Nano-based DDS for Posterior Segment Diseases: Comparison
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The complex anatomy of the eye presents a major challenge in the treatment of posterior segment eye diseases, hindering the effective delivery of medications. Conventional treatments, including topical eye drops and intravitreal injections, are limited by poor bioavailability and short residence time, necessitating frequent dosing to manage the disease. Intravitreal injections can also lead to serious ocular complications. Biodegradable nano-based drug delivery systems (DDSs) have emerged as a potential solution to these limitations, offering longer residence time in ocular tissues and better penetration through ocular barriers. Furthermore, the biodegradable polymers used to create these systems are nanosized, reducing the risk of toxicity and adverse reactions.

This review provides a comprehensive overview of the latest advances in biodegradable nano-based DDSs for treating posterior segment diseases. By examining current therapeutic challenges and exploring various types of biodegradable nanocarriers, we aim to highlight the potential of these systems to enhance treatment outcomes. Our review includes pre-clinical and clinical studies published between 2017 and 2022, demonstrating the rapid evolution of nano-based DDSs. As biodegradable materials continue to advance, and our understanding of ocular pharmacology improves, nano-based DDSs hold great promise for overcoming obstacles encountered in clinical practice. 

  • ocular surface disease
  • retinal disease
  • nanosystems for ocular drug delivery
  • nanocarriers
  • biodegradable polymers
  • ocular drug delivery system
  • hydrogels
  • ocular inserts
  • exosomes

Posterior Segment Diseases

1. Posterior Segment Diseases

The delivery of treatments to the posterior segment of the eye presents a challenge in achieving adequate bioavailability through systemic or topical routes. Systemic medications, whether administered orally or intravenously, struggle to cross the blood–retinal barrier (BRB), necessitating high-dose administration that can result in systemic side effects. Topical eye drops have limitations due to the multiple ocular barriers impeding the medication's path from the ocular surface to the posterior segment, as previously discussed. Intravitreal injections are invasive and carry potential sight-threatening complications such as endophthalmitis or retinal detachment. They require a sterile administration and need to be injected frequently during multiple ophthalmologist visits that contributes to decreasing patient compliance. Nanomedicine has been extensively researched to overcome these issues and improve drug delivery to the posterior eye in a targeted and prolonged manner, as summarized in Table 1.

 

Retinitis Pigmentosa

Retinitis pigmentosa (RP) is a genetic disorder that causes progressive vision loss, starting with night blindness and peripheral vision loss due to the degeneration of photoreceptor cells, primarily rods. With over 3000 known mutations targeting specific systems or proteins, effective therapies for a large patient population are needed. Successful nano-based DDSs hold great promise for targeted and maximal therapeutic effect. In this regard, several studies have focused on administering neuroprotective agents to prevent retinal degeneration and promote the survival of retinal cells by reducing inflammation, decreasing oxidative stress, and promoting repair of damaged cells [70].

Arranz-Romera et al. used PLGA microspheres to co-deliver GDNF and TUDCA for promoting neuronal survival in retinal degeneration models [71]. These biodegradable microspheres provided a sustained, erosion-driven controlled release of effective drug concentrations for at least 91 days in vitro. Optimization of drug loading and the addition of vitamin E during microsphere formulations and water-soluble ethanol as a co-solvent significantly improved encapsulation efficiency of GDNF and TUDCA [72]. Furthermore, the external morphology of the microspheres was found to affect the release profile of encapsulated proteins. Sen et al. developed self-assembling nanoparticles based on mPEG-cholane and mPEG-cholesterol to improve the solubility and therapeutic potential of ML240, an inhibitor of valosin-containing protein (VCP) [74]. In retinal explants, the nanoparticles showed photoreceptor protection for up to 21 days in an ex vivo rat model, with in vivo studies demonstrating their safety and tolerability in wild-type rat eyes. However, it remains to be seen whether these results are translatable to rats or humans with RP. Platania et al. developed a topical formulation of myriocin-loaded nanostructured lipid carriers (Myr-NLCs) in the form of eye-drops [75]. The Myr-NLC formulation was well-tolerated and decreased retinal sphingolipid levels in rabbit eyes, showing potential for treating RP by inhibiting ceramide synthesis. Nonetheless, the performance of these NLCs in vivo is uncertain, especially given that myriocin has limited stability at physiological temperature. While the studies highlight the significant role of nano-based drug delivery systems in making therapeutic targets accessible, the biodegradability of specific formulations and their effects on the body must be explored further.

Currently, it is unclear which nano-based DDSs are most effective for RP due to the limited number of studies and the high heterogeneity in the type and formulation of the DDSs and active substances assessed. However, PLGA microspheres have shown the longest sustained release with a reduced initial burst release. Nonetheless, it remains unclear whether longer release time necessarily correlates with drug efficacy and disease treatment. Successful DDSs enhance drug residency time, improve stability of potential therapeutic targets, and modulate neuroprotective effects in the retina, leading to more promising clinical applications. While preliminary ex vivo, in vitro, and in vivo experiments have been conducted, there is a need for larger in vivo models, such as rodents with similar eye anatomy to humans, to further investigate therapeutic efficacy for RP that can be translated to clinical settings.

 

Age-Related Macular Degeneration and Choroidal Neovascularization

Age-related macular degeneration (AMD) is a common eye disorder that affects people over the age of 50 and is a significant contributor to vision loss in the elderly. There are two types of AMD: dry and wet. The dry form progresses gradually over time, while the wet form is less common but more severe and results from the growth of abnormal blood vessels under the macula. These vessels leak fluid and blood, leading to a rapid decline in vision. AMD can be targeted in various ways, such as reducing inflammation and drusen formation, improving RPE survival, inhibiting angiogenesis, and treating choroidal neovascularization (CNV) found in wet-AMD. Management of AMD depends on its severity and type. Nutritional supplements can be used to manage dry AMD, while regular intravitreal injections of anti-VEGF drugs are typically required for wet AMD [77, 78].

In the treatment of wet AMD and CNV, anti-VEGF therapy has been commonly used, and nano-based DDS systems have been developed to enhance its delivery [CITE]. However, a significant proportion of patients exhibit a poor response to anti-VEGF treatments, and the therapy may lead to severe complications such as endophthalmitis and retinal detachment. Additionally, the effectiveness of anti-VEGF treatment is dependent on patient compliance [CITE]. To address these limitations, it is important to optimize therapies targeting inflammation, degeneration, and the development of neovascularization.

Efforts have been made to create biomimetic nano-based DDSs for targeted delivery to CNV lesion sites in the eyes of AMD patients. For instance, Zhang et al. utilized mesenchymal stem cells (MSCs) to carry PLGA nanoparticles containing HIF-1α siRNA to reduce a variety of pro-angiogenic factors upstream of VEGF [81].

To improve targeted delivery to CNV lesion sites, Zhang et al. used mesenchymal stem cells (MSCs) to carry PLGA nanoparticles loaded with HIF-1α siRNA in a hypoxic environment. The biodegradable nanoparticles improved drug-carrying capacity and sustained release, making MSC-guided delivery promising for retinal disorders. Combining siRNA with PLGA NPs proved effective in decreasing expression of HIF-1α for 7 days in RPE cells. However, more work is needed to characterize the physiological and functional improvement, and the formulation requires further optimization and safety testing on animals to ensure therapeutic benefit for AMD and CNV. Nonetheless, this study demonstrates the compounded benefit of combination therapy, which overcomes individual barriers to each component, such as the protective effect of PLGA NPs on siRNA prone to enzymatic degradation and the enhanced drug loading and efficacy of MSCs engineered with NPs.

In the treatment of CNV, biomimetic DDSs have shown promise in improving targeted delivery to the lesion sites in the eyes of AMD patients. Xia et al. developed a DDS using macrophages to carry PLGA nanoparticles loaded with rapamycin intravenously. Rapamycin is known to suppress inflammation and enhance dysregulated autophagy observed in AMD, while acting upstream to VEGF-mediated inhibition of angiogenesis. Despite its promise, rapamycin's low water solubility and poor accumulation at lesion sites have historically limited its use. Xia et al. used the knowledge that macrophages are recruited to areas of RPE atrophy and CNV lesions to successfully deliver PLGA-rapamycin nanoparticles intravenously in a laser-induced CNV mouse model, improving bioavailability, suppressing neovascularization, inflammation and enhancing autophagy both in vitro and in vivo in a CNV mouse model. Similarly, Mei et al. used synthetic high-density lipoprotein (sHDL) nanoparticles to deliver rapamycin intravitreally, providing a non-toxic, synergistic, anti-inflammatory effect, reducing lipid deposition, and improving bioavailability and distribution of rapamycin to the RPE layer. Combined with the observed benefits of macrophage-guided rapamycin delivery, rapamycin shows promise for treating AMD and CNV. The use of nanocarriers is critical in delivering hydrophobic drugs in largely hydrophilic environments such as the ocular environment. However, neither study has explored the longevity of their formulations and the effects of long-term delivery of rapamycin in the posterior eye segment. Further studies using disease animal models are needed to validate therapeutic efficacy and modify these therapies for clinical translation. Moreover, adverse side effects associated with frequent intravitreal injections should also be noted.

Oxidative stress and reactive oxidative species (ROS) have been linked to AMD, making ROS production an attractive target for antioxidant therapies. Nguyen et al. developed a potential therapy for wet AMD by co-delivering resveratrol and metformin using poly(ε-caprolactone) (PCL) nanoparticles [83]. Resveratrol provides antioxidant and anti-inflammatory effects, while metformin has anti-angiogenic properties. As ROS cause multifaceted RPE damage, targeting several components at once is desirable. PCL, a biodegradable polymer, is more biocompatible in the RPE regions than PLA and PLGA, and its degraded by-products are less acidic, avoiding inflammation. Cell-penetrating peptides (CPPs) improved retinal permeability, and sustained release for up to 56 days, and therapeutic effects were observed in a rat model of AMD. Lai et al. suggested a co-delivery system for berberine hydrochloride and chrysophanol, with potent antioxidant, anti-angiogenic, and anti-inflammatory properties [54]. These drugs have potential in the treatment of AMD. However, their poor stability and bioavailability were addressed using polyamidoamine dendrimers (PAMAM) and liposomes to effectively deliver the drugs to the retina. PAMAM-coated DDS revealed a negative zeta potential, preferred for drug delivery to the retina, and enhanced drug loading. PAMAM-liposome systems (P-CBLs) improved berberine hydrochloride bioavailability, with no side effects observed on the ocular surface structure of rabbits. Although the study did not evaluate the release profiles of the drugs in the posterior segment of the eye, the P-CBL system shows potential for treating AMD and other ocular diseases.

Oxidative stress and reactive oxidative species (ROS) are involved in the pathophysiology and progression of age-related macular degeneration (AMD). Targeting ROS production to initiate antioxidative effects is a potential therapeutic strategy for AMD. Nguyen et al. investigated the intravitreal co-delivery of resveratrol and metformin using poly(ε-caprolactone) (PCL) nanoparticles to simultaneously target multiple components of AMD [83]. Resveratrol provides antioxidant and anti-inflammatory effects, while metformin has anti-angiogenic effects. PCL is biocompatible in the RPE regions and degrades into less acidic by-products compared to other polymers. The polymer was further modified with cell-penetrating peptides (CPPs) to significantly improve retinal permeability. The sustained release of the therapy for up to 56 days and therapeutic effects were observed in a rat model of AMD. Lai et al. suggested a co-delivery system for berberine hydrochloride and chrysophanol using polyamidoamine dendrimers (PAMAM) and liposomes [54]. PAMAM acts as an external coating for the compound-loaded liposomes to enhance drug loading, cellular permeability, and bio-adhesion on corneal epithelial cells. The PAMAM-liposome system substantially improved berberine hydrochloride bioavailability. No side effects were observed on the rabbit ocular surface structure after the administration of P-CBLs. Although the release profiles of the drugs in the posterior segment of the eye were not assessed, the P-CBL system has potential for treating AMD and other ocular diseases.

 

Diabetic Retinopathy

Diabetic retinopathy is a chronic condition in diabetic patients that results from damage to the blood vessels in the retina. The condition progresses over time and has two stages: non-proliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR). NPDR is characterized by increased vascular permeability, capillary occlusion, and the formation of microaneurysms, hemorrhages, cotton wool spots, and hard exudates. PDR, which occurs in advanced stages of diabetic retinopathy, leads to retinal ischemia and the release of pro-angiogenic factors such as VEGF, stimulating the formation of new abnormal blood vessels. These vessels can cause various vision-threatening complications such as vitreous hemorrhage and tractional retinal detachment, as well as glaucoma. Treatment of PDR primarily focuses on reducing the production of VEGF through laser photocoagulation or intravitreal anti-VEGF injections.

The treatment of diabetic retinopathy (DR) may involve the use of antioxidants, anti-inflammatory agents, and neurotrophic factors [84]. Nano-carriers, such as PLGA-based nanoparticles, have been suggested to improve drug delivery to the diabetic retina. For instance, Zeng et al. used PLGA nanoparticles to deliver Interleukin-12 (IL-12), which has been shown to reduce the levels of matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor (VEGF-A), both of which contribute to DR severity [85]. IL-12-PNP exhibited better inhibition against VEGF-A and MMP-9 expression, resulting in significantly reduced retinal damage in a DR mouse model with increased thickness and reduced neovascularization. Similarly, Romeo et al. proposed to deliver melatonin with PLGA-PEG lipid-polymer hybrid nanoparticles (LPHN) [86], which demonstrated neuroprotective and antioxidant effects on a model of glucose-induced DR on human retinal endothelial cells. The use of a biodegradable polymer in this study showed high encapsulation efficacy (79.8%) and no signs of cytotoxicity or ocular irritation in vivo. Romeo et al. observed a prolonged and sustained release for up to 8 days compared to a rapid burst release of free melatonin, which is necessary for its ocular delivery. These studies highlight the potential of nano-carriers in improving the therapeutic efficacy of drugs limited by inefficient delivery routes.

Zingale et al. used nanostructured lipid carriers (NLCs) to deliver diosmin, a flavonoid known for its anti-inflammatory, cytoprotective, and antioxidant effects in high glucose environments [87]. This delivery system achieved high encapsulation efficiency and was found safe and well-tolerated in vitro. However, surfactants are commonly used in the preparation of lipid-based nanocarriers, which may cause irritation and sensitizing action [88]. Further studies are being conducted to confirm the clinically relevant anti-inflammatory effects of diosmin NLCs. NLCs have the advantage of minimal toxicity and can be stored stably for long periods [89]. They can also be applied as topical eye drops, as demonstrated by Platania et al. [74], which greatly increases patient compliance. However, further exploration is needed to better assess the release profiles of drug loaded NLCs and determine how often administration is required.

Various types of biodegradable nanoparticles have been studied for the treatment of diabetic retinopathy. One study by Radwan et al. used bovine serum albumin nanoparticles coated with hyaluronic acid to deliver the anti-VEGF factor apatinib, resulting in sustained biphasic release with high mucoadhesion and improved retinal thickness and microstructure [90]. Another study by Mahaling et al. used nanoparticles with a hydrophobic polycaprolactone core and hydrophilic Pluronic® F68 shell to deliver triamcinolone acetonide, demonstrating significant structural and functional improvements in a DR rat model [91]. These findings indicate the potential of non-invasive, patient self-administered nanoparticle-based delivery systems for the treatment of diabetic retinopathy, overcoming challenges associated with intravitreal administration. The use of PCL as a biodegradable polymer for nanoparticle systems has been particularly advantageous in DR treatments, given its strong bioavailability in the retina during topical administration [92].

 

Diabetic Macular Edema (DME)

Diabetic macular edema (DME) is a frequent complication of diabetic retinopathy, characterized by the accumulation of fluid in the macula, resulting in a rapid decline in visual acuity. This is caused by increased permeability and inflammation in the retinal vessels [84].

In addition to intravitreal anti-VEGF injection and topical NSAIDs, intravitreal triamcinolone acetonide (TA) can be used to reduce inflammation associated with diabetic macular edema (DME), but it can lead to complications such as IOP elevation and cataract formation. To overcome these issues, liposomes have been used for topical delivery of TA. Navarro-Partida et al. found TA-loaded liposomes to be safe and tolerable in healthy patients through a Phase 1 clinical assay and reported a sustained therapeutic effect in DME patients in an open-label, non-randomized study. However, further studies are needed to confirm long-term safety and therapeutic efficacy. Chitosan-coated liposomes have been used by Khalil et al. to improve the biodegradability and mucoadhesion of liposomes, enhancing bioavailability and prolonging the release of TA in in vivo models. Although their efficiency of drug release was demonstrated on a CNV rat model, the authors recommend this DDS for any posterior segment disease, particularly DME, proliferative diabetic retinopathy, and CNV related to AMD. Lipid-based nanomaterials show initial clinical success with TA topical administration, demonstrating the superiority of lipid-based DDSs and the flexibility afforded by nano-based DDSs to improve retention time, permeability, encapsulation efficiency, and personalize treatment to the drug, disease, and area of interest.

 

For delivering treatments to the posterior segment of the eye, bioavailability becomes a challenge using a systemic or topical route. Most systemic medications, whether administered orally or intravenously, have difficulty crossing the blood–retinal barrier (BRB), requiring a high-dose administration that can result in systemic side effects. Topical eye drops also have limitations due to the multiple ocular barriers that impede the medication’s path from the ocular surface to the posterior segment, as discussed in a previous section of this article. Intravitreal injections are more invasive and can lead to potential sight-threatening complications such as endophthalmitis or retinal detachment. Additionally, they have a short retention time and require multiple visits to the ophthalmologist for administration in a sterile condition, which decreases patient compliance

[1]

. To ameliorate these issues, there has been extensive research done within nanomedicine to improve drug delivery to the posterior eye in a targeted, prolonged manner.

2. Retinitis Pigmentosa

Retinitis pigmentosa (RP) is a group of inherited disorders that affect the retina. It is caused by various genetic mutations, leading to the degeneration of the photoreceptor cells, primarily rods rather than cones, and subsequent progressive vision loss beginning with night blindness and peripheral vision loss. As RP is a genetic condition with over 3000 known mutations that target specific systems or proteins, which are affected by multiple mutations, it is an effective approach to maximizing the therapeutic effect in a large patient population. Successful nano-based DDSs of therapies, which have shown success in this front, thus hold great promise. Several studies have instead focused on targeting the posterior eye to prevent retinal degeneration, such as preventing photoreceptor death and promoting its survival. This is typically accomplished by administering neuroprotective agents to retinal cells. These agents have neurotrophic, anti-apoptotic, or antioxidant properties aimed at reducing retinal inflammation, decreasing oxidative stress, and promoting repair of damaged neurons and cells

[2]

.
Arranz–Romera et al. used PLGA microspheres to co-deliver the growth-derived neurotrophic factor (GDNF) to promote neuronal survival, with tauroursodeoxycholic acid (TUDCA), a substance shown to have anti-apoptotic, antioxidant, anti-inflammatory, and cytoprotective attributes in retinal degeneration models

[3]

The biodegradable nature of this microsphere allowed for a sustained, erosion-driven controlled drug release in the target tissue at effective concentrations. Through the optimization of drug loading, they were able to improve TUDCA entrapment while reducing the initial burst effect of GDNF. They observed a sustained release for at least 91 days in vitro, an essential component for RP since it requires long-acting drug responses. One benefit of nano-based formulations is the possibility of small-scale modifications that have a significant impact on the final behaviour of the DDSs and drugs. In this study, the addition of vitamin E during microsphere formulations allowed for a greater stability of GDNF during the emulsion, translating to improved GDNF function and prolonged release in vitro. Furthermore, the use of the water-soluble ethanol (EtOH) as a co-solvent-affected DDS solidification and microsphere porosity and structure, contributing to improved encapsulation efficiency of both GDNF and TUDCA. The external morphology of microparticles, modified through the addition of EtOH and other substances, affects the release profile of their encapsulated proteins

[4]

. Finally, combination therapy holds its own benefits, and in this experiment, it was observed that the presence of amphiphilic TUDCA modulated the release of hydrophilic GDNF. Another substance found to attenuate retinal degeneration is ML240, which inhibits the valosin-containing protein (VCP), a potential therapeutic target for autosomal-dominant RP

[5]

. To improve solubility and thereby maximize ML240’s therapeutic potential, Sen et al. used methoxy-poly (ethylene glycol) (mPEG)-cholane and mPEG-cholesterol-based nanoparticles that self-assemble to encapsulate the drug and improve its retention time

[6]

. The formulations prolonged the drug release over 10 days, and neuroprotection, particularly photoreceptor protection, was observed for up to 21 days in retinal explants with decreased inflammatory microglial responses in an ex vivo rat model. It was also observed that the formulations were safe and well-tolerated in in vivo wild-type rat eyes. However, this may not translate to rats or humans with RP as there are secondary insults and biological changes that are not present in wild-type counterparts. The study nevertheless highlights the significant role of nano-based DDSs for making accessible therapeutic targets that have shown an initial promise but are limited by their delivery and behaviour in vivo without support. Furthermore, they observed small particle sizes of mPEG-loaded nanoparticles, ranging from 32 to 55 nm, which is optimal for corneal penetration, absorption, reduced eye irritation, and patient compliance as this requires smaller needles. However, as with the above study, in vivo work is required to concretely establish therapeutic success as many initially promising therapies fail to instigate the desired effect in the complicated in vivo system. It should also be noted that neither study directly assessed the biodegradability of its proposed DDS. While both PLGA and PEG are biocompatible and degradable, it is worth exploring the biodegradability, and subsequent long-term effects of the degraded components, for specific formulations. Prioritizing patient comfort, Platania et al. developed a novel topical formulation of myriocin-loaded nanostructured lipid carriers (Myr-NLCs) in the form of eye-drops

[7]

. They observed that this system considerably decreased retinal sphingolipid levels in rabbit eyes, showing potential in the treatment of RP by inhibiting ceramide synthesis. The researchers observed that the Myr-NLC formulation is well-tolerated after delivery and indicated effective levels of myriocin in the posterior eye. In previous work, myriocin has shown promise in lowering retinal ceremide levels in RP mouse models when loaded in solid lipid nanocarriers (SLNs)

[8]

. This current work went one step further to highlight the superiority of NLCs over SLNs, particularly for drug solubility and, thus, loading. SLNs face challenges with long-term storage as there is a high chance of drug expulsion that can be overcome with NLCs, allowing for possible large-scale production if clinical success is achieved

[1]

. However, it is currently unclear how well these NLCs translate to in vivo efficacy. In particular, myriocin has limited stability at temperatures above 0 °C and, despite the increased stability afforded by the NLC system, it is unclear how the drug will respond at physiological temperature.
Due to the limited number of studies, and the high heterogeneity in the type and formulation of the DDSs and the active substances assessed, it is currently unclear which nano-based DDSs are most effective for RP. The longest sustained release, with a reduced initial burst release, was observed with the use of PLGA microspheres. However, whether longer release time necessarily correlates to drug efficacy and disease treatment is unclear. Regardless, it can be concluded that DDSs, which successfully enhance residence time and the stability of potential therapeutic targets that have been previously limited in their use and modulate neuroprotective effects in the retina, are likely to show the most promise in clinical applications. Overall, all studies mentioned above conducted preliminary ex vivo, in vitro, and in vivo experiments. Therefore, there is a need for in-vivo models on bigger rodents with similar anatomy to the human eye to further elucidate the therapeutic efficacy in a way that can be clinically translatable for RP.

3. Age-Related Macular Degeneration and Choroidal Neovascularization

Age-related macular degeneration (AMD) is a prevalent eye disorder that affects individuals over the age of 50 and is a major contributor to vision loss and blindness among the elderly. The condition affects the macula and results in difficulties with tasks such as reading and facial recognition. AMD can be classified into two types: dry and wet. The dry form is the most common type and progresses gradually over time. The wet form, while less common, is more severe and results from the growth of abnormal blood vessels under the macula, which then leak fluid and blood, leading to a rapid decline in vision. There are various delivery targets for AMD, including reducing inflammation and drusen formations, improving RPE survival, inhibiting angiogenesis, as well as treating choroidal neovascularization (CNV) found in wet-AMD. In a clinical setting, the treatment for AMD depends on its severity and type. Dry AMD can be monitored and managed with nutritional supplements, while wet AMD typically requires regular intravitreal injections of anti-VEGF drugs [9][10].
Anti-VEGF therapy has been one of the most common therapies for treating wet-AMD and CNV, and nano-based DDS systems to improve its delivery will be extensively reviewed in the next sections. However, one-third of patients respond poorly to anti-VEGF based treatments, and there are potential vision-threatening complications such as endophthalmitis or retinal detachment. Intravitreal injections of anti-VEGF also heavily rely on a patient’s compliance

[11][12]

. Therefore, there is a need for optimizing therapies targeting the inflammation, degeneration, and development of the neovascularisation.
There have been efforts in creating biomimetic nano-based DDSs to improve targeted delivery to CNV lesion sites in the eyes of AMD patients. Zhang et al. used mesenchymal stem cells (MSCs) to carry PLGA nanoparticles loaded with HIF-1α siRNA. Inhibiting HIF-1α can reduce a variety of pro-angiogenic factors working upstream of VEGF

[13]

.
Given that hypoxia plays a major role in the pathogenesis of CNV, the study was conducted within a hypoxic environment. MSCs were able to target CNV lesion sites in this environment with the biodegradable nanoparticles improving the drug-carrying capacity and sustained release. Drug delivery through stem cell loading reached clinical trials in several cases, including apoptotic-inducing factors and oncolytic viruses, holding promise for MSC-guided delivery in retinal disorders

[14]

. Here, a compounded benefit is observed in which combination therapy overcomes the individual barriers to each component. siRNA alone is prone to RNAse enzymatic degradation, but encapsulation in PLGA NPs has proven protective for siRNA. Likewise, MSCs alone have poor drug carrier capacity due to poor drug loading, which can be ameliorated with the engineering of MSCs with NPs, enhancing drug loading and therapeutic efficacy. The PLGA NPs-loaded HIF siRNA effectively decreases expression of HIF-1α for 7 days in retinal pigment epithelial (RPE) cells. However, no significant difference was observed in the proliferation, apoptosis, or migration of RPEs when compared to control groups, suggesting that more work is needed to characterize how well MSC-guided delivery translates to physiological and functional improvement. Overall, this formulation requires further optimization and safety testing on animals to ensure a therapeutic benefit for AMD and CNV.
To treat CNV intravenously, Xia et al. provide another biomimetic DDS using macrophages to disguise PLGA nanoparticles loaded with rapamycin

[9]

. Rapamycin is an mTOR inhibitor that is known to suppress inflammation, enhance the dysregulated autophagy observed in AMD, and act upstream to VEGF-mediated inhibition of angiogenesis. Although a promising therapeutic drug for AMD, rapamycin’s low water solubility and poor accumulation at lesion sites have historically limited its use. Using the knowledge that macrophages are generally recruited to areas of RPE atrophy and CNV lesions, Xia et al. applied this to deliver PLGA-rapamycin nanoparticles intravenously in a laser-induced CNV mouse model. PLGA, as a hydrophobic drug carrier, opens the door to several potential drugs with limited water solubility despite an initial promise. The drug successfully traversed the impaired BRB, improved the bioavailability of rapamycin, and, along with anti-angiogenic effects, contributed to suppressed neovascularization. Rapamycin delivery also suppressed inflammation and enhanced autophagy both in vitro and in vivo in a CNV mouse model. Xia et al. carefully parsed out the mechanisms of action of macrophage-guided drug delivery and subsequent impact on the retinal microenvironment successfully, and characterized both in vitro and in vivo behaviour, paving the way for future clinical work to characterize the use of this formulation more effectively in humans. Using biomimetic carriers could, therefore, provide an alternative way to improve posterior ocular delivery. Rapamycin was also delivered intravitreally using synthetic high-density lipoprotein (sHDL) nanoparticles in a study by Mei et al. [10]. They particularly focused on a treatment for dry AMD, using rapamycin to suppress inflammation through the inhibition of NF-κB, as well as enhance autophagy, and using sHDL to also reduce lipid deposition, contributing to drusen formation. This DDS altogether provided a non-toxic, synergistic, anti-inflammatory effect and improved the bioavailability and distribution of rapamycin to the RPE layer following intravitreal administration in rats, with as much as a 125-fold increase in drug aqueous concentration. Combined with the observed benefits of macrophage-guided rapamycin delivery, it can be said that rapamycin is a promising drug for AMD and CNV, both because of its influence on VEGF production as well as the general effects on apoptosis, autophagy, and inflammation. This study also highlights the benefits of combined therapy, as sHDL itself had protective effects through the removal of excess cholesterol alongside its role as the nanocarrier. It also circles back to the influence of nanocarriers in effectively delivering hydrophobic drugs in largely hydrophilic environments, such as the ocular environment. However, it should be noted that neither study exploring rapamycin efficacy has explored the longevity of their formulations and the effects of long-term delivery of rapamycin in the posterior eye segment. Further studies using disease animal models are also needed to validate therapeutic efficacy and modify these therapies for clinical translation. Moreover, there are adverse side effects associated with frequent intravitreal injections.
Oxidative stress and the production of reactive oxidative species (ROS) have also been implicated in the pathophysiology and progression of AMD, thus targeting ROS production to initiate antioxidative effects. To explore this, Nguyen et al. intravitreally co-delivered resveratrol and metformin using poly(ε-caprolactone) (PCL) nanoparticles as a potential therapy for wet AMD [15]. Combined with metformin’s anti-angiogenic effects, resveratrol has been noted to provide antioxidant and anti-inflammatory effects. Due to the multifaceted effects of ROS-initiated RPE damage, therapies that can simultaneously target several components at once are highly desirable. The advantages of PCL, including its biodegradability, are mentioned, where PCL is not only considered more biocompatible in the RPE regions, but its degraded by-products are less acidic when compared to PLGA and PLA, which result in the build-up of lactic acid, avoiding unnecessary associated inflammation. It is also FDA-approved, thus easing progression in clinical trials. The polymer was further modified with cell-penetrating peptides (CPPs) to significantly improve retinal permeability. A sustained release for up to 56 days, as well as therapeutic effects, were observed in a rat model of AMD. This study provides a foundation for future long-term efficacy and safety studies. Another co-delivery system was suggested by Lai et al. for berberine hydrochloride and chrysophanol, which possesses potent antioxidant, anti-angiogenic, and anti-inflammatory properties

[16]

. These drugs have demonstrated potential in the treatment of AMD in animal studies. Previously limited in their application due to poor stability and bioavailability, Lai et al. proposed using polyamidoamine dendrimers (PAMAM) and liposomes to effectively deliver berberine hydrochloride and chrysophanol to the retina. PAMAM acts as an external coating for the compound-loaded liposomes due to its high water-binding ability and low toxicity. In comparison to uncoated compound liposomes, this coated DDS revealed a negative zeta potential, which is preferred for drug delivery to the retina, and significantly improved encapsulation efficiency, demonstrating that PAMAM coating enhanced drug loading. Results show considerable cellular permeability and increased bio-adhesion on corneal epithelial cells. PAMAM-liposome systems (P-CBLs) also substantially improved berberine hydrochloride bioavailability. Further, no side effects were observed on rabbit ocular surface structure after the administration of P-CBLs. While the drugs exhibited stability for 7 h in vivo, the study did not assess the release profiles of the drugs in the posterior segment of the eye, leaving questions regarding the functionality of this DDS in AMD. Regardless, the P-CBL system displays a potential use for treating AMD and, potentially, other ocular diseases.
Oxidative stress and the production of reactive oxidative species (ROS) have also been implicated in the pathophysiology and progression of AMD. Thus, targeting ROS production to initiate antioxidative effects. To explore this, Nguyen et al. intravitreally co-delivered resveratrol and metformin using poly(ε-caprolactone) (PCL) nanoparticles as a potential therapy for wet AMD

[15]

. Combined with metformin’s anti-angiogenic effects, resveratrol has been noted to provide antioxidant and anti-inflammatory effects. Due to the multifaceted effects of ROS-initiated RPE damage, therapies that can simultaneously target several components at once are highly desirable. The advantages of PCL, including its biodegradability, are mentioned, where PCL is not only considered more biocompatible in the RPE regions, but its degraded by-products are less acidic when compared to PLGA and PLA, which result in build-up of lactic acid, avoiding unnecessary associated inflammation. It is also FDA-approved, thus easing progression in clinical trials. The polymer was further modified with cell-penetrating peptides (CPPs) to significantly improve retinal permeability. A sustained release for up to 56 days, as well as therapeutic effects, were observed in a rat model of AMD. This study provides a foundation for future long-term efficacy and safety studies. Another co-delivery system was suggested by Lai et al. for berberine hydrochloride and chrysophanol, which possesses potent antioxidant, anti-angiogenic, and anti-inflammatory properties [16]. These drugs have demonstrated potential in the treatment of AMD in animal studies. Previously limited in their application due to poor stability and bioavailability, Lai et al. proposed using polyamidoamine dendrimers (PAMAM) and liposomes to effectively deliver berberine hydrochloride and chrysophanol to the retina. PAMAM acts as an external coating for the compound-loaded liposomes due to its high water-binding ability and low toxicity. In comparison to uncoated compound liposomes, this coated DDS revealed a negative zeta potential, which is preferred for drug delivery to the retina and significantly improved encapsulation efficiency, demonstrating that PAMAM coating enhanced drug loading. Results show considerable cellular permeability and increased bio-adhesion on corneal epithelial cells. PAMAM-liposome systems (P-CBLs) also substantially improved berberine hydrochloride bioavailability. Further, no side effects were observed on the rabbit ocular surface structure after the administration of P-CBLs. While the drugs exhibited stability for 7 h in vivo, the study did not assess the release profiles of the drugs in the posterior segment of the eye, leaving questions regarding the functionality of this DDS in AMD. Regardless, the P-CBL system displays a potential use for treating AMD and, potentially, other ocular diseases.

4. Diabetic Retinopathy

Diabetic retinopathy is a chronic ocular condition affecting diabetic patients. The condition results from damage to the blood vessels in the retina and can progress over time. There are two main stages of diabetic retinopathy: non-proliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR). NPDR is characterized by increased vascular permeability and capillary occlusion, and can lead to the formation of microaneurysms, dot and blot hemorrhages, cotton wool spots, and hard exudates. PDR occurs in advanced stages of diabetic retinopathy due to continued damage to the retinal blood vessels, leading to significant retinal ischemia. The ischemic retinal tissue releases pro-angiogenic factors, including the vascular endothelial growth factor (VEGF), which stimulates the production of new and abnormal blood vessels. These neo-vessels can lead to various vision-threatening complications, such as a neovascularization of the disc and retina causing vitreous hemorrhage and tractional retinal detachment, and neovascularization of the iris and angle resulting in glaucoma. The management of Proliferative Diabetic Retinopathy primarily focuses on reducing the production of VEGF by ischemic tissue through laser photocoagulation or intravitreal anti-VEGF injections.
Antioxidants, anti-inflammatory agents, and neurotrophic factors are considered promising options to treat the neuronal and vascular abnormalities that progress with diabetic retinopathy (DR) [17]. Nano-carriers have been proposed to improve the targeting of the diabetic retina. Due to their high biocompatibility, PLGA-based nanoparticles have been used to improve the therapeutic efficacy of drugs that are currently limited due to inefficient delivery routes. For example, Zeng et al. used PLGA nanoparticles to deliver Interleukin-12 (IL-12), a cytokine that can diminish the levels of matrix metalloproteinase-9 (MMP-9) and VEGF-A, both of which are known to affect the severity of diabetic retinopathy

[18]

. Previously limited due to it being prone to rapid degradation, when IL-12 was carried by PLGA nanoparticles (IL-12-PNP), it had an appreciable drug encapsulation efficiency (~34.7%) and prolonged drug release. IL-12-PNP exhibited better inhibition against VEGF-A and MMP-9 expression in diabetic retinopathic mouse retina and rat endothelial cells. Moreover, this treatment resulted in significantly decreased retinal damage in a DR mouse model with increased thickness and reduced neovascularization. Similarly, Romeo et al. proposed to deliver melatonin with PLGA-PEG Lipid-polymer hybrid nanoparticles (LPHN)

[19]

. Melatonin offers various neuroprotective strategies suitable for treating this DR. However, at high doses, it may compromise retina morphology and functioning. The DDS developed in this study targeted the retina without unnecessary high dosages to deliver melatonin. Using a biodegradable polymer, they found no signs of cytotoxicity or ocular irritation in vivo and confirmed neuroprotective and antioxidant effects on a model of glucose-induced diabetic retinopathy on Human Retinal Endothelial Cells (HREC). They also observed high encapsulation efficacy (79.8%) using this hybrid model, suggesting its superiority to a PLGA only nanoparticle. In previous work, the neuroprotective effects of melatonin have been observed only after prolonged exposure of greater than 72 h, necessitating a stable, sustained release DDS for its ocular delivery. Romeo et al. successfully observed a prolonged and sustained release for up to 8 days compared to a rapid burst release of free melatonin.
Another example of a lipid-modified nanoparticle system is a study by Zingale et al., where they used nanostructured lipid carriers (NLCs) to deliver diosmin, a flavonoid known for its anti-inflammatory, cytoprotective, and antioxidant effects, especially in high glucose environments

[20]

. They were able to achieve a high encapsulation efficiency, and the DDS was found safe and well-tolerated in vitro. However, a common issue observed with using lipid-based nanocarriers is the need to use surfactants for their preparation that may cause irritation and a sensitizing action

[21]

. Further studies are being conducted to confirm the clinically relevant anti-inflammatory effects of diosmin NLCs. As mentioned above, NLCs have the advantage of minimal toxicity as it can be manufactured without the requirement of toxic organic solvents

[22]

. They can also be stored stably for long periods, as Zingale et al. observed stability under different storage conditions for up to 60 days. NLCs further possess the versatility of being applied as topical eye drops as demonstrated here and also by Platania et al., which greatly increases patient compliance

[6]

. What’s currently unclear and garners further exploration is the release profiles of drug-loaded NLCs, to better assess how often administration is required.
Other types of biodegradable nanoparticles have also been assessed for optimizing treatments for diabetic retinopathy. Radwan et al. investigated an alternative non-invasive delivery with an anti-VEGF factor, apatinib, encapsulated into bovine serum albumin nanoparticles, which are coated with hyaluronic acid [23]. With a relatively high entrapment efficiency (~69%), these apatinib-loaded nanoparticles (Apa-HA-BSA-NPs) illustrated a sustained biphasic release rate with an initial burst, appreciable mucoadhesion, and no cytotoxicity were detected on rabbit corneal epithelial cells. This 2021 study indicated improved retinal thickness and lessen retinal microstructural and ultrastructural changes in Apa–HA–BSA–NP-treated eyes. Moreover, the authors observed better retinal accumulation through this topical treatment while avoiding ocular complications resulting from frequent intravitreal injections. As aforementioned in the AMD section, using PCL as a biodegradable polymer for nanoparticle systems has many advantages

[15]

. For diabetic retinopathy, Mahaling et al. developed nanoparticles with a hydrophobic polycaprolactone (PCL) core and a hydrophilic Pluronic® F68 shell, containing triamcinolone acetonide [24]. TA has demonstrated efficacy in both NPDR and PDR, attributed to its anti-inflammatory, anti-angiogenic, and neuroprotective properties. Likewise, NPs containing PCL and PF68 have previously demonstrated strong bioavailability in retina during topical administration

[25]

. In a DR rat model, a topical administration of these nanoparticles resulted in significant structural improvements, particularly retinal thickness and vascular health, as well as functional improvements. The authors found diminished retinal inflammation, decreased glial cell hyperplasia, and reduced microvascular complications. These findings demonstrate the potential of a triamcinolone acetonide-loaded nanoparticle delivery system in the treatment of diabetic retinopathy. Topical administration has observed significant success in DR animal models, opening the door to non-invasive, patient self-administered delivery routes. This overcomes several challenges of intravitreal administration, including intraocular bleeding, increased intraocular pressure, endophthalmitis, and discomfort.

5. Diabetic Macular Edema (DME)

Diabetic macular edema (DME) is a common complication in diabetic retinopathy where fluid accumulates in the macula causing rapidly progressive decrease in visual acuity. It occurs due to increased permeability and inflammation in the retinal vessels

[17]

.
Other than intravitreal anti-VEGF injection and topical NSAIDs, intravitreal triamcinolone acetonide (TA) can sometimes be used to reduce associated inflammation with DME. However, intravitreal triamcinolone is associated with excessively high rates of complications, such as IOP elevation and cataract formation. Navarro–Partida et al. provided a topical route for delivering TA by loading it on liposomes [26]. This was a feasibility study, where they first found TA-loaded liposomes to be safe and tolerable in healthy patients through a Phase 1 clinical assay. They further presented a sustained therapeutic effect of reduced central fovea thickness (CFT) in DME patients through an open-label, non-randomized study. Further studies are required to confirm the long-term safety and therapeutic efficacy, such as ensuring TA at high concentrations does not adversely affect intraocular morphology and function

[27]

. To improve the biodegradability and mucoadhesion of liposomes, Khalil et al. used chitosan-coated liposomes to deliver TA to the posterior segment

[28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80][81][82][83][84][85][86][87][88][89][90][91][92][93][94][95][96][97][98][99][100][101][102][103][104][105][106][107][108][109][110][111][112][113][114][115][116][117][118][119][120][121][122][123][124][125][126][127][128][129][130][131][132][133][134][135][136][137][138][139][140][141][142][143][144][145][146][147][148][149][150][151][152][153][154][155][156][157][158][159][160][161][162][163][164][165][166][167][168][169][170][171][172][173][174][175][176][177][178][179][180][181][182][183][184][185][186][187][188][189][190][191][192][193][194][195][196][197][198][199]

. This enhanced bioavailability and prolonged the release of TA in their in vivo models. Although their efficiency of drug release was done on a CNV rat model, the authors recommend this DDS for any posterior segment disease, particularly highlighting DME, proliferative diabetic retinopathy, and CNV related to AMD. Further in vivo studies are required to validate the therapeutic efficacy of this DDS, ensuring its clinical significance. Initial clinical success with TA topical administration in lipid-based nanomaterial has further supported both the superiority of lipid-based DDSs and topical administration in ocular drug delivery. Khalil et al. further demonstrate the flexibility afforded by nano-based DDS, as base constructs, such as liposomes, can be modified to improve retention time, permeability, encapsulation efficiency, and personalize treatment to the drug, disease, and area of interest.

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