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. 

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.

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

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.

 

2. Retinitis Pigmentosa

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][1].

Arranz-Romera et al. used PLGA microspheres to co-deliver GDNF and TUDCA for promoting neuronal survival in retinal degeneration models [71][2]. 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][3]. 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][4]. 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][5]. 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.

 

3. Age-Related Macular Degeneration and Choroidal Neovascularization

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][6][7].

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][8][9]. 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][10].

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 restudyearch 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][11]. 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][12]. 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][11]. 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][12]. 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.

 

4. Diabetic Retinopathy

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][13]. 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][14]. 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][15], 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 restudyearch 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][16]. 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][17]. 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][18]. They can also be applied as topical eye drops, as demonstrated by Platania et al. [74][4], 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][19]. 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][20]. 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][21].

 

5. Diabetic Macular Edema (DME)

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][13].

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.

 

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