopathy by an intravitreal injection of the nanoparticles. The nanoparticles with the plasmid were

890


882 883 884 885 886 887 888 889

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able to mediate a sustained and efficient expression of K5 in the retina, reducing the retinal vascular leakage and retinal neovascularization.

916

5. Nanomaterials and diabetic retinopathy

917

962

The use of nanoparticles-based approaches to improve the prevention and treatment of DR is emerging in ocular administration. Despite the loading of some drugs that could avoid the progression of DR, nanoparticles seem to be promising, simply by the use of materials such as silver, gold, silica and titanium dioxide [235]. As mentioned above, retinal neovascularization is the most typical and risky factor occurring in DR pathogenesis. Jo and coworkers developed silicate (SI) nanoparticles and tested their anti-angiogenic effects on retinal neovascularization induced by VEGF [236]. SI nanoparticles are biodegradable and safe, and were administered to mice via intravitreal injection. The results of this study demonstrated that SI nanoparticles have no toxic effect on retinal tissues by histological analysis and were shown to inhibit retinal neovascularization. Additionally, in vitro migration and tube formation of retinal microvascular endothelial cells were also observed. Thus, SI nanoparticles showed to be efficient in the treatment of VEGF-induced retinal neovascularization without acute toxicity, and can be applied in patients with DR. Another study involving gold nanoparticles was reported by Kin and co-workers who demonstrated the nanoparticles ability to inhibit retinal neovascularization [237]. The particles were administered in a mouse model by intravitreal injection. The results were shown to be promising and the gold nanoparticles effectively suppressed VEGF-induced in vitro angiogenesis of retinal microvascular endothelial cells including proliferation, migration and capillary-like networks formation. In addition, these particles showed to be safe and did not affect the cellular viability of retinal microvascular endothelial cells and induced no retinal toxicity. These could be useful for DR proliferative mediated by VEGF. From the available studies, it is possible to conclude that several types of nanoparticles are being employed in the treatment of retinal neovascularization. Other types of nanoparticles reported by Jo and co-workers were bare titanium dioxide (TiO2) nanoparticles [238]. These nanoparticles were applied topically onto the eye surface of a mouse model. The particles were effective in suppressing in vitro angiogenesis without showing any toxicity effects in the retina. In vivo retinal neovascularization was also suppressed when particles were administered by intravitreal injection. This study demonstrated that TiO2 nanoparticles could be used at adequate concentration levels for the treatment of retinopathy mouse models. The properties of silver nanoparticles seem to provide beneficial effects in the inhibition of angiogenesis. A study carried out by Gurunathan and co-workers [239] showed that these particles could inhibit the formation of new blood microvessels induced by VEGF in mouse models.

963

6. Conclusions

964

DR is an eye disease that severely affects patient’s quality of life and leads to a high risk of blindness. Despite the uncertain biochemical and biological mechanisms that contribute to its course, the multifactorial nature of the disease is evident, and thus its treatment remains a clinical challenge. The main biochemical pathways affected by DR are discussed, as well as the possible pharmacological strategies. The traditional and current strategies for the treatment and management of DR including pharmacological and surgical are discussed along with the major efforts that have been carried out using innovative drug delivery systems.

918 919 920 921 922 923 924 925 926 927 928 929 930 931 932 933 934 935 936 937 938 939 940 941 942 943 944 945 946 947 948 949 950 951 952 953 954 955 956 957 958 959 960 961

965 966 967 968 969 970 971 972 973

11

Controlling and maintaining the optimal glycemic levels is apparently not enough to avoid DR in diabetic patients. In an early stage, pharmacological strategies may help delaying the course of the disease. In cases of DME and PDR, surgical strategies are employed; however, they are an invasive strategy associated with severe and risky side effects. Thus, the development of new drug delivery systems for ocular drug delivery has gained much attention and became an important field of research. The development of sustained and prolonged action, non-invasive, safe and innovative drug delivery systems may overcome some of the major barriers and difficulties provided by the anatomy and physiology of the eye provides to the entrance of drugs. Additionally, these nanoparticles could be a rationale alternative over invasive, high risk and painful treatments that have been applied for the management of DR. Thus, these advances have possibility to improve the therapeutic efficacy and patient’s compliance, providing better results over the current therapeutic strategies.

974

Conflict of interest

991

None declared.

975 976 977 978 979 980 981 982 983 984 985 986 987 988 989 990

Q6

992

Acknowledgments

993

Ms. Joana Fangueiro wishes to acknowledge Fundação para a Ciência e Tecnologia do Ministério da Ciência e Tecnologia (FCT, Portugal) under the reference SFRH/BD/80335/2011. FCT and FEDER/COMPETE are also acknowledged under the reference PEst-C/AGR/UI4033/2014.

994

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Current management of diabetic retinopathy.

Current management of diabetic retinopathy.

Current concepts of proliferative diabetic retinopathy management.

Management of diabetic retinopathy.

Novel therapeutic approaches for diabetic nephropathy and retinopathy.

Current hypotheses for the biochemical basis of diabetic retinopathy.

Surgical management of diabetic retinopathy.

Clinical biomarkers and molecular basis for optimized treatment of diabetic retinopathy: current status and future prospects.

New Therapeutic Approaches in Diabetic Retinopathy.

Diabetic retinopathy: current concepts and emerging therapy.

Current and Next Generation Portable Screening Devices for Diabetic Retinopathy.

Pars plana vitrectomy for the management of sever diabetic retinopathy.

Current trends in the monitoring and treatment of diabetic retinopathy in young adults.

Diabetic retinopathy (DR): management and referral.

Laser treatment of diabetic retinopathy.

The treatment of diabetic retinopathy: a view for the internist.

Current and future management of diabetic retinopathy: a personalized evidence-based approach.

Perspectives in the treatment of diabetic retinopathy.

A Review of Ranibizumab for the Treatment of Diabetic Retinopathy.

Systemic medical management of diabetic retinopathy.

New Diagnostic and Therapeutic Approaches for Preventing the Progression of Diabetic Retinopathy.

New developments in the pathophysiology and management of diabetic retinopathy.

Inflammation and pharmacological treatment in diabetic retinopathy.

Somatostatin and diabetic retinopathy: current concepts and new therapeutic perspectives.