Advanced DDS for Delivering Anti-VEGF Agents: Comparison
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The treatment of posterior segment eye diseases is challenging due to the complex anatomy of the eye, which limits the effective delivery of medications. Conventional treatments such as topical eye drops and intravitreal injections have poor bioavailability and short residence time, requiring frequent dosing. Biodegradable nano-based drug delivery systems (DDSs) offer a potential solution to these limitations, with longer residence time in ocular tissues and better penetration through ocular barriers. These DDSs use biodegradable polymers that are nanosized, reducing the risk of toxicity and adverse reactions.

The treatment of posterior segment eye diseases is challenging due to the complex anatomy of the eye, which limits the effective delivery of medications. Conventional treatments such as topical eye drops and intravitreal injections have poor bioavailability and short residence time, requiring frequent dosing. Biodegradable nano-based drug delivery systems (DDSs) offer a potential solution to these limitations, with longer residence time in ocular tissues and better penetration through ocular barriers. These DDSs use biodegradable polymers that are nanosized, reducing the risk of toxicity and adverse reactions.

In this review, we provide a comprehensive overview of the latest advances in biodegradable nano-based DDSs for treating posterior segment diseases, examining current therapeutic challenges and exploring various types of biodegradable nanocarriers (Figure 1). Our review includes pre-clinical and clinical studies published between 2017 and 2022, highlighting the potential of these systems to enhance treatment outcomes. With advancing biodegradable materials and improved understanding of ocular pharmacology, nano-based DDSs hold great promise for overcoming obstacles encountered by ophthalmologists. 

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

1. Anti-VEGF Agents

Anti-VEGF Agents

Pathological neovascularization is involved in various retinal diseases, including proliferative diabetic retinopathy (PDR), retinopathy of prematurity (RoP), and retinal vein occlusion (RVO), caused by retinal hypoxia [101,102]. On the other hand, choroidal neovascularization (CNV) is often caused by a ruptured or damaged Bruch’s membrane and is associated with various retinal disorders, such as wet age-related macular degeneration, pathologic myopia, presumed ocular histoplasmosis syndrome (POHS), and traumatic choroidal rupture [103]. Anti-VEGF agents are the gold standard treatment for ocular neovascular diseases, including PDR, RoP, RVO, and CNV. Bevacizumab (Avastin™), Ranibizumab (Lucentis™), Aflibercept (Eylea™), and Pegaptanib (Macugen®) are commonly used anti-VEGF drugs [104]. These monoclonal antibodies target retinal and choroidal endothelial cells to stop angiogenesis. However, their large size limits their penetration through ocular barriers, resulting in poor bioavailability and the need for frequent intravitreal injections [104].

Non-degradable implants have been suggested as an alternative for anti-VEGF delivery. However, they have some drawbacks. Although they provide long-term drug release, their removal requires secondary surgery, which is associated with additional risks and potential complications. Additionally, these implants can cause several issues, such as impacting the visual axis due to their large size and migration to the anterior chamber, leading to corneal edema and permanent endothelial decompensation caused by direct contact with the endothelium, mechanical trauma, or chemical toxicity [105].

The use of biodegradable nanocarriers for sustained-release of anti-VEGF drugs presents a potentially favorable option for enhancing the efficacy, bioavailability, bioactivity, duration of action, and safety of treatment, while minimizing the adverse effects associated with non-degradable implants. These carriers utilize biopolymers that can be gradually degraded within the eye, eliminating the need for a second surgery, and their release rate can be adjusted by modifying the composition and molecular weight of the carrier. Additionally, the small size of these carriers ensures optical clarity and reduces the risk of visual disturbances. A comprehensive overview of the latest and most pertinent studies on biodegradable nanocarriers can be found in Table 2, offering valuable insights and key findings. [105]

The most commonly used anti-VEGF drugs in ocular drug delivery systems are bevacizumab, aflibercept, and ranibizumab [106]. Bevacizumab is frequently used in studies and for wet-AMD due to its well-known toxicity and pharmacokinetic characteristics [107]. Aflibercept and ranibizumab are also used for treating wet-AMD. Aflibercept is a potent drug that requires less frequent dosing and may improve patient adherence, but there are concerns about rare but severe adverse effects [108]. It is also more expensive than bevacizumab, which may explain why it is not commonly used in current clinical practice.

 

Novel DDS for Anti-VEGF Agents

Nanocarriers, which can be lipid-based, polymers, or inorganic nanoparticles, present advantages and challenges, and can be classified according to their material components. However, protecting anti-VEGF agents from conformational changes and preserving their bioactivity while minimizing interaction with the nanocarrier is still a challenge, as too strong interactions can compromise drug capture and release processes and lead to protein denaturation [109].

 

Hydrogel

Hydrogel nanocarriers are a promising option for drug delivery due to their unique properties. They are three-dimensional polymer networks with a porous structure that can interact with water-soluble molecules. Despite a high initial burst of drug release, they are biocompatible, biodegradable, and safe. Hydrogel nanocarriers can carry water molecules while remaining in a solid state, and are known to maintain drug stability. However, their delicate structure can be affected by sterilization processes.

Hydrogels that can change their properties in response to environmental triggers, such as pH or temperature changes, are often referred to as “smart” hydrogels [112]. In a study by Osswald et al., a thermoresponsive hydrogel composed of suspended PLGA microspheres was developed to carry ranibizumab and aflibercept [113]. The addition of microspheres in the hydrogel resulted in extended drug release by 27.2%, with the DDS remaining bioactive for 196 days in vitro. The DDS showed promising results in inhibiting human umbilical vein endothelial cell (HUVEC) proliferation, which prompted further experiments on in vivo models. In a subsequent study on laser-induced rat CNV models, the nanotherapeutic significantly reduced CNV lesion areas by 60% compared to the control group in vivo [114]. Over the course of 12-week treatment, less drugs were needed in the novel nanotherapeutics compared to the standard posology delivered via bolus administration. However, it is important to note that the small animal samples per treatment group, which was of four eyes, limited the results. The potential advantages of this DDS over standard treatment include limiting toxicity related to high drug dosage.

Hu et al. developed a thermoresponsive mPEG-PLGA-BOX hydrogel to test the efficacy of bevacizumab in inhibiting angiogenesis induced by retinal laser photocoagulation [115]. The hydrogel transitioned from a solution phase to a gel-phase after body temperature exposure, and both in vitro and in Rex rabbits, it successfully inhibited angiogenesis for 35 days while maintaining the anti-angiogenic bioactivity of bevacizumab. No cytotoxic effects were reported during nanocarrier biodegradation in the rabbits. Although this study was conducted on only 11 Rex rabbits divided into two groups, the results are promising, demonstrating the potential of DDS as a novel therapeutic gelling carrier against angiogenesis.

Xue et al. developed a thermoresponsive hydrogel made of PED–PPG–PCL and encapsulated bevacizumab and aflibercept [116]. In vitro tests on HUVEC showed that both drugs significantly inhibited proliferation. Ex vivo choroidal sprouting model studies also showed that both drugs, when independently injected with the nanocarrier, significantly reduced the relative sprouting percentage by more than 80%. Anti-angiogenic effects were observed ex vivo and in vivo in a persistent retinal neovascularization rabbit model. The drug release rate was extended by fine-tuning the hydrophilic/lipophilic ratio of the hydrogel, with the longest drug release of 40 days in vitro and at least 28 days in vivo achieved by increasing the hydrogel concentration to 20 weight percent with an optimized PEG/PPG ratio of 4:1. This DDS has a prolonged drug release rate that can be extended via polymer fine-tuning and represents a promising bioactive drug carrier.

Studies on the use of thermoresponsive hydrogels as drug delivery systems (DDS) have yielded optimistic results in vitro and in vivo, although for limited time periods. For instance, Liu et al. investigated the use of a thermoresponsive hydrogel to deliver bevacizumab over six months in vitro using PGLA in a PEG–PLLA–DA/NIPAAm hydrogel loaded with ranibizumab [38]. By optimizing the cross-linker concentration and microsphere load quantity, the hydrogel achieved enhanced biodegradability, drug release, and needle-injection feasibility. The hydrogel was effective in vitro for 190 days and was also tested with aflibercept in vitro, which was successfully released for six months while maintaining bioactive therapeutic levels [117]. The biodegradable cross-linker PEG–PLLA–DA prolonged the hydrogel nanocarrier degradation. Liu et al. further evaluated the nanotherapeutic's efficacy by intravitreally injecting it into a laser-induced CNV rat model, where it proved as effective as bimonthly aflibercept injections for six consecutive months, while avoiding inflammation and ocular complications [118]. This nanotherapeutic showed promising results on the rodent eye model, but its applicability to humans may be limited by anatomical differences and potential differences in drug pharmacokinetics and immune reactions.

Fan et al. demonstrated a promising approach for delivering conbercept, a novel anti-VEGF drug with a short half-life, using a short chain pH-sensitive peptide hydrogel DDS in vitro [119]. The nano-based DDS inhibited HREC proliferation and tube formation, indicating its potential therapeutic application for neovascular AMD. Moreover, the hydrogel peptide nanocarrier demonstrated good biocompatibility with HRECs. However, further in vivo studies are necessary to determine the pharmacokinetics of the DDS, and therefore, the results remain preliminary.

Li et al. developed an injectable hydrogel (cSA@Lip-HAC) loaded with sunitinib and acriflavine liposomes, which demonstrated high antiangiogenic properties in vitro and increased drug residency in vivo [120]. The combination of co-drug-loaded liposomes in the hydrogel and subtenon administration route led to increased efficacy and significant anti-CNV results. The DDS remained active for 21 days in vivo, showing promise for a novel therapeutic avenue with fewer complications than with the intravitreal route. However, the limited time of the DDS may affect patient compliance, and further investigation is necessary to extend its duration of activity.

 

Polymers Nanoparticles and Microparticles (MPs)

Polymers have become the most widely studied drug delivery system for anti-VEGF drugs in recent years due to their versatility and tunability. They can encapsulate a wide range of hydrophilic and hydrophobic molecules, from peptides to biological macromolecules. Their pharmacokinetic characteristics can be adjusted by modifying their composition, ratios, and combining different biomaterials. Polymers offer several advantages, including biodegradability, non-toxicity, and the ability to customize their environmental, release, and retention rate features. They can be natural, synthetic, or a combination thereof. The most successful formulas are bevacizumab-loaded PLGA and chitosan-based nanoparticles.

PLGA-based nanocarriers are a versatile and promising synthetic option for drug delivery, owing to their biocompatibility, nontoxicity, degradability, and FDA-approved status. They consist of a hydrophobic core for carrying the drug and a hydrophilic outer shell (corona) that controls drug release. This amphiphilic nature makes them compatible with a wide range of drugs, enhancing their utility.

In vitro studies have shown that PLGA microspheres developed by Tanetsugu et al. can deliver ranibizumab biosimilar with more than 80% drug release achieved after three weeks [121]. Additionally, the DDS has been observed to inhibit tube formation in HUVECs. The microsphere fully degrades within 1.5 months, making it a promising candidate for prolonged anti-VEGF drug release treatment.

Sousa et al. developed PLGA-based nanoparticles loaded with bevacizumab, which showed a prolonged drug release time and preserved drug bioactivity in vitro [122, 123]. They also demonstrated that bevacizumab could be stored for over 6 months while retaining its angiogenic effect using a lyophilized protocol. In another study, Zhang et al. encapsulated bevacizumab in PLGA-based nanoparticles, which were more efficient than free bevacizumab in inhibiting HUVEC proliferation and tube formation in vitro [124]. In vivo experiments on mouse models showed increased drug bioactivity in inhibiting CNV and RNV angiogenesis, with no reported toxicity or cytotoxicity. These findings suggest that PLGA-based nanoparticles loaded with bevacizumab may represent a safe and effective treatment option.

Kelly et al. investigated the use of PLGA nanoparticles to deliver aflibercept for retinal diseases treatment [125]. The study demonstrated that the DDS exhibited high encapsulation efficacy and prolonged drug release up to seven days. On day seven, 75% of the drug was released with the DDS, compared to 100% drug release after 24 h following a standard aflibercept injection. These results show the potential of the polymer as a promising nanocarrier for delivering aflibercept.

Nanocarriers have been shown to improve anti-CNV activity. Yan et al. developed a novel nanocarrier for AMD treatment composed of PLGA-PEGylated magnetic nanoparticles, which demonstrated increased antiangiogenic efficacy [126]. The magnetic nanoparticles conferred several advantages to the DDS, such as stability, biocompatibility, and tunable surface modification. Additionally, the PEG-PLGA copolymer tested in vitro showed effective antiangiogenic activity, making this DDS a promising therapy for AMD.

Liu et al. demonstrated the potential benefits of combining multiple drugs within nanocarriers. They developed a novel poly (D, L-lactide-co-glycolide) and polyethylenimine nanoparticle that was loaded with dexamethasone and had bevacizumab added to the nanoparticle surface (eBev-DPPNs) [127]. The eBev-DPPNs were shown to effectively inhibit HUVECs angiogenesis and VEGF secretion in vitro. Furthermore, when injected intravitreally in rabbit laser models of CNV, the nanotherapeutic significantly decreased CNV leakage areas after 28 days. This demonstrates the potential of this DDS in treating CNV in vivo.

Heljak et al. developed a computational model to predict the behavior of intravitreally injected PLGA bevacizumab loaded microspheres, complementing the in vivo and in vitro studies [128]. The model successfully predicted the experimental results, indicating its potential for assessing and planning anti-VEGF treatments in clinical settings.

PLGA-based nanocarriers have shown promise for prolonged drug release. However, degradation of PLGA microspheres due to accumulation of lactic and glycolic acids can denature the drug, leading to complications. To address this issue, Liu et al. prepared a polymeric blend of poly (d, l-lactide-co-glycolide)/poly(cyclohexane-1,4-diyl acetone dimethylene ketal) (PLGA/PCADK) to deliver bevacizumab-dextran using a solid-in-oil-in-water (S/O/W) emulsification technique [129]. This novel polymer blend demonstrated increased biocompatibility compared to PLGA alone and limited the initial burst release to ensure sustained drug release. The DDS delivered drugs over a 50-day period in vitro and in vivo in a rabbit model, demonstrating the potential for this nanocarrier to become a long-term anti-VEGF treatment option.

Tsujinaka et al. developed a promising nanocarrier by using a polymer blend of PLGA-PEG to deliver sunitinib [130]. After intravitreal injection, the DDS formed a depot that impressively released drug for 6 months in a laser-induced CNV mouse model, which successfully suppressed CNV over the drug release period. The nanotherapeutic also showed potential in progressive DR therapy as it reduced VEGF-induced leukostasis and nonperfusion in a different mouse model.

Jiang et al. explored the use of polydopamine (PDA) nanoparticles as a nanocarrier for bevacizumab to treat AMD [131]. In addition to its antiangiogenic activity, the biodegradable nanocarrier reduced reactive oxygen species (ROS) and successfully delivered bevacizumab in vitro and on ex-vivo porcine eyes. The DDS has the potential to become a practical dual system for delivering antiangiogenic drugs while minimizing ROS production.

Cai et al. developed a novel drug delivery system (DDS) using modified S-PEG polymers with arginine-glycine-aspartic acid (RGD) peptide to deliver anti-VEGF agents intravenously [132]. The nanoparticles exhibited antiangiogenic activity in vitro and effectively decreased CNV lesion areas in laser-induced CNV mouse models. Moreover, the nanoparticles displayed good specificity by spending minimal time in the entire organism and by not accumulating in organs other than CNV areas, indicating their biosafety.

Natural polymers are attractive candidates for anti-VEGF nanocarriers due to their easy degradability. Although the intravitreal route remains the most common method of anti-VEGF administration, HSA nanoparticles have been explored as a potential topical route for drug delivery. HSA nanoparticles are simple to prepare and adhere well to the corneal epithelium, resulting in sustained drug bioavailability without any reported toxicity. In a study by Luis de Redin et al., bevacizumab was loaded onto HSA nanoparticles, resulting in a 13% increase in loading capacity compared to nanoparticles cross-linked with glutaraldehyde. The initial burst release of the drug was evaluated to 35% of the loaded drug within the first five minutes in vitro, with a decreased rate over the next 24 hours. In rats, the DDS was released over 4 hours before being evacuated in the gastrointestinal tract. In vivo, bevacizumab-nanoparticles showed a better antiangiogenic activity in CNV rat models than bevacizumab alone, reducing the required drug dosage by 2.4 times. The nanoparticles also significantly improved bevacizumab neovascularization inhibiting efficacy and decreased fibrosis, inflammation, and edema in rats treated with them. Although the results of this study are promising, further validation on animal models that can be easily transposed to human eye anatomy is necessary.

Llabot et al. also investigated the use of HSA nanoparticles to deliver anti-VEGF agents topically, but with the addition of Gantrez® ES-425 polymer as a stabilizing coating [135]. The nanoparticles were tested in vitro and designed to treat CNV. Gantrez® polymer was found to be a better stabilizing agent than glutaraldehyde, with improved drug stability and preserved bioactivity. In vitro release studies showed that suramin was released faster than bevacizumab, with 80% released within 8 h compared to 50% for bevacizumab. In vivo animal studies for CNV treatment with these nanoparticles are yet to be conducted.

Abdi et al. investigated the potential of chitosan nanoparticles as a carrier for bevacizumab and found that the two had minimal interactions, allowing for efficient capture and release of the drug. The study suggested that the combination of bevacizumab and chitosan nanoparticles could be a promising nanocarrier approach.

Several studies have utilized chitosan nanoparticles as a drug delivery system (DDS) for sustained drug release. Pandit et al. developed a subconjunctival injection of bevacizumab loaded PLGA nanoparticles coated with chitosan, which reduced initial drug burst release to 25%. In vitro studies showed that the DDS extended drug residency in the retina and sustained drug release for 72 h. Similarly, Ugurlu et al. administered chitosan particles loaded with bevacizumab through subtenon injection in rabbits’ eyes, resulting in a sustained drug release for 3 weeks in vitro. However, in vivo results decreased within one week despite better control and progressive drug release from the DDS. Savin et al. synthesized bevacizumab loaded chitosan grafted-poly(ethylene glycol) methacrylate nanoparticles, which successfully released bevacizumab in vitro for 14-30 days. Overall, chitosan nanoparticles have shown promise as a suitable DDS for sustained drug release.

Jiang et al. developed a chitosan-based nanocarrier capable of releasing drugs over months to treat AMD. Their polycaprolactone (PLA) chitosan bi-layered hybrid shell capsule can load high drug amounts and impressively released drug over one year while preserving drug potency. Jian et al. also developed a novel DDS combining natural and synthetic polymers to carry bevacizumab in microparticles. Their chitosan-polycaprolactone core-shell microparticles increased loading capacity by 25% and decreased initial burst release to nearly 30%, while maintaining drug potency for six months. The nanotherapeutic was biocompatible with over 90% cell viability. In vivo studies remain needed to assess safety and drug efficacy.

Chaharband et al. investigated gene delivery therapy using chitosan-hyaluronic acid nano-polyplexes to deliver VEGFR-2 siRNA intravitreally in a rabbit and rat laser model of CNV [141]. The DDS was found to effectively suppress VEGFR-2 expression by 70% in vitro and significantly reduce CNV in vivo after 14 days. Although gene delivery therapy remains limited by the 1-month drug release threshold, the study suggests that the chitosan-hyaluronic acid nano-polyplexes could become an efficient intravitreal gene delivery therapy.

 

Lipid-Based

Formica et al. developed a hybrid lipid-based nanocapsule for co-loading bevacizumab and triamcinolone acetonide. This approach offers the potential for more effective treatment of diseases by reducing inflammation and neovascularization. The nanocarrier was shown to inhibit capillary formation in vitro, demonstrating its potential for loading multiple drugs [142].

Liposomes are a promising drug delivery system due to their hydrophilic core and hydrophobic outer shell that can be modified to improve tissue penetration. However, interactions with macrophages, pH changes, and enzymes can affect their performance, making it challenging to predict their physiological behavior accurately. In a study by Mu et al., multivesicular liposomes (MVLs) were used to encapsulate bevacizumab. The MVLs had a size ranging from 1 to 100 µm, which enabled them to avoid being captured by macrophages and to be rapidly degraded. The liposomes showed minimal toxicity, good biocompatibility, encapsulation efficacy, and low immunotoxicity. In vitro, bevacizumab was released by diffusion and erosion while maintaining its integral structure. In the laser-induced CNV rat model, the nanocarrier sustainably released the drug, and after 28 days of treatment, the DDS inhibited CNV lesions. Compared to bevacizumab solution, the DDS could potentially reduce the frequency of intravitreal injections.

Kayland Karumanchi et al. developed liposomes to encapsulate bevacizumab, achieving even longer drug release than previous studies. In vivo results showed that the DDS maintained therapeutic levels of the drug for 22 weeks, compared to less than 6 weeks for bevacizumab solution, while preserving drug potency. This suggests that liposomes have potential for prolonged and controlled drug release. [144]

Liposomes have also shown potential in cancer treatment. De Cristo Soares Alves et al. developed a chitosan-coated lipid core nanocapsule for the delivery of bevacizumab to treat solid tumors, such as glioblastoma [145]. In vitro studies showed that the drug-loaded nanocarrier induced significantly more apoptosis than bevacizumab alone. In addition, in the chicken embryo chorioallantoic membrane (CAM) assay, the nanocarrier required 5.6 times less bevacizumab than the bevacizumab solution to exhibit higher antiangiogenic effects. This suggests that the nanocarrier may reduce the toxicity and adverse effects associated with high drug doses. The results of this study suggest that this DDS has the potential to be used in the treatment of solid ocular tumors.

 

 

As highlighted in the previous section, pathological neovascularization plays a role in the underlying mechanism of various retinal diseases. This type of neovascularization is caused by retinal hypoxia and is involved in the pathophysiology of several retinal disorders, including proliferative diabetic retinopathy (PDR), retinopathy of prematurity (RoP), and retinal vein occlusion (RVO) [1][2]. On the other hand, CNV often occurs due to a ruptured or damaged Bruch’s membrane, which can be caused by various retinal disorders such as wet age-related macular degeneration, pathologic myopia, presumed ocular histoplasmosis syndrome (POHS), and traumatic choroidal rupture [3]. Anti-VEGF agents have emerged as the gold standard treatment to treat ocular neovascular diseases. Commonly used anti-VEGF drugs include Bevacizumab (Avastin™), Ranibizumab (Lucentis™), Aflibercept (Eylea™), and Pegaptanib (Macugen®). These drugs, which are monoclonal antibodies that target retinal and choroidal endothelial cells to stop angiogenesis, face a challenge in terms of bioavailability and targeted delivery. This is due to their large size, which makes it difficult for them to penetrate through ocular barriers such as the blood–aqueous barrier and blood–retinal barrier. Anti-VEGF agents have a short half-life and, thus, need to be administered regularly by intravitreal injections. The latter is associated with potential sight-threatening complications such as endophthalmitis and retinal detachment [4].
The use of non-degradable implants for anti-VEGF delivery has been proposed, but it has some drawbacks. While non-degradable implants can provide a long-term drug release, they require secondary surgery to remove the depleted material, which is associated with additional risks and potential complications. Moreover, these non-degradable implants have the potential to cause several issues. The large size of the non-biodegradable implant may impact the visual axis. There is also a risk of implant migration to the anterior chamber, which may lead to corneal edema and permanent endothelial decompensation caused by direct contact with the endothelium, mechanical trauma, or chemical toxicity [5].
The use of biodegradable nanocarriers minimizes the adverse effects associated with non-degradable implants containing anti-VEGF. These biodegradable, anti-VEGF sustained-release drugs utilize biopolymers to deliver the drug for sustained release. The carrier material is gradually degraded within the eye, eliminating the need for a second surgery, and the release rate can be adjusted by modifying the composition and molecular weight of the carrier. Furthermore, their small size allows for optical clarity and reduces the risk of visual disturbances [5]. In summary, biodegradable nanocarriers present, potentially, a favorable option for enhancing the efficacy, bioavailability, bioactivity, duration of action, and safety of anti-VEGF treatment.
The most used anti-VEGF drug in ocular DDS is bevacizumab, followed by aflibercept and ranibizumab [6]. Bevacizumab is the most used in the following studies, especially with wet-AMD, as it is also one of the oldest anti-VEGF drugs [7]. Therefore, its toxicity and pharmacokinetic characteristics are well-known. Aflibercept and ranibizumab are also used for treating wet-AMD. Aflibercept is the most potent drug and has been shown to require less frequent dosing due to its longer duration of action, which can be advantageous in terms of patient adherence. However, there are also some concerns about the rare but severe adverse effects related to its use [8]. It is also much more costly compared to bevacizumab. This may explain why it is not the most common anti-VEGF drug in the current clinical practice.

2. Novel DDS for Anti-VEGF Agents

Nanocarriers can be classified according to their material components: lipid-based, polymers and inorganic nanoparticles. Each class has its advantages and challenges. Anti-VEGF agents are sensitive to conformational changes, and their stability can be easily compromised by in vivo triggers. It remains a challenge to protect the drugs from protein denaturation while minimizing the interaction with the nanocarrier to preserve the drug’s bioactivity. If interactions are too strong, they can compromise drug capture and release processes [9].

2.1. Hydrogel

Hydrogel nanocarriers are three-dimensional polymer networks with porous structure. The polymers are hydrophilic and can, thus, interact with molecules that have a high-water solubility. Hydrogels possess the unique feature of carrying water molecules yet remain under a solid state [10]. Hydrogel emerged as a top nanocarrier choice for its excellent biocompatibility, biodegradability, and safety profile [11]. They are known to have a rapid high initial burst whereby 10–50% of the drug can be lost through diffusion [10]. Sterilization processes can affect their delicate structure [12].
Some hydrogels are referred to as “smart” because they can change their properties in response to environmental triggers, such as pH or temperature changes [13]. Osswald et al. previously developed a PNIPAAm–PEG–diacrylate thermoresponsive hydrogel composed of suspended PLGA microspheres to carry ranibizumab and aflibercept [14]. They discovered that by suspending the microspheres in the hydrogel, the drug release was extended by 27.2%. Therefore, the nano-based DDS successfully released ranibizumab, or aflibercept, for 196 days while remaining bioactive in vitro. Promising findings were obtained in vitro as the DDS inhibited human umbilical vein endothelial cell (HUVEC) proliferation. It, thus, encouraged the team to pursue experiments on in vivo models. Later in 2017, Osswald et al. published results on laser-induced rat CNV models [15]. The nanotherapeutic significantly reduced CNV lesion areas by 60% compared to the control group in vivo. Over the course of 12-week treatment, less drugs were needed in the novel nanotherapeutics compared to the standard posology delivered via bolus administration. While this DDS could become advantageous compared to the standard treatment by limiting toxicity related to high drug dosage, it is important to highlight the small animal samples per treatment group, which was of four eyes. The results are, thus, limited.
Similarly, Hu et al. tested bevacizumab in a synthesized thermoresponsive mPEG–PLGA–BOX hydrogel [16]. The hydrogel transitioned from a solution phase to a gel-phase after body temperature exposition. Both in vitro and in Rex rabbits, the nanotherapeutic inhibited angiogenesis induced by retinal laser photocoagulation over the course of 35 days. After intravitreal injection, the anti-angiogenic bioactivity of bevacizumab was maintained. No cytotoxic effects during the nanocarrier biodegradation were reported in Rex rabbits. This experiment was conducted on 11 Rex rabbits divided in two groups. Given this small animal sample, results remain preliminary. However, it shows that DDS might offer promising results as a novel therapeutic gelling carrier against angiogenesis.
Xue et al. encapsulated bevacizumab and aflibercept in a thermoresponsive hydrogel synthesized with PED–PPG–PCL [17]. As expected, the hydrogel exhibited good biocompatibility and no toxicity. Tests were conducted in vitro on bevacizumab and aflibercept separately. Both drugs significantly inhibited proliferation in HUVEC. Both anti-VEGF drugs were independently injected with the nanocarrier in an ex vivo choroidal sprouting model and significantly reduced the relative sprouting percentage by more than 80% compared to the control hydrogel. Anti-angiogenic effects were reported ex vivo and in vivo on a persistent retinal neovascularization rabbit model. This confirmed sustained drug bioactivity in the nanocarrier. The hydrogel was fine-tuned by modifying the hydrophilic/lipophilic ratio to extend the prolonged drug release rate. After increasing the hydrogel concentration to 20 weight percent with the optimized PEG/PPG ratio of 4:1, the longest drug release of 40 days in vitro and of at least 28 days in vivo was obtained. The novel DDS represents a potential bioactive drug carrier with a prolonged drug release rate that can be extended via polymer fine tuning.
Thermoresponsive hydrogel studies have shown optimistic results in vitro and in vivo, but for limited periods of time ranging from days to weeks. Liu et al. also explored the use of a thermorepsonsive hydrogel to deliver bevacizumab, but over the course of 6 months in vitro. They used PGLA in a poly(ethylene glycol)-co-(L-lactic-acid) diacrylate/N-isopropylacrylamide (PEG–PLLA–DA/NIPAAm) thermoresponsive hydrogel loaded with ranibizumab [18]. By increasing cross-linker concentration and not charging the microsphere with more than 20 mg/mL, optimal conditions were achieved through enhanced biodegradability, drug release, and needle-injection feasibility. The hydrogel proved to be effective in vitro for 190 days. Liu et al. then pursued to test the novel DDS with aflibercept in vitro [19]. Aflibercept was successfully released for 6 months while maintaining bioactive therapeutic levels. Drug quantity and release could be tuned based on cross-linker PEG–PLLA–DA concentration and microsphere load quantity. The biodegradable cross-linker PEG–PLLA–DA prolonged the hydrogel nanocarrier degradation. Liu et al. then proceeded to inject intravitreally the aflibercept-DDS in a laser-induced CNV rat model [20]. The nanotherapeutic was as effective as a bimonthly aflibercept injection to treat CNV lesion areas for 6 consecutive months while avoiding inflammation and ocular complications. This nanotherapeutic proved to be safe and biocompatible in vivo on the rodent eye model. An important limitation of this promising DDS is its potential non-applicability to humans given the anatomical differences between the rodent and human eyes. Therefore, the drug pharmacokinetics and DDS-related immune reactions may differ.
Fan et al. developed a short chain peptide to deliver conbercept, a novel anti-VEGF drug with a short half-life, in vitro [21]. The peptide was pH-sensitive and self-assembled as a hydrogel when triggered by a pH under 7.4. The nano-based DDS inhibited the proliferation and tube formation of human retinal endothelial cells (HREC), which suggests its potential therapeutic avenue for neovascular AMD. The hydrogel peptide nanocarrier did not affect the viability of human retinal endothelial cells (HRECs), which shows its biocompatibility. However, given that the DDS was not tested in vivo, the pharmacokinetics of the DDS remain theoretical. Results are too preliminary to further comment.
Hydrogels can be combined with different materials to gain new properties. In this recent study, Li et al. injected co-loaded sunitinib and acriflavine liposomes in a hydrogel (cSA@Lip-HAC) [22]. Acriflavine inhibits the hypoxia-inducible factor, while sunitinib acts as an anti-VEGF agent. In vitro results demonstrated that the nanocarrier exhibited high antiangiogenic properties. The increased antiangiogenic effect was enabled by the combination of co-drug-loaded liposomes in the injectable hydrogen and the chosen sub-tenon administration route. Increased retinal and choroid drug residency were reported, as well as significant anti-CNV results. The drug was able to remain 21 days in the nanocarrier in vivo. Impressively, the nanotherapeutic showed increased anti-CNV efficacy in the laser-induced CNV rat models when compared to an intravitreal commercial conbercept injection. This DDS thus represents a promising novel therapeutic avenue with less complications than with the intravitreal administrative route. The drug was able to remain 21 days in the nanocarrier in vivo, which is a good preliminary result. Nonetheless, the DDS remains limited in time. To ensure patient compliance, the DDS should ideally remain active for months in the eye.

2.2. Polymers Nanoparticles and Microparticles (MPs)

In recent years, polymers have been the most tested DDS with anti-VEGF drugs. This is due to their high versatility and tuning properties. They can encapsulate various types of hydrophilic and hydrophobic molecules ranging from peptides to biological macromolecules. Polymers are widely studied as their drug release rate and other pharmacokinetic characteristics can be modified by adjusting their composition and ratios as well as combining different biomaterials. They represent promising nanocarriers due to their biodegradability and nontoxic profile. They can either be natural, synthetic or a mix of to gain desired environmental, release and retention rate features. The most studied and successful formula are bevacizumab loaded PLGA and chitosan-based nanoparticles.
PLGA-based nanocarriers are one of the most promising synthetic nanocarriers given their biocompatibility, nontoxicity, degradability, and versatility. They are FDA-approved polymers in clinical applications. They are composed of a hydrophobic core that carries hydrophobic drug and a hydrophilic outer shell (corona) that modulates drug release. Due to its amphiphilic nature, PLGA-based polymers can be used with a variety of drugs.
Tanetsugu et al. developed PLGA microspheres that delivered ranibizumab biosimilar in vitro [23]. After three weeks, more than 80% of the drug was delivered. The DDS also inhibited HUVECs tube formation. The microsphere completely degraded after 1.5 months. This DDS could become a practical system in prolonged anti-VEGF drug release treatment.
Longer drug release results were obtained by Sousa et al. who also encapsulated bevacizumab in PLGA loaded nanoparticles [24]. In vitro results showed that the DDS preserved the drug bioactivity and could deliver drugs to targeted cells in HUVEC. In 2018, Sousa et al. developed a lyophilized protocol to study the stability of encapsulated bevacizumab loaded PLGA nanoparticles [25]. They successfully stored over 6 months bevacizumab while preserving its angiogenic effect. This shows that bevacizumab could be used for prolonged release time. Similarly, Zhang et al. used PLGA nanoparticles to encapsulate bevacizumab [26]. In vitro results showed that the nanotherapeutic was more efficient than bevacizumab alone to inhibit HUVEC proliferation and tube formation. In vivo experiments on oxygen-induced retinopathy (OIR) mouse models showed that the nanotherapeutic increased the drug bioactivity in inhibiting CNV and RNV angiogenesis. No toxicity or cytotoxicity was reported in vitro and in vivo. Therefore, this PLGA drug loaded nanoparticles could become a safe in vivo treatment.
Other than bevacizumab, few other anti-VEGF drugs were tested. Kelly et al. tested in vitro aflibercept encapsulated PLGA nanoparticles [27]. 75% of the drug was released on day seven with the DDS, compared to 100% drug release after 24 h following a standard aflibercept injection. Thus, the polymer exhibited prolonged drug release over seven days and high encapsulation efficacy. This nanocarrier has the potential to be a promising DDS for delivering aflibercept to treat retinal diseases.
Some studies show that nanocarriers can improve anti-CNV activity. Yan et al. developed a novel nanocarrier composed of PLGA-PEGylated magnetic nanoparticles to treat AMD [28]. The magnetic nanoparticles conferred multiple advantages to the DDS such as stability, biocompatibility, tunable surface modification and even increased antiangiogenic efficacy. The PEG-PLGA copolymer tested in vitro exhibited effective antiangiogenic activity. This DDS could become an effective ArMD therapy.
The use of multiple drugs within nanocarriers could increase this effect. Liu et al. developed a novel poly (D, L-lactide-co-glycolide) and polyethylenimine nanoparticle loaded with dexamethasone and added bevacizumab on the nanoparticle surface (eBev-DPPNs) [29]. The novel DDS conjugated with dexamethasone and bevacizumab increased efficacy of CNV inhibition. This was shown by effective inhibition of HUVECs angiogenesis and VEGF secretion. When injected intravitreally in rabbit laser models of CNV, the nanotherapeutic significantly decreased CNV leakage areas after 28 days.
While in vivo and in vitro studies have been conducted, Heljak et al. developed a computational model to predict behaviour of intravitreally injected PLGA bevacizumab loaded microspheres [30]. The model exhibited similar results than those obtained experimentally, which suggests its future use to assess and plan anti-VEGF treatments in clinical practice.
Some prolonged drug release results were obtained with PLGA-based nanocarrier. A different preparation technique was employed to protect bevacizumab stability. It was shown that the degradability of PLGA drug loaded microspheres can be compromised by the accumulation of lactic and glycolic acids that denature the drug, thus leading to complications. For this reason, Liu et al. explored the use of a polymeric blend composed of poly (d, l-lactide-co-glycolide)/poly(cyclohexane-1,4-diyl acetone dimethylene ketal) (PLGA/PCADK) to deliver bevacizumab-dextran [31]. They prepared the DDS with a solid-in-oil-in-water (S/O/W) emulsification, which limited the initial burst release to ensure progressed drug release that maintained therapeutic level. The novel polymer blend exhibited increased biocompatibility compared to PLGA alone. The DDS delivered drug over the course of a 50-day period in vitro and in vivo in a rabbit model. By extending drug release to over one month in vivo, this nanocarrier could become a potential anti-VEGF treatment.
Tsujinaka et al. used a polymer blend composed of PLGA-PEG to deliver sunitinib [32]. Impressively, after intravitreal injection, the DDS formed a depot that released drug over 6 months in a laser induced CNV mouse model. CNV was suppressed in the type II CNV mouse model over the drug release period. In a different mouse model, the nanotherapeutic reduced VEGF-induced leukostasis and nonperfusion, which suggests it could also be used in progressive DR therapy.
Other synthetic polymers have been studied. Jiang et al. developed a polydopamine (PDA) nanoparticle that encapsulated bevacizumab to treat AMD [33]. The nanocarrier alone possessed an antiangiogenic activity by reducing reactive oxygen species (ROS). When tested in vitro and on ex-vivo porcine eyes, the novel biodegradable nano-based DDS successfully delivered bevacizumab when triggered by ROS. This DDS has the potential to become a practical dual system that delivers antiangiogenic drugs while minimizing the production of ROS.
Cai et al. synthesized modified S-PEG polymers with arigine-glycine-aspartic acid (RGD) peptide (S-PEG-ICG-RGD-RBZ nanoparticles) to deliver anti-VEGF agents intravenously [34]. The nanoparticles exhibited an antiangiogenic activity in vitro. In laser induced CNV mouse models, the nanoparticles significantly decreased CNV lesion areas. Interestingly, the nanoparticles displayed good specificity by spending minimal time in the entire organism and by not accumulating in organs other than CNV areas, demonstrating the biosafety of this drug delivery system (DDS).
Natural polymers hold the advantage of degrading easily and are thus investigated in anti-VEGF nanocarriers. Topical route is less explored as there are more barriers to penetrate before reaching the posterior eye segments. While the current anti-VEGF administrative route in clinical practice is intravitreal injection, some studies assessed the topical route with human serum albumin (HSA) nanoparticles. HSA nanoparticles are easy to preparate and exhibit adhering properties to the mucosa of the corneal epithelium, which allows the drug to remain longer bioavailable. No toxicity is reported with the advantage of accommodating a variety of drug types and molecular sizes. This phenomenon is explained by the chemical bonding between the nanoparticles and mucins. No enzymatic cross-linkage was used to stabilize the nanoparticles. In fact, this would be due to the protein interactions between the drug and the albumin. Luis de Redin et al. used HSA nanoparticles to carry bevacizumab [35]. The bevacizumab-nanoparticles increased loading capacity by 13% compared to nanoparticles cross-linked with glutaraldehyde, which is a commonly used cross-linkage reagent. During the first five minutes in vitro, the initial burst release was evaluated to 35% of the loaded drug, followed by a decreased rate over the next 24 h. When delivered to rats as eye drops, the DDS was released over 4 h before being evacuated in the gastrointestinal tract, compared to HSA control group which was cleared in less than 1 h. These results indicated that the DDS could become a potential daily eye drop treatment. However, the DDS should remain longer in the eye. Luis de Redin et al. tested the model in vivo. Similarly to their previous study, they loaded bevacizumab in albumin nanoparticles to treat CNV [36]. The eye drops were applied daily for 1 week. In vivo, the drug loaded nanoparticles exhibited better antiangiogenic activity than with bevacizumab alone and thus used 2.4 times less drug quantity. The nanocarrier significantly increased bevacizumab neovascularization inhibiting efficacy in CNV rat models. Histopathological results revealed decreased fibrosis, inflammation and edema in rats treated with bevacizumab nanoparticles. These promising results suggest that this drug delivery system could be utilized as a daily eye drop therapy with reduced dosing requirements. Given that the in vivo experiment was only conducted on Wistar rats, the results lack validation on animal models that can be more easily transposed to the human eye anatomy.
Llabot et al. also used HSA, but with added Gantrez® ES-425 polymer to coat bevacizumab or suramin loaded nanoparticles [37]. The nanoparticles were tested in vitro topically and developed to treat CNV. Bevacizumab released in a small initial burst and was progressively released. The stabilizing polymer Gantrez® was compared with the common cross-linked reagent, glutaraldehyde. Gantrez® polymer exhibited better results than glutaraldehyde in terms of drug stability and preserved bioactivity. In vitro release results showed that 80% of suramin was released within 8 h compared to 50% for suramin. In vivo studies will be carried out on animal CNV models.
Abdi et al. explored the interaction between chitosan nanoparticles and bevacizumab [38]. Study showed that chitosan and bevacizumab had low interactions between one another, thus allowing efficient capture and release of bevacizumab. This study reported that bevacizumab and chitosan could form a successful nanocarrier. As seen in other studies, the combination of this drug and nanocarrier appears to be promising.
Several studies that used chitosan nanoparticles report effective drug release for less than 1 month. Pandit et al. merged PLGA and chitosan in nanoparticles to deliver bevacizumab through a subconjunctival injection [39]. Coating PLGA nanoparticles with chitosan reduced initial drug burst release to 25% as opposed to the drug solution control which released 90% of drug content within 24 h. In vitro, the DDS extended drug residency in the retina. The drug was released sustainably over 72 h. These preliminary results show that the nanocarrier could become a suitable DDS for the subconjunctival administration route. Ugurlu et al. proceeded by a subtenon injection of loaded chitosan particles with bevacizumab in rabbits’ eyes [40]. In vitro, the DDS progressively released drug for 3 weeks. However, in vivo results decrease within one week despite better control and more progressive drug release from the DDS (6 μg/mL for DDS and 4 μg/mL for bevacizumab). In Savin et al. study, they synthesized bevacizumab loaded chitosan grafted-poly(ethylene glycol) methacrylate nanoparticles. The solubility of chitosan polymer was increased through Michael addition reaction. The nanoparticles exhibited no toxic effect and released successfully bevacizumab in vitro for an estimate time ranging from 14 to 30 days [41].
Unlike previous studies, Jiang et al. developed a chitosan-based nanocarrier that can release drugs over months. They designed a polycaprolactone (PLA) chitosan bi-layered hybrid shell capsule that delivers bevacizumab in hope to treat AMD [42]. This structure was chosen to load high drug amounts. In vitro results impressively showed that the DDS released drug over one year while preserving drug potency. Jian et al. also developed a novel DDS, which combines natural and synthetic polymers to carry bevacizumab in microparticles [43]. They developed chitosan-polycaprolactone core-shell microparticles and tested the novel DDS in vitro and on ex vivo porcine eye models. The designed core-shell microparticles were able to increase the loading capacity by 25% and decrease the initial burst release to nearly 30%. The drug was released in vitro for 6 months and maintained drug potency. The nanotherapeutic proved to be biocompatible with over 90% cell viability. In vivo studies remain needed to assess safety and drug efficacy.
Gene delivery therapy was studied yet also remains below the 1-month drug release threshold. Chaharband et al. used gene therapy to deliver intravitreally VEGFR-2 siRNA in rabbit and rat laser model of CNV through chitosan-hyaluronic acid nano-polyplexes [44]. In vitro, the DDS suppressed VEGFR-2 expression by 70%, and it significantly reduced CNV in vivo after 14 days. The DDS could become an efficient intravitreal gene delivery therapy.

2.3. Lipid-Based

Lipid-based nanocarriers have shown potential for co-loading multiple drugs, as demonstrated by Formica et al., who developed a hybrid lipid-based nanocapsule containing both bevacizumab on the surface and triamcinolone acetonide in the core. This co-loading approach offers the potential for more effective treatment of diseases, as seen with the reduction of both inflammation and neovascularization in the case of bevacizumab and TA. In vitro studies showed that this novel formulation significantly inhibited capillary formation, making it a promising drug delivery system for loading multiple drugs [45].
Liposomes are a promising drug delivery system (DDS) due to their hydrophilic core and hydrophobic outer shell, which can be modified to improve tissue penetration. However, the interactions of liposomes with macrophages, changes in pH, and enzymes can affect their performance, making it difficult to accurately predict their physiological behavior. In the study of Mu et al., they used multivesicular liposomes (MVLs) to encapsule bevacizumab [46]. The MVLs had a size ranging from 1 to 100 μm, which enabled them to not be captured by macrophages and, thus, be rapidly degraded. Liposomes are known for minimal toxicity, good biocompatibility, encapsulation efficacy, and low immunotoxicity. Bevacizumab was released by diffusion and erosion and kept its integral structure in vitro. After intravitreal injection in the laser-induced CNV rat model, the nanocarrier sustainably released the drug as opposed to the bevacizumab solution. After 28 days of treatment, the DDS could inhibit CNV lesions, unlike the bevacizumab solution. With these promising findings, this DDS could potentially reduce the frequency of intravitreal injections.
Kayland Karumanchi et al. similarly encapsulated bevacizumab in liposomes [47], but they obtained even longer prolonged drug release results. In vivo, the DDS maintained drug release at therapeutic levels for 22 weeks compared to less than 6 weeks for bevacizumab solution. Drug potency also remained preserved. Therefore, liposomes could offer a promising prolonged and controlled drug release.
Lastly, it was shown that liposomes could also become potential nanocarriers in cancer treatments. De Cristo Soares Alves et al. developed a chitosan-coated lipid core nanocapsules that transports bevacizumab to treat solid tumors like glioblastoma [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]. Within 24 h, bevacizumab and the DDS were compared in their ability to induce apoptosis. Bevacizumab alone did not significantly induce more apoptosis. Impressively, in chicken embryo chorioallantoic membrane (CAM), the drug-loaded nanocarrier used 5.6 times less doses of bevacizumab than in bevacizumab solution. The nanocarrier, thus, exhibits higher potent antiangiogenic effects. This shows that fewer drugs could be used in clinical practice, thus reducing high drug dose toxicity and adverse effects. With these promising results, this DDS has the potential to be used in the treatment of solid ocular tumors.

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References

  1. Sun, Q.; Shen, Y.; Su, L.; Xu, X. Inhibition of Pathological Retinal Neovascularization by a Small Peptide Derived from Human Tissue-Type Plasminogen Kringle 2. Front. Pharmacol. 2020, 10, 1639. Urtti, A. Challenges and Obstacles of Ocular Pharmacokinetics and Drug Delivery. Adv. Drug Deliv. Rev. 2006, 58, 1131–1135. [Google Scholar] [CrossRef]
  2. Ishibazawa, A.; Nagaoka, T.; Yokota, H.; Takahashi, A.; Omae, T.; Song, Y.S.; Takahashi, T.; Yoshida, A. Characteristics of Retinal Neovascularization in Proliferative Diabetic Retinopathy Imaged by Optical Coherence Tomography Angiography. Investig. Ophthalmol. Vis. Sci. 2016, 57, 6247–6255. Akhter, M.H.; Ahmad, I.; Alshahrani, M.Y.; Al-Harbi, A.I.; Khalilullah, H.; Afzal, O.; Altamimi, A.S.A.; Najib Ullah, S.N.M.; Ojha, A.; Karim, S. Drug Delivery Challenges and Current Progress in Nanocarrier-Based Ocular Therapeutic System. Gels 2022, 8, 82. [Google Scholar] [CrossRef]
  3. Sacconi, R.; Fragiotta, S.; Sarraf, D.; Sadda, S.V.R.; Freund, K.B.; Parravano, M.; Corradetti, G.; Cabral, D.; Capuano, V.; Miere, A.; et al. Towards a Better Understanding of Non-Exudative Choroidal and Macular Neovascularization. Prog. Retin. Eye Res. 2023, 92, 101113. Addo, R.T. Ocular Drug Delivery: Advances, Challenges and Applications. In Ocular Drug Delivery: Advances, Challenges and Applications; Springer: Berlin/Heidelberg, Germany, 2016; pp. 1–185. [Google Scholar] [CrossRef]
  4. Fernandes, A.R.; dos Santos, T.; Granja, P.L.; Sanchez-Lopez, E.; Garcia, M.L.; Silva, A.M.; Souto, E.B. Permeability, Anti-Inflammatory and Anti-VEGF Profiles of Steroidal-Loaded Cationic Nanoemulsions in Retinal Pigment Epithelial Cells under Oxidative Stress. Int. J. Pharm. 2022, 617, 121615. Chang, A.Y.; Purt, B. Biochemistry, Tear Film. In StatPearls; StatPearls Publishing: Treasure Island, FL, USA, 2022. [Google Scholar]
  5. García-Estrada, P.; García-Bon, M.A.; López-Naranjo, E.J.; Basaldúa-Pérez, D.N.; Santos, A.; Navarro-Partida, J. Polymeric Implants for the Treatment of Intraocular Eye Diseases: Trends in Biodegradable and Non-Biodegradable Materials. Pharmaceutics 2021, 13, 701. Bachu, R.D.; Chowdhury, P.; Al-Saedi, Z.H.F.; Karla, P.K.; Boddu, S.H.S. Ocular Drug Delivery Barriers—Role of Nanocarriers in the Treatment of Anterior Segment Ocular Diseases. Pharmaceutics 2018, 10, 28. [Google Scholar] [CrossRef]
  6. Gil-Martínez, M.; Santos-Ramos, P.; Fernández-Rodríguez, M.; Abraldes, M.J.; Rodríguez-Cid, M.J.; Santiago-Varela, M.; Fernández-Ferreiro, A.; Gómez-Ulla, F. Pharmacological Advances in the Treatment of Age-Related Macular Degeneration. Curr. Med. Chem. 2020, 27, 583–598. Wu, K.Y.; Kulbay, M.; Tanasescu, C.; Jiao, B.; Nguyen, B.H.; Tran, S.D. An Overview of the Dry Eye Disease in Sjögren’s Syndrome Using Our Current Molecular Understanding. Int. J. Mol. Sci. 2023, 24, 1580. [Google Scholar] [CrossRef] [PubMed]
  7. Ferrara, N.; Adamis, A.P. Ten Years of Anti-Vascular Endothelial Growth Factor Therapy. Nat. Rev. Drug Discov. 2016, 15, 385–403. Goel, M.; Picciani, R.G.; Lee, R.K.; Bhattacharya, S.K. Aqueous Humor Dynamics: A Review. Open Ophthalmol. J. 2010, 4, 52–59. [Google Scholar] [CrossRef] [PubMed]
  8. Klettner, A.; Recber, M.; Roider, J. Comparison of the Efficacy of Aflibercept, Ranibizumab, and Bevacizumab in an RPE/Choroid Organ Culture. Graefes Arch. Clin. Exp. Ophthalmol. 2014, 252, 1593–1598. Chen, M.-S.; Hou, P.-K.; Tai, T.-Y.; Lin, B.J. Blood-Ocular Barriers. Tzu Chi Med. J. 2008, 20, 25–34. [Google Scholar] [CrossRef]
  9. Oo, C.; Kalbag, S.S. Leveraging the Attributes of Biologics and Small Molecules, and Releasing the Bottlenecks: A New Wave of Revolution in Drug Development. Expert. Rev. Clin. Pharmacol. 2016, 9, 747–749. Cunha-Vaz, J.; Bernardes, R.; Lobo, C. Blood-Retinal Barrier. Eur. J. Ophthalmol. 2011, 21, 3–9. [Google Scholar] [CrossRef] [PubMed]
  10. Li, J.; Mooney, D.J. Designing Hydrogels for Controlled Drug Delivery. Nat. Rev. Mater. 2016, 1, 16071. Bertens, C.J.F.; Gijs, M.; van den Biggelaar, F.J.H.M.; Nuijts, R.M.M.A. Topical Drug Delivery Devices: A Review. Exp. Eye Res. 2018, 168, 149–160. [Google Scholar] [CrossRef] [PubMed]
  11. Gorantla, S.; Rapalli, V.K.; Waghule, T.; Singh, P.P.; Dubey, S.K.; Saha, R.N.; Singhvi, G. Nanocarriers for Ocular Drug Delivery: Current Status and Translational Opportunity. RSC Adv. 2020, 10, 27835–27855. Singh Malik, D.; Mital, N.; Kaur, G. Topical Drug Delivery Systems: A Patent Review. Expert Opin. Ther. Pat. 2016, 26, 213–228. [Google Scholar] [CrossRef]
  12. Galante, R.; Pinto, T.J.A.; Colaço, R.; Serro, A.P. Sterilization of Hydrogels for Biomedical Applications: A Review. J. Biomed. Mater. Res. B Appl. Biomater. 2018, 106, 2472–2492. Farkouh, A.; Frigo, P.; Czejka, M. Systemic Side Effects of Eye Drops: A Pharmacokinetic Perspective. Clin. Ophthalmol. 2016, 10, 2433–2441. [Google Scholar] [CrossRef]
  13. Bordbar-Khiabani, A.; Gasik, M. Smart Hydrogels for Advanced Drug Delivery Systems. Int. J. Mol. Sci. 2022, 23, 3665. Wu, W.; He, Z.; Zhang, Z.; Yu, X.; Song, Z.; Li, X. Intravitreal Injection of Rapamycin-Loaded Polymeric Micelles for Inhibition of Ocular Inflammation in Rat Model. Int. J. Pharm. 2016, 513, 238–246. [Google Scholar] [CrossRef] [PubMed]
  14. Osswald, C.R.; Kang-Mieler, J.J. Controlled and Extended In Vitro Release of Bioactive Anti-Vascular Endothelial Growth Factors from a Microsphere-Hydrogel Drug Delivery System. Curr. Eye Res. 2016, 41, 1216–1222. Abrishami, M.; Shariati, M.M.; Malaekeh-Nikouei, B.; Tajani, A.S.; Mahmoudi, A.; Abrishami, M.; Khameneh, B. Preparation and in Vivo Evaluation of Nanoliposomes Containing Vancomycin after Intravitreal Injection in Albino Rabbits. Iran. J. Basic Med. Sci. 2020, 23, 551–555. [Google Scholar] [CrossRef] [PubMed]
  15. Osswald, C.R.; Guthrie, M.J.; Avila, A.; Valio, J.A.; Mieler, W.F.; Kang-Mieler, J.J. In Vivo Efficacy of an Injectable Microsphere-Hydrogel Ocular Drug Delivery System. Curr. Eye Res. 2017, 42, 1293–1301. García-Caballero, C.; Prieto-Calvo, E.; Checa-Casalengua, P.; García-Martín, E.; Polo-Llorens, V.; García-Feijoo, J.; Molina-Martínez, I.T.; Bravo-Osuna, I.; Herrero-Vanrell, R. Six Month Delivery of GDNF from PLGA/Vitamin E Biodegradable Microspheres after Intravitreal Injection in Rabbits. Eur. J. Pharm. Sci. 2017, 103, 19–26. [Google Scholar] [CrossRef]
  16. Hu, C.C.; Chiu, Y.C.; Chaw, J.R.; Chen, C.F.; Liu, H.W. Thermo-Responsive Hydrogel as an Anti-VEGF Drug Delivery System to Inhibit Retinal Angiogenesis in Rex Rabbits. Technol. Health Care 2019, 27, S153–S163. Park, J.G.; Callaway, N.F.; Ludwig, C.A.; Mahajan, V.B. Intravitreal Methotrexate and Fluocinolone Acetonide Implantation for Vogt-Koyanagi-Harada Uveitis. Am. J. Ophthalmol. Case Rep. 2020, 19, 100859. [Google Scholar] [CrossRef] [PubMed]
  17. Xue, K.; Zhao, X.; Zhang, Z.; Qiu, B.; Tan, Q.S.W.; Ong, K.H.; Liu, Z.; Parikh, B.H.; Barathi, V.A.; Yu, W.; et al. Sustained Delivery of Anti-VEGFs from Thermogel Depots Inhibits Angiogenesis without the Need for Multiple Injections. Biomater. Sci. 2019, 7, 4603–4614. Glendenning, A.; Crews, K.; Sturdivant, J.; deLong, M.A.; Kopczynski, C.; Lin, C.-W. Sustained Release, Biodegradable PEA Implants for Intravitreal Delivery of the ROCK/PKC Inhibitor AR-13503. Investig. Ophthalmol. Vis. Sci. 2018, 59, 5672. [Google Scholar]
  18. Liu, W.; Borrell, M.A.; Venerus, D.C.; Mieler, W.F.; Kang-Mieler, J.J. Characterization of Biodegradable Microsphere-Hydrogel Ocular Drug Delivery System for Controlled and Extended Release of Ranibizumab. Transl. Vis. Sci. Technol. 2019, 8, 12. Blazaki, S.; Pachis, K.; Tzatzarakis, M.; Tsilimbaris, M.; Antimisiaris, S.G. Novel Liposome Aggregate Platform (LAP) System for Sustained Retention of Drugs in the Posterior Ocular Segment Following Intravitreal Injection. Int. J. Pharm. 2020, 576, 118987. [Google Scholar] [CrossRef]
  19. Liu, W.; Lee, B.S.; Mieler, W.F.; Kang-Mieler, J.J. Biodegradable Microsphere-Hydrogel Ocular Drug Delivery System for Controlled and Extended Release of Bioactive Aflibercept In Vitro. Curr. Eye Res. 2019, 44, 264–274. Agban, Y.; Thakur, S.S.; Mugisho, O.O.; Rupenthal, I.D. Depot Formulations to Sustain Periocular Drug Delivery to the Posterior Eye Segment. Drug Discov. Today 2019, 24, 1458–1469. [Google Scholar] [CrossRef]
  20. Liu, W.; Tawakol, A.P.; Rudeen, K.M.; Mieler, W.F.; Kang-Mieler, J.J. Treatment Efficacy and Biocompatibility of a Biodegradable Aflibercept-Loaded Microsphere-Hydrogel Drug Delivery System. Transl. Vis. Sci. Technol. 2020, 9, 13. Radhakrishnan, K.; Vincent, A.; Joseph, R.R.; Moreno, M.; Dickescheid, A.; Agrawal, R.; Venkatraman, S. Hollow Microcapsules as Periocular Drug Depot for Sustained Release of Anti-VEGF Protein. Pharmaceutics 2019, 11, 330. [Google Scholar] [CrossRef]
  21. Fan, W.; Li, S.; Tao, J.; Yu, C.; Sun, M.; Xie, Z.; Wu, X.; Ge, L.; Wu, Y.; Liu, Y. Anti-Vascular Endothelial Growth Factor Drug Conbercept-Loaded Peptide Hydrogel Reduced Angiogenesis in the Neovascular Age-Related Macular Degeneration. J. Biomed. Nanotechnol. 2022, 18, 277–287. Yiu, G.; Chung, S.H.; Mollhoff, I.N.; Nguyen, U.T.; Thomasy, S.M.; Yoo, J.; Taraborelli, D.; Noronha, G. Suprachoroidal and Subretinal Injections of AAV Using Transscleral Microneedles for Retinal Gene Delivery in Nonhuman Primates. Mol. Ther. Methods Clin. Dev. 2020, 16, 179–191. [Google Scholar] [CrossRef]
  22. Li, J.; Tian, Q.; Sun, H.; Zhang, Y.; Yang, X.; Kaur, P.; Wang, R.; Fang, Y.; Yan, H.; Du, X.; et al. A Novel, Liposome-Loaded, Injectable Hydrogel for Enhanced Treatment of Choroidal Neovascularization by Sub-Tenon’s Injection. Mater. Today Nano 2022, 20, 100264. Weijtens, O.; Feron, E.J.; Schoemaker, R.C.; Cohen, A.F.; Lentjes, E.G.W.M.; Romijn, F.P.H.T.M.; Van Meurs, J.C. High Concentration of Dexamethasone in Aqueous and Vitreous after Subconjunctival Injection. Am. J. Ophthalmol. 1999, 128, 192–197. [Google Scholar] [CrossRef]
  23. Tanetsugu, Y.; Tagami, T.; Terukina, T.; Ogawa, T.; Ohta, M.; Ozeki, T. Development of a Sustainable Release System for a Ranibizumab Biosimilar Using Poly(Lactic-Co-Glycolic Acid) Biodegradable Polymer-Based Microparticles as a Platform. Biol. Pharm. Bull. 2017, 40, 145–150. Salama, H.A.; Ghorab, M.; Mahmoud, A.A.; Abdel Hady, M. PLGA Nanoparticles as Subconjunctival Injection for Management of Glaucoma. AAPS PharmSciTech 2017, 18, 2517–2528. [Google Scholar] [CrossRef] [PubMed]
  24. Sousa, F.; Cruz, A.; Fonte, P.; Pinto, I.M.; Neves-Petersen, M.T.; Sarmento, B. A New Paradigm for Antiangiogenic Therapy through Controlled Release of Bevacizumab from PLGA Nanoparticles. Sci. Rep. 2017, 7, 3736. Fu, J.; Sun, F.; Liu, W.; Liu, Y.; Gedam, M.; Hu, Q.; Fridley, C.; Quigley, H.A.; Hanes, J.; Pitha, I. Subconjunctival Delivery of Dorzolamide-Loaded Poly(Ether-Anhydride) Microparticles Produces Sustained Lowering of Intraocular Pressure in Rabbits. Mol. Pharm. 2016, 13, 2987–2995. [Google Scholar] [CrossRef] [PubMed]
  25. Sousa, F.; Cruz, A.; Pinto, I.M.; Sarmento, B. Nanoparticles Provide Long-Term Stability of Bevacizumab Preserving Its Antiangiogenic Activity. Acta Biomater. 2018, 78, 285–295. Cuming, R.S.; Abarca, E.M.; Duran, S.; Wooldridge, A.A.; Stewart, A.J.; Ravis, W.; Babu, R.J.; Lin, Y.J.; Hathcock, T. Development of a Sustained-Release Voriconazole-Containing Thermogel for Subconjunctival Injection in Horses. Investig. Ophthalmol. Vis. Sci. 2017, 58, 2746–2754. [Google Scholar] [CrossRef] [PubMed]
  26. Zhang, X.P.; Sun, J.G.; Yao, J.; Shan, K.; Liu, B.H.; Yao, M.D.; Ge, H.M.; Jiang, Q.; Zhao, C.; Yan, B. Effect of Nanoencapsulation Using Poly (Lactide-Co-Glycolide) (PLGA) on Anti-Angiogenic Activity of Bevacizumab for Ocular Angiogenesis Therapy. Biomed. Pharmacother. 2018, 107, 1056–1063. Martínez-Carrasco, R.; Sánchez-Abarca, L.I.; Nieto-Gómez, C.; Martín García, E.; Sánchez-Guijo, F.; Argüeso, P.; Aijón, J.; Hernández-Galilea, E.; Velasco, A. Subconjunctival Injection of Mesenchymal Stromal Cells Protects the Cornea in an Experimental Model of GVHD. Ocul. Surf. 2019, 17, 285–294. [Google Scholar] [CrossRef] [PubMed]
  27. Kelly, S.J.; Hirani, A.; Shahidadpury, V.; Solanki, A.; Halasz, K.; Gupta, S.V.; Madow, B.; Sutariya, V. Aflibercept Nanoformulation Inhibits VEGF Expression in Ocular In Vitro Model: A Preliminary Report. Biomedicines 2018, 6, 92. Lindholm, J.M.; Taipale, C.; Ylinen, P.; Tuuminen, R. Perioperative Subconjunctival Triamcinolone Acetonide Injection for Prevention of Inflammation and Macular Oedema after Cataract Surgery. Acta Ophthalmol. 2020, 98, 36–42. [Google Scholar] [CrossRef]
  28. Yan, J.; Peng, X.; Cai, Y.; Cong, W. Development of Facile Drug Delivery Platform of Ranibizumab Fabricated PLGA-PEGylated Magnetic Nanoparticles for Age-Related Macular Degeneration Therapy. J. Photochem. Photobiol. B 2018, 183, 133–136. Schneider, M.E.; Milstein, D.E.; Oyakawa, R.T.; Ober, R.R.; Campo, R. Ocular Perforation from a Retrobulbar Injection. Am. J. Ophthalmol. 1988, 106, 35–40. [Google Scholar] [CrossRef]
  29. Liu, J.; Zhang, X.; Li, G.; Xu, F.; Li, S.; Teng, L.; Li, Y.; Sun, F. Anti-Angiogenic Activity Of Bevacizumab-Bearing Dexamethasone-Loaded PLGA Nanoparticles For Potential Intravitreal Applications. Int. J. Nanomed. 2019, 14, 8819–8834. Safi, M.; Ang, M.J.; Patel, P.; Silkiss, R.Z. Rhino-Orbital-Cerebral Mucormycosis (ROCM) and Associated Cerebritis Treated with Adjuvant Retrobulbar Amphotericin B. Am. J. Ophthalmol. Case Rep. 2020, 19, 100771. [Google Scholar] [CrossRef]
  30. Heljak, M.K.; Swieszkowski, W. In Silico Model of Bevacizumab Sustained Release from Intravitreal Administrated PLGA Drug-Loaded Microspheres. Mater. Lett. 2021, 307, 131080. Arbisser, L.B. Safety of Intracameral Moxifloxacin for Prophylaxis of Endophthalmitis after Cataract Surgery. J. Cataract. Refract. Surg. 2008, 34, 1114–1120. [Google Scholar] [CrossRef]
  31. Liu, J.; Li, S.; Li, G.; Li, X.; Yu, C.; Fu, Z.; Li, X.; Teng, L.; Li, Y.; Sun, F. Highly Bioactive, Bevacizumab-Loaded, Sustained-Release PLGA/PCADK Microspheres for Intravitreal Therapy in Ocular Diseases. Int. J. Pharm. 2019, 563, 228–236. Christopher, K.; Chauhan, A. Contact Lens Based Drug Delivery to the Posterior Segment Via Iontophoresis in Cadaver Rabbit Eyes. Pharm. Res. 2019, 36. [Google Scholar] [CrossRef]
  32. Tsujinaka, H.; Fu, J.; Shen, J.; Yu, Y.; Hafiz, Z.; Kays, J.; McKenzie, D.; Cardona, D.; Culp, D.; Peterson, W.; et al. Sustained Treatment of Retinal Vascular Diseases with Self-Aggregating Sunitinib Microparticles. Nat. Commun. 2020, 11, 694. Jung, J.H.; Chiang, B.; Grossniklaus, H.E.; Prausnitz, M.R. Ocular Drug Delivery Targeted by Iontophoresis in the Suprachoroidal Space Using a Microneedle. J. Control. Release 2018, 277, 14–22. [Google Scholar] [CrossRef]
  33. Luo, L.; Yang, J.; Oh, Y.; Hartsock, M.J.; Xia, S.; Kim, Y.C.; Ding, Z.; Meng, T.; Eberhart, C.G.; Ensign, L.M.; et al. Controlled Release of Corticosteroid with Biodegradable Nanoparticles for Treating Experimental Autoimmune Uveitis. J. Control. Release 2019, 296, 68–80. See, G.L.; Sagesaka, A.; Torizuka, H.; Todo, H.; Sugibayashi, K. Iontophoresis-Aided Drug Delivery into the Eyeball via Eyelid Skin. J. Drug Deliv. Sci. Technol. 2018, 47, 380–385. [Google Scholar] [CrossRef]
  34. Cai, W.; Chen, Q.; Shen, T.; Yang, Q.; Hu, W.; Zhao, P.; Yu, J. Intravenous Anti-VEGF Agents with RGD Peptide-Targeted Core Cross-Linked Star (CCS) Polymers Modified with Indocyanine Green for Imaging and Treatment of Laser-Induced Choroidal Neovascularization. Biomater. Sci. 2020, 8, 4481–4491. dos Santos, G.A.; Ferreira-Nunes, R.; Dalmolin, L.F.; dos Santos Ré, A.C.; Anjos, J.L.V.; Mendanha, S.A.; Aires, C.P.; Lopez, R.F.V.; Cunha-Filho, M.; Gelfuso, G.M.; et al. Besifloxacin Liposomes with Positively Charged Additives for an Improved Topical Ocular Delivery. Sci. Rep. 2020, 10, 19285. [Google Scholar] [CrossRef] [PubMed]
  35. Luis de Redín, I.; Boiero, C.; Martínez-Ohárriz, M.C.; Agüeros, M.; Ramos, R.; Peñuelas, I.; Allemandi, D.; Llabot, J.M.; Irache, J.M. Human Serum Albumin Nanoparticles for Ocular Delivery of Bevacizumab. Int. J. Pharm. 2018, 541, 214–223. Habot-Wilner, Z.; Noronha, G.; Wykoff, C.C. Suprachoroidally Injected Pharmacological Agents for the Treatment of Chorio-Retinal Diseases: A Targeted Approach. Acta Ophthalmol. 2019, 97, 460–472. [Google Scholar] [CrossRef]
  36. Luis de Redín, I.; Boiero, C.; Recalde, S.; Agüeros, M.; Allemandi, D.; Llabot, J.M.; García-Layana, A.; Irache, J.M. In Vivo Effect of Bevacizumab-Loaded Albumin Nanoparticles in the Treatment of Corneal Neovascularization. Exp. Eye Res. 2019, 185, 107697. Allyn, M.M.; Luo, R.H.; Hellwarth, E.B.; Swindle-Reilly, K.E. Considerations for Polymers Used in Ocular Drug Delivery. Front. Med. 2022, 8, 787644. [Google Scholar] [CrossRef]
  37. Llabot, J.M.; Luis de Redin, I.; Agüeros, M.; Dávila Caballero, M.J.; Boiero, C.; Irache, J.M.; Allemandi, D. In Vitro Characterization of New Stabilizing Albumin Nanoparticles as a Potential Topical Drug Delivery System in the Treatment of Corneal Neovascularization (CNV). J. Drug Deliv. Sci. Technol. 2019, 52, 379–385. Bodratti, A.M.; Alexandridis, P. Amphiphilic Block Copolymers in Drug Delivery: Advances in Formulation Structure and Performance. Expert. Opin. Drug Deliv. 2018, 15, 1085–1104. [Google Scholar] [CrossRef] [PubMed]
  38. Abdi, F.; Arkan, E.; Mansouri, K.; Shekarbeygi, Z.; Barzegari, E. Interactions of Bevacizumab with Chitosan Biopolymer Nanoparticles: Molecular Modeling and Spectroscopic Study. J. Mol. Liq. 2021, 339, 116655. Liu, W.; Borrell, M.A.; Venerus, D.C.; Mieler, W.F.; Kang-Mieler, J.J. Characterization of Biodegradable Microsphere-Hydrogel Ocular Drug Delivery System for Controlled and Extended Release of Ranibizumab. Transl. Vis. Sci. Technol. 2019, 8, 12. [Google Scholar] [CrossRef]
  39. Pandit, J.; Sultana, Y.; Aqil, M. Chitosan-Coated PLGA Nanoparticles of Bevacizumab as Novel Drug Delivery to Target Retina: Optimization, Characterization, and in Vitro Toxicity Evaluation. Artif. Cells Nanomed. Biotechnol. 2017, 45, 1397–1407. Zhang, X.; Wei, D.; Xu, Y.; Zhu, Q. Hyaluronic Acid in Ocular Drug Delivery. Carbohydr. Polym. 2021, 264, 118006. [Google Scholar] [CrossRef]
  40. Ugurlu, N.; Aşık, M.D.; Çakmak, H.B.; Tuncer, S.; Turk, M.; Çagıl, N.; Denkbas, E.B. Transscleral Delivery of Bevacizumab-Loaded Chitosan Nanoparticles. J. Biomed. Nanotechnol. 2019, 15, 830–838. Orasugh, J.T.; Dutta, S.; Das, D.; Nath, J.; Pal, C.; Chattopadhyay, D. Utilization of Cellulose Nanocrystals (CNC) Biopolymer Nanocomposites in Ophthalmic Drug Delivery System (ODDS). J. Nanotechnol. Res. 2019, 1, 75–87. [Google Scholar]
  41. Savin, C.L.; Popa, M.; Delaite, C.; Costuleanu, M.; Costin, D.; Peptu, C.A. Chitosan Grafted-Poly(Ethylene Glycol) Methacrylate Nanoparticles as Carrier for Controlled Release of Bevacizumab. Mater. Sci. Eng. C Mater. Biol. Appl. 2019, 98, 843–860. Gupta, B.; Mishra, V.; Gharat, S.; Momin, M.; Omri, A. Cellulosic Polymers for Enhancing Drug Bioavailability in Ocular Drug Delivery Systems. Pharmaceuticals 2021, 14, 1201. [Google Scholar] [CrossRef]
  42. Jiang, P.; Chaparro, F.J.; Cuddington, C.T.; Palmer, A.F.; Ohr, M.P.; Lannutti, J.J.; Swindle-Reilly, K.E. Injectable Biodegradable Bi-Layered Capsule for Sustained Delivery of Bevacizumab in Treating Wet Age-Related Macular Degeneration. J. Control. Release 2020, 320, 442–456. Tavakolian, M.; Jafari, S.M.; van de Ven, T.G.M. A Review on Surface-Functionalized Cellulosic Nanostructures as Biocompatible Antibacterial Materials. Nanomicro Lett. 2020, 12, 73. [Google Scholar] [CrossRef]
  43. Jiang, P.; Jacobs, K.M.; Ohr, M.P.; Swindle-Reilly, K.E. Chitosan-Polycaprolactone Core-Shell Microparticles for Sustained Delivery of Bevacizumab. Mol. Pharm. 2020, 17, 2570–2584. Junnuthula, V.; Boroujeni, A.S.; Cao, S.; Tavakoli, S.; Ridolfo, R.; Toropainen, E.; Ruponen, M.; van Hest, J.C.M.; Urtti, A. Intravitreal Polymeric Nanocarriers with Long Ocular Retention and Targeted Delivery to the Retina and Optic Nerve Head Region. Pharmaceutics 2021, 13, 445. [Google Scholar] [CrossRef] [PubMed]
  44. Chaharband, F.; Daftarian, N.; Kanavi, M.R.; Varshochian, R.; Hajiramezanali, M.; Norouzi, P.; Arefian, E.; Atyabi, F.; Dinarvand, R. Trimethyl Chitosan-Hyaluronic Acid Nano-Polyplexes for Intravitreal VEGFR-2 SiRNA Delivery: Formulation and in Vivo Efficacy Evaluation. Nanomedicine 2020, 26, 102181. Kianersi, S.; Solouk, A.; Saber-Samandari, S.; Keshel, S.H.; Pasbakhsh, P. Alginate Nanoparticles as Ocular Drug Delivery Carriers. J. Drug Deliv. Sci. Technol. 2021, 66, 102889. [Google Scholar] [CrossRef]
  45. Formica, M.L.; Legeay, S.; Bejaud, J.; Montich, G.G.; Ullio Gamboa, G.V.; Benoit, J.P.; Palma, S.D. Novel Hybrid Lipid Nanocapsules Loaded with a Therapeutic Monoclonal Antibody—Bevacizumab—And Triamcinolone Acetonide for Combined Therapy in Neovascular Ocular Pathologies. Mater. Sci. Eng. C Mater. Biol. Appl. 2021, 119, 111398. Wong, F.S.Y.; Tsang, K.K.; Chu, A.M.W.; Chan, B.P.; Yao, K.M.; Lo, A.C.Y. Injectable Cell-Encapsulating Composite Alginate-Collagen Platform with Inducible Termination Switch for Safer Ocular Drug Delivery. Biomaterials 2019, 201, 53–67. [Google Scholar] [CrossRef] [PubMed]
  46. Mu, H.; Wang, Y.; Chu, Y.; Jiang, Y.; Hua, H.; Chu, L.; Wang, K.; Wang, A.; Liu, W.; Li, Y.; et al. Multivesicular Liposomes for Sustained Release of Bevacizumab in Treating Laser-Induced Choroidal Neovascularization. Drug Deliv. 2018, 25, 1372–1383. Jiang, G.; Jia, H.; Qiu, J.; Mo, Z.; Wen, Y.; Zhang, Y.; Wen, Y.; Xie, Q.; Ban, J.; Lu, Z.; et al. PLGA Nanoparticle Platform for Trans-Ocular Barrier to Enhance Drug Delivery: A Comparative Study Based on the Application of Oligosaccharides in the Outer Membrane of Carriers. Int. J. Nanomed. 2020, 15, 9373–9387. [Google Scholar] [CrossRef] [PubMed]
  47. Karumanchi, D.K.; Skrypai, Y.; Thomas, A.; Gaillard, E.R. Rational Design of Liposomes for Sustained Release Drug Delivery of Bevacizumab to Treat Ocular Angiogenesis. J. Drug Deliv. Sci. Technol. 2018, 47, 275–282. Swetledge, S.; Carter, R.; Stout, R.; Astete, C.E.; Jung, J.P.; Sabliov, C.M. Stability and Ocular Biodistribution of Topically Administered PLGA Nanoparticles. Sci. Rep. 2021, 11, 12270. [Google Scholar] [CrossRef]
  48. de Cristo Soares Alves, A.; Lavayen, V.; Figueiró, F.; Dallemole, D.R.; de Fraga Dias, A.; Cé, R.; Battastini, A.M.O.; Guterres, S.S.; Pohlmann, A.R. Chitosan-Coated Lipid-Core Nanocapsules Functionalized with Gold-III and Bevacizumab Induced In Vitro Cytotoxicity against C6 Cell Line and In Vivo Potent Antiangiogenic Activity. Pharm. Res. 2020, 37, 91. Weng, Y.H.; Ma, X.W.; Che, J.; Li, C.; Liu, J.; Chen, S.Z.; Wang, Y.Q.; Gan, Y.L.; Chen, H.; Hu, Z.B.; et al. Nanomicelle-Assisted Targeted Ocular Delivery with Enhanced Antiinflammatory Efficacy In Vivo. Adv. Sci. 2017, 5, 1700455. [Google Scholar] [CrossRef]
  49. Dai, L.; Li, X.; Yao, M.; Niu, P.; Yuan, X.; Li, K.; Chen, M.; Fu, Z.; Duan, X.; Liu, H.; et al. Programmable Prodrug Micelle with Size-Shrinkage and Charge-Reversal for Chemotherapy-Improved IDO Immunotherapy. Biomaterials 2020, 241, 119901. [Google Scholar] [CrossRef]
  50. Hwang, D.; Ramsey, J.D.; Kabanov, A.V. Polymeric Micelles for the Delivery of Poorly Soluble Drugs: From Nanoformulation to Clinical Approval. Adv. Drug Deliv. Rev. 2020, 156, 80–118. [Google Scholar] [CrossRef] [PubMed]
  51. Sun, H.; Meng, F.; Cheng, R.; Deng, C.; Zhong, Z. Reduction-Responsive Polymeric Micelles and Vesicles for Triggered Intracellular Drug Release. Antioxid. Redox Signal. 2014, 21, 755–767. [Google Scholar] [CrossRef] [PubMed]
  52. Yu, Y.; Chen, D.; Li, Y.; Yang, W.; Tu, J.; Shen, Y. Improving the Topical Ocular Pharmacokinetics of Lyophilized Cyclosporine A-Loaded Micelles: Formulation, in Vitro and in Vivo Studies. Drug Deliv. 2018, 25, 888–899. [Google Scholar] [CrossRef]
  53. Xu, X.; Sun, L.; Zhou, L.; Cheng, Y.; Cao, F. Functional Chitosan Oligosaccharide Nanomicelles for Topical Ocular Drug Delivery of Dexamethasone. Carbohydr. Polym. 2020, 227, 115356. [Google Scholar] [CrossRef] [PubMed]
  54. Lai, S.; Wei, Y.; Wu, Q.; Zhou, K.; Liu, T.; Zhang, Y.; Jiang, N.; Xiao, W.; Chen, J.; Liu, Q.; et al. Liposomes for Effective Drug Delivery to the Ocular Posterior Chamber. J. Nanobiotechnol. 2019, 17, 64. [Google Scholar] [CrossRef] [PubMed]
  55. Abdi, F.; Arkan, E.; Mansouri, K.; Shekarbeygi, Z.; Barzegari, E. Interactions of Bevacizumab with Chitosan Biopolymer Nanoparticles: Molecular Modeling and Spectroscopic Study. J. Mol. Liq. 2021, 339, 116655. [Google Scholar] [CrossRef]
  56. Ishida, T.; Harashima, H.; Kiwada, H. Liposome Clearance. Biosci. Rep. 2002, 22, 197–224. [Google Scholar] [CrossRef] [PubMed]
  57. Jin, X.; Zhu, L.; Xue, B.; Zhu, X.; Yan, D. Supramolecular Nanoscale Drug-Delivery System with Ordered Structure. Natl. Sci. Rev. 2019, 6, 1128–1137. [Google Scholar] [CrossRef] [PubMed]
  58. Ji, T.; Kohane, D.S. Nanoscale Systems for Local Drug Delivery. Nano Today 2019, 28, 100765. [Google Scholar] [CrossRef]
  59. Di, J.; Gao, X.; Du, Y.; Zhang, H.; Gao, J.; Zheng, A. Size, Shape, Charge and “Stealthy” Surface: Carrier Properties Affect the Drug Circulation Time in Vivo. Asian J. Pharm. Sci. 2021, 16, 444–458. [Google Scholar] [CrossRef]
  60. Rebibo, L.; Tam, C.; Sun, Y.; Shoshani, E.; Badihi, A.; Nassar, T.; Benita, S. Topical Tacrolimus Nanocapsules Eye Drops for Therapeutic Effect Enhancement in Both Anterior and Posterior Ocular Inflammation Models. J. Control. Release 2021, 333, 283–297. [Google Scholar] [CrossRef]
  61. Duan, Y.; Dhar, A.; Patel, C.; Khimani, M.; Neogi, S.; Sharma, P.; Siva Kumar, N.; Vekariya, R.L. A Brief Review on Solid Lipid Nanoparticles: Part and Parcel of Contemporary Drug Delivery Systems. RSC Adv. 2020, 10, 26777–26791. [Google Scholar] [CrossRef]
  62. Lancina, M.G.; Yang, H. Dendrimers for Ocular Drug Delivery. Can. J. Chem. 2017, 95, 897–902. [Google Scholar] [CrossRef]
  63. Lin, D.; Lei, L.; Shi, S.; Li, X. Stimulus-Responsive Hydrogel for Ophthalmic Drug Delivery. Macromol. Biosci. 2019, 19, e1900001. [Google Scholar] [CrossRef] [PubMed]
  64. Lynch, C.R.; Kondiah, P.P.D.; Choonara, Y.E.; du Toit, L.C.; Ally, N.; Pillay, V. Hydrogel Biomaterials for Application in Ocular Drug Delivery. Front. Bioeng. Biotechnol. 2020, 8, 228. [Google Scholar] [CrossRef] [PubMed]
  65. Nagai, N.; Otake, H. Novel Drug Delivery Systems for the Management of Dry Eye. Adv. Drug Deliv. Rev. 2022, 191, 114582. [Google Scholar] [CrossRef] [PubMed]
  66. Jacob, S.; Nair, A.B.; Shah, J. Emerging Role of Nanosuspensions in Drug Delivery Systems. Biomater. Res. 2020, 24, 3. [Google Scholar] [CrossRef]
  67. Xie, J.; Luo, Y.; Liu, Y.; Ma, Y.; Yue, P.; Yang, M. Novel Redispersible Nanosuspensions Stabilized by Co-Processed Nanocrystalline Cellulose-Sodium Carboxymethyl Starch for Enhancing Dissolution and Oral Bioavailability of Baicalin. Int. J. Nanomed. 2019, 14, 353–369. [Google Scholar] [CrossRef]
  68. Gade, S.S.; Pentlavalli, S.; Mishra, D.; Vora, L.K.; Waite, D.; Alvarez-Lorenzo, C.I.; Herrero Vanrell, M.R.; Laverty, G.; Larraneta, E.; Donnelly, R.F.; et al. Injectable Depot Forming Thermoresponsive Hydrogel for Sustained Intrascleral Delivery of Sunitinib Using Hollow Microneedles. J. Ocul. Pharmacol. Ther. 2022, 38, 433–448. [Google Scholar] [CrossRef]
  69. Gorantla, S.; Rapalli, V.K.; Waghule, T.; Singh, P.P.; Dubey, S.K.; Saha, R.N.; Singhvi, G. Nanocarriers for Ocular Drug Delivery: Current Status and Translational Opportunity. RSC Adv. 2020, 10, 27835–27855. [Google Scholar] [CrossRef]
  70. Cuenca, N.; Fernández-Sánchez, L.; Campello, L.; Maneu, V.; De la Villa, P.; Lax, P.; Pinilla, I. Cellular Responses Following Retinal Injuries and Therapeutic Approaches for Neurodegenerative Diseases. Prog. Retin. Eye Res. 2014, 43, 17–75. [Google Scholar] [CrossRef]
  71. Arranz-Romera, A.; Esteban-Pérez, S.; Molina-Martínez, I.T.; Bravo-Osuna, I.; Herrero-Vanrell, R. Co-Delivery of Glial Cell-Derived Neurotrophic Factor (GDNF) and Tauroursodeoxycholic Acid (TUDCA) from PLGA Microspheres: Potential Combination Therapy for Retinal Diseases. Drug Deliv. Transl. Res. 2021, 11, 566–580. [Google Scholar] [CrossRef]
  72. Martín-Sabroso, C.; Fraguas-Sánchez, A.I.; Aparicio-Blanco, J.; Cano-Abad, M.F.; Torres-Suárez, A.I. Critical Attributes of Formulation and of Elaboration Process of PLGA-Protein Microparticles. Int. J. Pharm. 2015, 480, 27–36. [Google Scholar] [CrossRef]
  73. Sen, M.; Bassetto, M.; Poulhes, F.; Zelphati, O.; Ueffing, M.; Arango-Gonzalez, B. Efficient Ocular Delivery of VCP SiRNA via Reverse Magnetofection in RHO P23H Rodent Retina Explants. Pharmaceutics 2021, 13, 225. [Google Scholar] [CrossRef] [PubMed]
  74. Sen, M.; Al-Amin, M.; Kicková, E.; Sadeghi, A.; Puranen, J.; Urtti, A.; Caliceti, P.; Salmaso, S.; Arango-Gonzalez, B.; Ueffing, M. Retinal Neuroprotection by Controlled Release of a VCP Inhibitor from Self-Assembled Nanoparticles. J. Control. Release 2021, 339, 307–320. [Google Scholar] [CrossRef] [PubMed]
  75. Platania, C.B.M.; Dei Cas, M.; Cianciolo, S.; Fidilio, A.; Lazzara, F.; Paroni, R.; Pignatello, R.; Strettoi, E.; Ghidoni, R.; Drago, F.; et al. Novel Ophthalmic Formulation of Myriocin: Implications in Retinitis Pigmentosa. Drug Deliv. 2019, 26, 237–243. [Google Scholar] [CrossRef]
  76. Strettoi, E.; Gargini, C.; Novelli, E.; Sala, G.; Piano, I.; Gasco, P.; Ghidoni, R. Inhibition of Ceramide Biosynthesis Preserves Photoreceptor Structure and Function in a Mouse Model of Retinitis Pigmentosa. Proc. Natl. Acad. Sci. USA 2010, 107, 18706–18711. [Google Scholar] [CrossRef] [PubMed]
  77. Xia, W.; Li, C.; Chen, Q.; Huang, J.; Zhao, Z.; Liu, P.; Xu, K.; Li, L.; Hu, F.; Zhang, S.; et al. Intravenous Route to Choroidal Neovascularization by Macrophage-Disguised Nanocarriers for MTOR Modulation. Acta Pharm. Sin. B 2022, 12, 2506–2521. [Google Scholar] [CrossRef] [PubMed]
  78. Mei, L.; Yu, M.; Liu, Y.; Weh, E.; Pawar, M.; Li, L.; Besirli, C.G.; Schwendeman, A.A. Synthetic High-Density Lipoprotein Nanoparticles Delivering Rapamycin for the Treatment of Age-Related Macular Degeneration. Nanomedicine 2022, 44, 102571. [Google Scholar] [CrossRef]
  79. Martin, D.F.; Maguire, M.G.; Fine, S.L.; Ying, G.; Jaffe, G.J.; Grunwald, J.E.; Toth, C.; Redford, M.; Ferris, F.L. Ranibizumab and Bevacizumab for Treatment of Neovascular Age-Related Macular Degeneration: Two-Year Results. Ophthalmology 2020, 127, S135–S145. [Google Scholar] [CrossRef]
  80. Feng, L.; Ju, M.; Lee, K.Y.V.; Mackey, A.; Evangelista, M.; Iwata, D.; Adamson, P.; Lashkari, K.; Foxton, R.; Shima, D.; et al. A Proinflammatory Function of Toll-Like Receptor 2 in the Retinal Pigment Epithelium as a Novel Target for Reducing Choroidal Neovascularization in Age-Related Macular Degeneration. Am. J. Pathol. 2017, 187, 2208–2221. [Google Scholar] [CrossRef]
  81. Zhang, L.; Yan, J.J.; Wang, H.Y.; Li, M.Q.; Wang, X.X.; Fan, L.; Wang, Y.S. A Trojan Horse Biomimetic Delivery System Using Mesenchymal Stem Cells for HIF-1α SiRNA-Loaded Nanoparticles on Retinal Pigment Epithelial Cells under Hypoxia Environment. Int. J. Ophthalmol. 2022, 15, 1743–1751. [Google Scholar] [CrossRef]
  82. Kimbrel, E.A.; Lanza, R. Next-Generation Stem Cells—Ushering in a New Era of Cell-Based Therapies. Nat. Rev. Drug Discov. 2020, 19, 463–479. [Google Scholar] [CrossRef]
  83. Nguyen, D.D.; Luo, L.J.; Yang, C.J.; Lai, J.Y. Highly Retina-Permeating and Long-Acting Resveratrol/Metformin Nanotherapeutics for Enhanced Treatment of Macular Degeneration. ACS Nano 2023, 17, 168–183. [Google Scholar] [CrossRef]
  84. Oshitari, T. Neurovascular Impairment and Therapeutic Strategies in Diabetic Retinopathy. Int. J. Environ. Res. Public Health 2021, 19, 439. [Google Scholar] [CrossRef]
  85. Zeng, L.; Ma, W.; Shi, L.; Chen, X.; Wu, R.; Zhang, Y.; Chen, H.; Chen, H. Poly(Lactic-Co-Glycolic Acid) Nanoparticle-Mediated Interleukin-12 Delivery for the Treatment of Diabetic Retinopathy. Int. J. Nanomed. 2019, 14, 6357–6369. [Google Scholar] [CrossRef]
  86. Romeo, A.; Bonaccorso, A.; Carbone, C.; Lupo, G.; Daniela Anfuso, C.; Giurdanella, G.; Caggia, C.; Randazzo, C.; Russo, N.; Luca Romano, G.; et al. Melatonin Loaded Hybrid Nanomedicine: DoE Approach, Optimization and in Vitro Study on Diabetic Retinopathy Model. Int. J. Pharm. 2022, 627, 122195. [Google Scholar] [CrossRef]
  87. Zingale, E.; Rizzo, S.; Bonaccorso, A.; Consoli, V.; Vanella, L.; Musumeci, T.; Spadaro, A.; Pignatello, R. Optimization of Lipid Nanoparticles by Response Surface Methodology to Improve the Ocular Delivery of Diosmin: Characterization and In-Vitro Anti-Inflammatory Assessment. Pharmaceutics 2022, 14, 1961. [Google Scholar] [CrossRef]
  88. Chauhan, I.; Yasir, M.; Verma, M.; Singh, A.P. Nanostructured Lipid Carriers: A Groundbreaking Approach for Transdermal Drug Delivery. Adv. Pharm. Bull. 2020, 10, 150–165. [Google Scholar] [CrossRef]
  89. Müller, R.H.; Shegokar, R.; Keck, C.M. 20 Years of Lipid Nanoparticles (SLN and NLC): Present State of Development and Industrial Applications. Curr. Drug Discov. Technol. 2011, 8, 207–227. [Google Scholar] [CrossRef] [PubMed]
  90. Radwan, S.E.S.; El-Kamel, A.; Zaki, E.I.; Burgalassi, S.; Zucchetti, E.; El-Moslemany, R.M. Hyaluronic-Coated Albumin Nanoparticles for the Non-Invasive Delivery of Apatinib in Diabetic Retinopathy. Int. J. Nanomed. 2021, 16, 4481–4494. [Google Scholar] [CrossRef]
  91. Mahaling, B.; Srinivasarao, D.A.; Raghu, G.; Kasam, R.K.; Bhanuprakash Reddy, G.; Katti, D.S. A Non-Invasive Nanoparticle Mediated Delivery of Triamcinolone Acetonide Ameliorates Diabetic Retinopathy in Rats. Nanoscale 2018, 10, 16485–16498. [Google Scholar] [CrossRef] [PubMed]
  92. Tang, B.C.; Dawson, M.; Lai, S.K.; Wang, Y.Y.; Suk, J.S.; Yang, M.; Zeitlin, P.; Boyle, M.P.; Fu, J.; Hanes, J. Biodegradable Polymer Nanoparticles That Rapidly Penetrate the Human Mucus Barrier. Proc. Natl. Acad. Sci. USA 2009, 106, 19268–19273. [Google Scholar] [CrossRef] [PubMed]
  93. Navarro-Partida, J.; Altamirano-Vallejo, J.C.; la Rosa, A.G.D.; Armendariz-Borunda, J.; Castro-Castaneda, C.R.; Santos, A. Safety and Tolerability of Topical Ophthalmic Triamcinolone Acetonide-Loaded Liposomes Formulation and Evaluation of Its Biologic Activity in Patients with Diabetic Macular Edema. Pharmaceutics 2021, 13, 322. [Google Scholar] [CrossRef] [PubMed]
  94. Chan, C.K.M.; Fan, D.S.P.; Chan, W.M.; Lai, W.W.; Lee, V.Y.W.; Lam, D.S.C. Ocular-Hypertensive Response and Corneal Endothelial Changes after Intravitreal Triamcinolone Injections in Chinese Subjects: A 6-Month Follow-up Study. Eye 2005, 19, 625–630. [Google Scholar] [CrossRef] [PubMed]
  95. Khalil, M.; Hashmi, U.; Riaz, R.; Rukh Abbas, S. Chitosan Coated Liposomes (CCL) Containing Triamcinolone Acetonide for Sustained Delivery: A Potential Topical Treatment for Posterior Segment Diseases. Int. J. Biol. Macromol. 2020, 143, 483–491. [Google Scholar] [CrossRef]
  96. Alambiaga-Caravaca, A.M.; Domenech-Monsell, I.M.; Sebastián-Morelló, M.; Calatayud-Pascual, M.A.; Merino, V.; Rodilla, V.; López-Castellano, A. Development, Characterization, and Ex Vivo Evaluation of an Insert for the Ocular Administration of Progesterone. Int. J. Pharm. 2021, 606, 120921. [Google Scholar] [CrossRef] [PubMed]
  97. Yadav, M.; Schiavone, N.; Guzman-Aranguez, A.; Giansanti, F.; Papucci, L.; Perez de Lara, M.J.; Singh, M.; Kaur, I.P. Correction to: Atorvastatin-Loaded Solid Lipid Nanoparticles as Eye Drops: Proposed Treatment Option for Age-Related Macular Degeneration (AMD). Drug Deliv. Transl. Res. 2020, 10, 1531. [Google Scholar] [CrossRef]
  98. Mitra, R.N.; Gao, R.; Zheng, M.; Wu, M.J.; Voinov, M.A.; Smirnov, A.I.; Smirnova, T.I.; Wang, K.; Chavala, S.; Han, Z. Glycol Chitosan Engineered Autoregenerative Antioxidant Significantly Attenuates Pathological Damages in Models of Age-Related Macular Degeneration. ACS Nano 2017, 11, 4669–4685. [Google Scholar] [CrossRef]
  99. Nagai, N.; Daigaku, R.; Motoyama, R.; Kaji, H.; Abe, T. Release of Ranibizumab Using a Porous Poly(Dimethylsiloxane) Capsule Suppressed Laser-Induced Choroidal Neovascularization via the Transscleral Route. J. Mater. Sci. Mater. Med. 2022, 34, 5. [Google Scholar] [CrossRef] [PubMed]
  100. Qiu, F.; Meng, T.; Chen, Q.; Zhou, K.; Shao, Y.; Matlock, G.; Ma, X.; Wu, W.; Du, Y.; Wang, X.; et al. Fenofibrate-Loaded Biodegradable Nanoparticles for the Treatment of Experimental Diabetic Retinopathy and Neovascular Age-Related Macular Degeneration. Mol. Pharm. 2019, 16, 1958–1970. [Google Scholar] [CrossRef]
  101. Sun, Q.; Shen, Y.; Su, L.; Xu, X. Inhibition of Pathological Retinal Neovascularization by a Small Peptide Derived from Human Tissue-Type Plasminogen Kringle 2. Front. Pharmacol. 2020, 10, 1639. [Google Scholar] [CrossRef]
  102. Ishibazawa, A.; Nagaoka, T.; Yokota, H.; Takahashi, A.; Omae, T.; Song, Y.S.; Takahashi, T.; Yoshida, A. Characteristics of Retinal Neovascularization in Proliferative Diabetic Retinopathy Imaged by Optical Coherence Tomography Angiography. Investig. Ophthalmol. Vis. Sci. 2016, 57, 6247–6255. [Google Scholar] [CrossRef]
  103. Sacconi, R.; Fragiotta, S.; Sarraf, D.; Sadda, S.V.R.; Freund, K.B.; Parravano, M.; Corradetti, G.; Cabral, D.; Capuano, V.; Miere, A.; et al. Towards a Better Understanding of Non-Exudative Choroidal and Macular Neovascularization. Prog. Retin. Eye Res. 2023, 92, 101113. [Google Scholar] [CrossRef] [PubMed]
  104. Fernandes, A.R.; dos Santos, T.; Granja, P.L.; Sanchez-Lopez, E.; Garcia, M.L.; Silva, A.M.; Souto, E.B. Permeability, Anti-Inflammatory and Anti-VEGF Profiles of Steroidal-Loaded Cationic Nanoemulsions in Retinal Pigment Epithelial Cells under Oxidative Stress. Int. J. Pharm. 2022, 617, 121615. [Google Scholar] [CrossRef] [PubMed]
  105. García-Estrada, P.; García-Bon, M.A.; López-Naranjo, E.J.; Basaldúa-Pérez, D.N.; Santos, A.; Navarro-Partida, J. Polymeric Implants for the Treatment of Intraocular Eye Diseases: Trends in Biodegradable and Non-Biodegradable Materials. Pharmaceutics 2021, 13, 701. [Google Scholar] [CrossRef] [PubMed]
  106. Gil-Martínez, M.; Santos-Ramos, P.; Fernández-Rodríguez, M.; Abraldes, M.J.; Rodríguez-Cid, M.J.; Santiago-Varela, M.; Fernández-Ferreiro, A.; Gómez-Ulla, F. Pharmacological Advances in the Treatment of Age-Related Macular Degeneration. Curr. Med. Chem. 2020, 27, 583–598. [Google Scholar] [CrossRef]
  107. Ferrara, N.; Adamis, A.P. Ten Years of Anti-Vascular Endothelial Growth Factor Therapy. Nat. Rev. Drug Discov. 2016, 15, 385–403. [Google Scholar] [CrossRef]
  108. Klettner, A.; Recber, M.; Roider, J. Comparison of the Efficacy of Aflibercept, Ranibizumab, and Bevacizumab in an RPE/Choroid Organ Culture. Graefes Arch. Clin. Exp. Ophthalmol. 2014, 252, 1593–1598. [Google Scholar] [CrossRef] [PubMed]
  109. Oo, C.; Kalbag, S.S. Leveraging the Attributes of Biologics and Small Molecules, and Releasing the Bottlenecks: A New Wave of Revolution in Drug Development. Expert. Rev. Clin. Pharmacol. 2016, 9, 747–749. [Google Scholar] [CrossRef]
  110. Li, J.; Mooney, D.J. Designing Hydrogels for Controlled Drug Delivery. Nat. Rev. Mater. 2016, 1, 16071. [Google Scholar] [CrossRef] [PubMed]
  111. Galante, R.; Pinto, T.J.A.; Colaço, R.; Serro, A.P. Sterilization of Hydrogels for Biomedical Applications: A Review. J. Biomed. Mater. Res. B Appl. Biomater. 2018, 106, 2472–2492. [Google Scholar] [CrossRef]
  112. Bordbar-Khiabani, A.; Gasik, M. Smart Hydrogels for Advanced Drug Delivery Systems. Int. J. Mol. Sci. 2022, 23, 3665. [Google Scholar] [CrossRef]
  113. Osswald, C.R.; Kang-Mieler, J.J. Controlled and Extended In Vitro Release of Bioactive Anti-Vascular Endothelial Growth Factors from a Microsphere-Hydrogel Drug Delivery System. Curr. Eye Res. 2016, 41, 1216–1222. [Google Scholar] [CrossRef] [PubMed]
  114. Osswald, C.R.; Guthrie, M.J.; Avila, A.; Valio, J.A.; Mieler, W.F.; Kang-Mieler, J.J. In Vivo Efficacy of an Injectable Microsphere-Hydrogel Ocular Drug Delivery System. Curr. Eye Res. 2017, 42, 1293–1301. [Google Scholar] [CrossRef] [PubMed]
  115. Hu, C.C.; Chiu, Y.C.; Chaw, J.R.; Chen, C.F.; Liu, H.W. Thermo-Responsive Hydrogel as an Anti-VEGF Drug Delivery System to Inhibit Retinal Angiogenesis in Rex Rabbits. Technol. Health Care 2019, 27, S153–S163. [Google Scholar] [CrossRef]
  116. Xue, K.; Zhao, X.; Zhang, Z.; Qiu, B.; Tan, Q.S.W.; Ong, K.H.; Liu, Z.; Parikh, B.H.; Barathi, V.A.; Yu, W.; et al. Sustained Delivery of Anti-VEGFs from Thermogel Depots Inhibits Angiogenesis without the Need for Multiple Injections. Biomater. Sci. 2019, 7, 4603–4614. [Google Scholar] [CrossRef]
  117. Liu, W.; Lee, B.S.; Mieler, W.F.; Kang-Mieler, J.J. Biodegradable Microsphere-Hydrogel Ocular Drug Delivery System for Controlled and Extended Release of Bioactive Aflibercept In Vitro. Curr. Eye Res. 2019, 44, 264–274. [Google Scholar] [CrossRef]
  118. Liu, W.; Tawakol, A.P.; Rudeen, K.M.; Mieler, W.F.; Kang-Mieler, J.J. Treatment Efficacy and Biocompatibility of a Biodegradable Aflibercept-Loaded Microsphere-Hydrogel Drug Delivery System. Transl. Vis. Sci. Technol. 2020, 9, 13. [Google Scholar] [CrossRef]
  119. Fan, W.; Li, S.; Tao, J.; Yu, C.; Sun, M.; Xie, Z.; Wu, X.; Ge, L.; Wu, Y.; Liu, Y. Anti-Vascular Endothelial Growth Factor Drug Conbercept-Loaded Peptide Hydrogel Reduced Angiogenesis in the Neovascular Age-Related Macular Degeneration. J. Biomed. Nanotechnol. 2022, 18, 277–287. [Google Scholar] [CrossRef] [PubMed]
  120. Li, J.; Tian, Q.; Sun, H.; Zhang, Y.; Yang, X.; Kaur, P.; Wang, R.; Fang, Y.; Yan, H.; Du, X.; et al. A Novel, Liposome-Loaded, Injectable Hydrogel for Enhanced Treatment of Choroidal Neovascularization by Sub-Tenon’s Injection. Mater. Today Nano 2022, 20, 100264. [Google Scholar] [CrossRef]
  121. Tanetsugu, Y.; Tagami, T.; Terukina, T.; Ogawa, T.; Ohta, M.; Ozeki, T. Development of a Sustainable Release System for a Ranibizumab Biosimilar Using Poly(Lactic-Co-Glycolic Acid) Biodegradable Polymer-Based Microparticles as a Platform. Biol. Pharm. Bull. 2017, 40, 145–150. [Google Scholar] [CrossRef]
  122. Sousa, F.; Cruz, A.; Fonte, P.; Pinto, I.M.; Neves-Petersen, M.T.; Sarmento, B. A New Paradigm for Antiangiogenic Therapy through Controlled Release of Bevacizumab from PLGA Nanoparticles. Sci. Rep. 2017, 7, 3736. [Google Scholar] [CrossRef]
  123. Sousa, F.; Cruz, A.; Pinto, I.M.; Sarmento, B. Nanoparticles Provide Long-Term Stability of Bevacizumab Preserving Its Antiangiogenic Activity. Acta Biomater. 2018, 78, 285–295. [Google Scholar] [CrossRef]
  124. Zhang, X.P.; Sun, J.G.; Yao, J.; Shan, K.; Liu, B.H.; Yao, M.D.; Ge, H.M.; Jiang, Q.; Zhao, C.; Yan, B. Effect of Nanoencapsulation Using Poly (Lactide-Co-Glycolide) (PLGA) on Anti-Angiogenic Activity of Bevacizumab for Ocular Angiogenesis Therapy. Biomed. Pharmacother. 2018, 107, 1056–1063. [Google Scholar] [CrossRef] [PubMed]
  125. Kelly, S.J.; Hirani, A.; Shahidadpury, V.; Solanki, A.; Halasz, K.; Gupta, S.V.; Madow, B.; Sutariya, V. Aflibercept Nanoformulation Inhibits VEGF Expression in Ocular In Vitro Model: A Preliminary Report. Biomedicines 2018, 6, 92. [Google Scholar] [CrossRef] [PubMed]
  126. Yan, J.; Peng, X.; Cai, Y.; Cong, W. Development of Facile Drug Delivery Platform of Ranibizumab Fabricated PLGA-PEGylated Magnetic Nanoparticles for Age-Related Macular Degeneration Therapy. J. Photochem. Photobiol. B 2018, 183, 133–136. [Google Scholar] [CrossRef] [PubMed]
  127. Liu, J.; Zhang, X.; Li, G.; Xu, F.; Li, S.; Teng, L.; Li, Y.; Sun, F. Anti-Angiogenic Activity Of Bevacizumab-Bearing Dexamethasone-Loaded PLGA Nanoparticles For Potential Intravitreal Applications. Int. J. Nanomed. 2019, 14, 8819–8834. [Google Scholar] [CrossRef]
  128. Heljak, M.K.; Swieszkowski, W. In Silico Model of Bevacizumab Sustained Release from Intravitreal Administrated PLGA Drug-Loaded Microspheres. Mater. Lett. 2021, 307, 131080. [Google Scholar] [CrossRef]
  129. Liu, J.; Li, S.; Li, G.; Li, X.; Yu, C.; Fu, Z.; Li, X.; Teng, L.; Li, Y.; Sun, F. Highly Bioactive, Bevacizumab-Loaded, Sustained-Release PLGA/PCADK Microspheres for Intravitreal Therapy in Ocular Diseases. Int. J. Pharm. 2019, 563, 228–236. [Google Scholar] [CrossRef]
  130. Tsujinaka, H.; Fu, J.; Shen, J.; Yu, Y.; Hafiz, Z.; Kays, J.; McKenzie, D.; Cardona, D.; Culp, D.; Peterson, W.; et al. Sustained Treatment of Retinal Vascular Diseases with Self-Aggregating Sunitinib Microparticles. Nat. Commun. 2020, 11, 694. [Google Scholar] [CrossRef] [PubMed]
  131. Luo, L.; Yang, J.; Oh, Y.; Hartsock, M.J.; Xia, S.; Kim, Y.C.; Ding, Z.; Meng, T.; Eberhart, C.G.; Ensign, L.M.; et al. Controlled Release of Corticosteroid with Biodegradable Nanoparticles for Treating Experimental Autoimmune Uveitis. J. Control. Release 2019, 296, 68–80. [Google Scholar] [CrossRef] [PubMed]
  132. Cai, W.; Chen, Q.; Shen, T.; Yang, Q.; Hu, W.; Zhao, P.; Yu, J. Intravenous Anti-VEGF Agents with RGD Peptide-Targeted Core Cross-Linked Star (CCS) Polymers Modified with Indocyanine Green for Imaging and Treatment of Laser-Induced Choroidal Neovascularization. Biomater. Sci. 2020, 8, 4481–4491. [Google Scholar] [CrossRef]
  133. Luis de Redín, I.; Boiero, C.; Martínez-Ohárriz, M.C.; Agüeros, M.; Ramos, R.; Peñuelas, I.; Allemandi, D.; Llabot, J.M.; Irache, J.M. Human Serum Albumin Nanoparticles for Ocular Delivery of Bevacizumab. Int. J. Pharm. 2018, 541, 214–223. [Google Scholar] [CrossRef]
  134. Luis de Redín, I.; Boiero, C.; Recalde, S.; Agüeros, M.; Allemandi, D.; Llabot, J.M.; García-Layana, A.; Irache, J.M. In Vivo Effect of Bevacizumab-Loaded Albumin Nanoparticles in the Treatment of Corneal Neovascularization. Exp. Eye Res. 2019, 185, 107697. [Google Scholar] [CrossRef]
  135. Llabot, J.M.; Luis de Redin, I.; Agüeros, M.; Dávila Caballero, M.J.; Boiero, C.; Irache, J.M.; Allemandi, D. In Vitro Characterization of New Stabilizing Albumin Nanoparticles as a Potential Topical Drug Delivery System in the Treatment of Corneal Neovascularization (CNV). J. Drug Deliv. Sci. Technol. 2019, 52, 379–385. [Google Scholar] [CrossRef]
  136. Pandit, J.; Sultana, Y.; Aqil, M. Chitosan-Coated PLGA Nanoparticles of Bevacizumab as Novel Drug Delivery to Target Retina: Optimization, Characterization, and in Vitro Toxicity Evaluation. Artif. Cells Nanomed. Biotechnol. 2017, 45, 1397–1407. [Google Scholar] [CrossRef]
  137. Ugurlu, N.; Aşık, M.D.; Çakmak, H.B.; Tuncer, S.; Turk, M.; Çagıl, N.; Denkbas, E.B. Transscleral Delivery of Bevacizumab-Loaded Chitosan Nanoparticles. J. Biomed. Nanotechnol. 2019, 15, 830–838. [Google Scholar] [CrossRef]
  138. Savin, C.L.; Popa, M.; Delaite, C.; Costuleanu, M.; Costin, D.; Peptu, C.A. Chitosan Grafted-Poly(Ethylene Glycol) Methacrylate Nanoparticles as Carrier for Controlled Release of Bevacizumab. Mater. Sci. Eng. C Mater. Biol. Appl. 2019, 98, 843–860. [Google Scholar] [CrossRef] [PubMed]
  139. Jiang, P.; Chaparro, F.J.; Cuddington, C.T.; Palmer, A.F.; Ohr, M.P.; Lannutti, J.J.; Swindle-Reilly, K.E. Injectable Biodegradable Bi-Layered Capsule for Sustained Delivery of Bevacizumab in Treating Wet Age-Related Macular Degeneration. J. Control. Release 2020, 320, 442–456. [Google Scholar] [CrossRef] [PubMed]
  140. Jiang, P.; Jacobs, K.M.; Ohr, M.P.; Swindle-Reilly, K.E. Chitosan-Polycaprolactone Core-Shell Microparticles for Sustained Delivery of Bevacizumab. Mol. Pharm. 2020, 17, 2570–2584. [Google Scholar] [CrossRef]
  141. Chaharband, F.; Daftarian, N.; Kanavi, M.R.; Varshochian, R.; Hajiramezanali, M.; Norouzi, P.; Arefian, E.; Atyabi, F.; Dinarvand, R. Trimethyl Chitosan-Hyaluronic Acid Nano-Polyplexes for Intravitreal VEGFR-2 SiRNA Delivery: Formulation and in Vivo Efficacy Evaluation. Nanomedicine 2020, 26, 102181. [Google Scholar] [CrossRef]
  142. Formica, M.L.; Legeay, S.; Bejaud, J.; Montich, G.G.; Ullio Gamboa, G.V.; Benoit, J.P.; Palma, S.D. Novel Hybrid Lipid Nanocapsules Loaded with a Therapeutic Monoclonal Antibody—Bevacizumab—And Triamcinolone Acetonide for Combined Therapy in Neovascular Ocular Pathologies. Mater. Sci. Eng. C Mater. Biol. Appl. 2021, 119, 111398. [Google Scholar] [CrossRef]
  143. Mu, H.; Wang, Y.; Chu, Y.; Jiang, Y.; Hua, H.; Chu, L.; Wang, K.; Wang, A.; Liu, W.; Li, Y.; et al. Multivesicular Liposomes for Sustained Release of Bevacizumab in Treating Laser-Induced Choroidal Neovascularization. Drug Deliv. 2018, 25, 1372–1383. [Google Scholar] [CrossRef] [PubMed]
  144. Karumanchi, D.K.; Skrypai, Y.; Thomas, A.; Gaillard, E.R. Rational Design of Liposomes for Sustained Release Drug Delivery of Bevacizumab to Treat Ocular Angiogenesis. J. Drug Deliv. Sci. Technol. 2018, 47, 275–282. [Google Scholar] [CrossRef]
  145. de Cristo Soares Alves, A.; Lavayen, V.; Figueiró, F.; Dallemole, D.R.; de Fraga Dias, A.; Cé, R.; Battastini, A.M.O.; Guterres, S.S.; Pohlmann, A.R. Chitosan-Coated Lipid-Core Nanocapsules Functionalized with Gold-III and Bevacizumab Induced In Vitro Cytotoxicity against C6 Cell Line and In Vivo Potent Antiangiogenic Activity. Pharm. Res. 2020, 37, 91. [Google Scholar] [CrossRef] [PubMed]
  146. Jiang, P.; Choi, A.; Swindle-Reilly, K.E. Controlled Release of Anti-VEGF by Redox-Responsive Polydopamine Nanoparticles. Nanoscale 2020, 12, 17298–17311. [Google Scholar] [CrossRef] [PubMed]
  147. Webber, A.L.; Sharwood, P. Practical Use and Prescription of Ocular Medications in Children and Infants. Clin. Exp. Optom. 2021, 104, 385–395. [Google Scholar] [CrossRef]
  148. Sheybani, N.D.; Yang, H. Pediatric Ocular Nanomedicines: Challenges and Opportunities. Chin. Chem. Lett. 2017, 28, 1817–1821. [Google Scholar] [CrossRef]
  149. Sunita, M.; Manisha, S.; Sanjeev, M.K.; Ravi, K.S.; Aarzoo, J.; Ajai, A. Anatomical and Clinical Characteristics of Paediatric and Adult Eyes. Natl. J. Clin. Anat. 2021, 10, 5. [Google Scholar] [CrossRef]
  150. Mudgil, P.; Borchman, D.; Ramasubramanian, A. Insights into Tear Film Stability from Babies and Young Adults: A Study of Human Meibum Lipid Conformation and Rheology. Int. J. Mol. Sci. 2018, 19, 3502. [Google Scholar] [CrossRef]
  151. Chidi-Egboka, N.C.; Briggs, N.E.; Jalbert, I.; Golebiowski, B. The Ocular Surface in Children: A Review of Current Knowledge and Meta-Analysis of Tear Film Stability and Tear Secretion in Children. Ocul. Surf. 2019, 17, 28–39. [Google Scholar] [CrossRef]
  152. Mutlu, F.M.; Sarici, S.U. Treatment of Retinopathy of Prematurity: A Review of Conventional and Promising New Therapeutic Options. Int. J. Ophthalmol. 2013, 6, 228–236. [Google Scholar] [CrossRef]
  153. Mukherjee, P.; Bhattacharya, R.; Wang, P.; Wang, L.; Basu, S.; Nagy, J.A.; Atala, A.; Mukhopadhyay, D.; Soker, S. Antiangiogenic Properties of Gold Nanoparticles. Clin. Cancer Res. 2005, 11, 3530–3534. [Google Scholar] [CrossRef]
  154. Saeed, B.A.; Lim, V.; Yusof, N.A.; Khor, K.Z.; Rahman, H.S.; Samad, N.A. Antiangiogenic Properties of Nanoparticles: A Systematic Review. Int. J. Nanomed. 2019, 14, 5135–5146. [Google Scholar] [CrossRef]
  155. Kim, J.H.; Kim, M.H.; Jo, D.H.; Yu, Y.S.; Lee, T.G.; Kim, J.H. The Inhibition of Retinal Neovascularization by Gold Nanoparticles via Suppression of VEGFR-2 Activation. Biomaterials 2011, 32, 1865–1871. [Google Scholar] [CrossRef] [PubMed]
  156. Kolosnjaj-Tabi, J.; Volatron, J.; Gazeau, F. Basic Principles of in Vivo Distribution, Toxicity, and Degradation of Prospective Inorganic Nanoparticles for Imaging. In Design and Applications of Nanoparticles in Biomedical Imaging; Springer: Cham, Switzerland, 2016; pp. 9–41. [Google Scholar] [CrossRef]
  157. Radomska, A.; Leszczyszyn, J.; Radomski, M.W. The Nanopharmacology and Nanotoxicology of Nanomaterials: New Opportunities and Challenges. Adv. Clin. Exp. Med. 2016, 25, 151–162. [Google Scholar] [CrossRef] [PubMed]
  158. Higbee-Dempsey, E.M.; Amirshaghaghi, A.; Case, M.J.; Bouché, M.; Kim, J.; Cormode, D.P.; Tsourkas, A. Biodegradable Gold Nanoclusters with Improved Excretion Due to PH-Triggered Hydrophobic-to-Hydrophilic Transition. J. Am. Chem. Soc. 2020, 142, 7783–7794. [Google Scholar] [CrossRef] [PubMed]
  159. Mitchell, M.J.; Billingsley, M.M.; Haley, R.M.; Wechsler, M.E.; Peppas, N.A.; Langer, R. Engineering Precision Nanoparticles for Drug Delivery. Nat. Rev. Drug Discov. 2020, 20, 101–124. [Google Scholar] [CrossRef] [PubMed]
  160. Bohley, M.; Dillinger, A.E.; Schweda, F.; Ohlmann, A.; Braunger, B.M.; Tamm, E.R.; Goepferich, A. A Single Intravenous Injection of Cyclosporin A-Loaded Lipid Nanocapsules Prevents Retinopathy of Prematurity. Sci. Adv. 2022, 8. [Google Scholar] [CrossRef]
  161. Li, Q.; Weng, J.; Wong, S.N.; Thomas Lee, W.Y.; Chow, S.F. Nanoparticulate Drug Delivery to the Retina. Mol. Pharm. 2021, 18, 506–521. [Google Scholar] [CrossRef]
  162. Bertrand, N.; Leroux, J.C. The Journey of a Drug-Carrier in the Body: An Anatomo-Physiological Perspective. J. Control. Release 2012, 161, 152–163. [Google Scholar] [CrossRef]
  163. Hagigit, T.; Abdulrazik, M.; Valamanesh, F.; Behar-Cohen, F.; Benita, S. Ocular Antisense Oligonucleotide Delivery by Cationic Nanoemulsion for Improved Treatment of Ocular Neovascularization: An in-Vivo Study in Rats and Mice. J. Control. Release 2012, 160, 225–231. [Google Scholar] [CrossRef]
  164. Hagigit, T.; Nassar, T.; Behar-Cohen, F.; Lambert, G.; Benita, S. The Influence of Cationic Lipid Type on In-Vitro Release Kinetic Profiles of Antisense Oligonucleotide from Cationic Nanoemulsions. Eur. J. Pharm. Biopharm. 2008, 70, 248–259. [Google Scholar] [CrossRef]
  165. Hagigit, T.; Abdulrazik, M.; Orucov, F.; Valamanesh, F.; Lambert, M.; Lambert, G.; Behar-Cohen, F.; Benita, S. Topical and Intravitreous Administration of Cationic Nanoemulsions to Deliver Antisense Oligonucleotides Directed towards VEGF KDR Receptors to the Eye. J. Control. Release 2010, 145, 297–305. [Google Scholar] [CrossRef] [PubMed]
  166. Xu, W.; Wu, Y.; Hu, Z.; Sun, L.; Dou, G.; Zhang, Z.; Wang, H.; Guo, C.; Wang, Y. Exosomes from Microglia Attenuate Photoreceptor Injury and Neovascularization in an Animal Model of Retinopathy of Prematurity. Mol. Ther. Nucleic Acids 2019, 16, 778–790. [Google Scholar] [CrossRef] [PubMed]
  167. Moisseiev, E.; Anderson, J.D.; Oltjen, S.; Goswami, M.; Zawadzki, R.J.; Nolta, J.A.; Park, S.S. Protective Effect of Intravitreal Administration of Exosomes Derived from Mesenchymal Stem Cells on Retinal Ischemia. Curr. Eye Res. 2017, 42, 1358–1367. [Google Scholar] [CrossRef] [PubMed]
  168. Ebneter, A.; Kokona, D.; Schneider, N.; Zinkernagel, M.S. Microglia Activation and Recruitment of Circulating Macrophages During Ischemic Experimental Branch Retinal Vein Occlusion. Investig. Ophthalmol. Vis. Sci. 2017, 58, 944–953. [Google Scholar] [CrossRef]
  169. Deliyanti, D.; Talia, D.M.; Zhu, T.; Maxwell, M.J.; Agrotis, A.; Jerome, J.R.; Hargreaves, E.M.; Gerondakis, S.; Hibbs, M.L.; Mackay, F.; et al. Foxp3+ Tregs Are Recruited to the Retina to Repair Pathological Angiogenesis. Nat. Commun. 2017, 8, 748. [Google Scholar] [CrossRef]
  170. Muffat, J.; Li, Y.; Yuan, B.; Mitalipova, M.; Omer, A.; Corcoran, S.; Bakiasi, G.; Tsai, L.H.; Aubourg, P.; Ransohoff, R.M.; et al. Efficient Derivation of Microglia-like Cells from Human Pluripotent Stem Cells. Nat. Med. 2016, 22, 1358–1367. [Google Scholar] [CrossRef]
  171. Wang, Z.; Liu, A.; Zhang, H.; Wang, M.; Tang, Q.; Huang, Y.; Wang, L. Inhibition of Retinal Neovascularization by VEGF SiRNA Delivered via Bioreducible Lipid-like Nanoparticles. Graefes Arch. Clin. Exp. Ophthalmol. 2020, 258, 2407–2418. [Google Scholar] [CrossRef]
  172. Singerman, L. Combination Therapy Using the Small Interfering RNA Bevasiranib. Retina 2009, 29, S49–S50. [Google Scholar] [CrossRef]
  173. Jiang, Y.; Huo, S.; Hardie, J.; Liang, X.J.; Rotello, V.M. Progress and Perspective of Inorganic Nanoparticle-Based SiRNA Delivery Systems. Expert Opin. Drug Deliv. 2016, 13, 547–559. [Google Scholar] [CrossRef]
  174. Huang, K.; Lin, Z.; Ge, Y.; Chen, X.; Pan, Y.; Lv, Z.; Sun, X.; Yu, H.; Chen, J.; Yao, Q. Immunomodulation of MiRNA-223-Based Nanoplatform for Targeted Therapy in Retinopathy of Prematurity. J. Control. Release 2022, 350, 789–802. [Google Scholar] [CrossRef] [PubMed]
  175. Sung, M.S.; Moon, M.J.; Thomas, R.G.; Kim, S.Y.; Lee, J.S.; Jeong, Y.Y.; Park, I.K.; Park, S.W. Intravitreal Injection of Liposomes Loaded with a Histone Deacetylase Inhibitor Promotes Retinal Ganglion Cell Survival in a Mouse Model of Optic Nerve Crush. Int. J. Mol. Sci. 2020, 21, 9297. [Google Scholar] [CrossRef] [PubMed]
  176. Wang, T.; Li, Y.; Guo, M.; Dong, X.; Liao, M.; Du, M.; Wang, X.; Yin, H.; Yan, H. Exosome-Mediated Delivery of the Neuroprotective Peptide PACAP38 Promotes Retinal Ganglion Cell Survival and Axon Regeneration in Rats With Traumatic Optic Neuropathy. Front. Cell Dev. Biol. 2021, 9, 659783. [Google Scholar] [CrossRef] [PubMed]
  177. Mezu-Ndubuisi, O.J.; Wang, Y.; Schoephoerster, J.; Falero-Perez, J.; Zaitoun, I.S.; Sheibani, N.; Gong, S. Intravitreal Delivery of VEGF-A165-Loaded PLGA Microparticles Reduces Retinal Vaso-Obliteration in an In Vivo Mouse Model of Retinopathy of Prematurity. Curr. Eye Res. 2019, 44, 275–286. [Google Scholar] [CrossRef] [PubMed]
  178. Hong, E.H.; Shin, Y.U.; Cho, H. Retinopathy of Prematurity: A Review of Epidemiology and Current Treatment Strategies. Clin. Exp. Pediatr. 2022, 65, 115–126. [Google Scholar] [CrossRef]
  179. Desjarlais, M.; Rivera, J.C.; Lahaie, I.; Cagnone, G.; Wirt, M.; Omri, S.; Chemtob, S. MicroRNA Expression Profile in Retina and Choroid in Oxygen-Induced Retinopathy Model. PLoS ONE 2019, 14, e0218282. [Google Scholar] [CrossRef]
  180. Lee, S.S.; Hughes, P.; Ross, A.D.; Robinson, M.R. Biodegradable Implants for Sustained Drug Release in the Eye. Pharm. Res. 2010, 27, 2043–2053. [Google Scholar] [CrossRef]
  181. Castro-Navarro, V.; Cervera-Taulet, E.; Navarro-Palop, C.; Monferrer-Adsuara, C.; Hernández-Bel, L.; Montero-Hernández, J. Intravitreal Dexamethasone Implant Ozurdex® in Naïve and Refractory Patients with Different Subtypes of Diabetic Macular Edema. BMC Ophthalmol. 2019, 19, 15. [Google Scholar] [CrossRef]
  182. Kuno, N.; Fujii, S. Biodegradable Intraocular Therapies for Retinal Disorders: Progress to Date. Drugs Aging 2010, 27, 117–134. [Google Scholar] [CrossRef]
  183. Khiev, D.; Mohamed, Z.A.; Vichare, R.; Paulson, R.; Bhatia, S.; Mohapatra, S.; Lobo, G.P.; Valapala, M.; Kerur, N.; Passaglia, C.L.; et al. Emerging Nano-Formulations and Nanomedicines Applications for Ocular Drug Delivery. Nanomaterials 2021, 11, 173. [Google Scholar] [CrossRef]
  184. Wong, J.G.; Chang, A.; Guymer, R.H.; Wickremasinghe, S.; Reilly, E.; Bell, N.; Vantipalli, S.; Moshfeghi, A.A.; Goldstein, M.H. Phase 1 Study of an Intravitreal Axitinib Hydrogel-Based Implant for the Treatment of Neovascular Age-Related Macular Degeneration (NAMD). Investig. Ophthalmol. Vis. Sci. 2021, 62, 218. [Google Scholar]
  185. Alshaikh, R.A.; Waeber, C.; Ryan, K.B. Polymer Based Sustained Drug Delivery to the Ocular Posterior Segment: Barriers and Future Opportunities for the Treatment of Neovascular Pathologies. Adv. Drug Deliv. Rev. 2022, 187, 114342. [Google Scholar] [CrossRef] [PubMed]
  186. Vinores, S.A. Pegaptanib in the Treatment of Wet, Age-Related Macular Degeneration. Int. J. Nanomed. 2006, 1, 263–268. [Google Scholar]
  187. Yang, M.; Peterson, W.M.; Yu, Y.; Kays, J.; Cardona, D.; Culp, D.; Gilger, B.C.; Cleland, J. GB-102 for Wet AMD: A Novel Injectable Formulation That Safely Delivers Active Levels of Sunitinib to the Retina and RPE/Choroid for Over Four Months. Investig. Ophthalmol. Vis. Sci. 2016, 57, 5037. [Google Scholar]
  188. Cheng, Y.; Burda, C. 2.01—Nanoparticles for Photodynamic Therapy. In Comprehensive Nanoscience and Technology; Andrews, D.L., Scholes, G.D., Wiederrecht, G.P., Eds.; Academic Press: Amsterdam, The Netherlands, 2011; pp. 1–28. ISBN 978-0-12-374396-1. [Google Scholar]
  189. Rodrigues, G.A.; Lutz, D.; Shen, J.; Yuan, X.; Shen, H.; Cunningham, J.; Rivers, H.M. Topical Drug Delivery to the Posterior Segment of the Eye: Addressing the Challenge of Preclinical to Clinical Translation. Pharm. Res. 2018, 35, 245. [Google Scholar] [CrossRef] [PubMed]
  190. Doukas, J.; Mahesh, S.; Umeda, N.; Kachi, S.; Akiyama, H.; Yokoi, K.; Cao, J.; Chen, Z.; Dellamary, L.; Tam, B.; et al. Topical Administration of a Multi-Targeted Kinase Inhibitor Suppresses Choroidal Neovascularization and Retinal Edema. J. Cell. Physiol. 2008, 216, 29–37. [Google Scholar] [CrossRef]
  191. Yafai, Y.; Yang, X.M.; Niemeyer, M.; Nishiwaki, A.; Lange, J.; Wiedemann, P.; King, A.G.; Yasukawa, T.; Eichler, W. Anti-Angiogenic Effects of the Receptor Tyrosine Kinase Inhibitor, Pazopanib, on Choroidal Neovascularization in Rats. Eur. J. Pharmacol. 2011, 666, 12–18. [Google Scholar] [CrossRef]
  192. Adams, C.M.; Anderson, K.; Artman, G.; Bizec, J.C.; Cepeda, R.; Elliott, J.; Fassbender, E.; Ghosh, M.; Hanks, S.; Hardegger, L.A.; et al. The Discovery of N-(1-Methyl-5-(Trifluoromethyl)-1H-Pyrazol-3-Yl)-5-((6- ((Methylamino)Methyl)Pyrimidin-4-Yl)Oxy)-1H-Indole-1-Carboxamide (Acrizanib), a VEGFR-2 Inhibitor Specifically Designed for Topical Ocular Delivery, as a Therapy for Neovascular Age-Related Macular Degeneration. J. Med. Chem. 2018, 61, 1622–1635. [Google Scholar] [CrossRef] [PubMed]
  193. Zernii, E.Y.; Baksheeva, V.E.; Iomdina, E.N.; Averina, O.A.; Permyakov, S.E.; Philippov, P.P.; Zamyatnin, A.A.; Senin, I.I. Rabbit Models of Ocular Diseases: New Relevance for Classical Approaches. CNS Neurol. Disord. Drug Targets 2016, 15, 267–291. [Google Scholar] [CrossRef]
  194. Owen, G.R.; Brooks, A.C.; James, O.; Robertson, S.M. A Novel in Vivo Rabbit Model That Mimics Human Dosing to Determine the Distribution of Antibiotics in Ocular Tissues. J. Ocul. Pharmacol. Ther. 2007, 23, 335–342. [Google Scholar] [CrossRef]
  195. Shen, J.; Durairaj, C.; Lin, T.; Liu, Y.; Burke, J. Ocular Pharmacokinetics of Intravitreally Administered Brimonidine and Dexamethasone in Animal Models with and without Blood-Retinal Barrier Breakdown. Investig. Ophthalmol. Vis. Sci. 2014, 55, 1056–1066. [Google Scholar] [CrossRef]
  196. Kang-Mieler, J.J.; Rudeen, K.M.; Liu, W.; Mieler, W.F. Advances in Ocular Drug Delivery Systems. Eye 2020, 34, 1371–1379. [Google Scholar] [CrossRef] [PubMed]
  197. Paunovska, K.; Loughrey, D.; Dahlman, J.E. Drug Delivery Systems for RNA Therapeutics. Nat. Rev. Genet. 2022, 23, 265–280. [Google Scholar] [CrossRef] [PubMed]
  198. Jahangirian, H.; Lemraski, E.G.; Webster, T.J.; Rafiee-Moghaddam, R.; Abdollahi, Y. A Review of Drug Delivery Systems Based on Nanotechnology and Green Chemistry: Green Nanomedicine. Int. J. Nanomed. 2017, 12, 2957–2978. [Google Scholar] [CrossRef] [PubMed]
  199. Sung, Y.K.; Kim, S.W. Recent Advances in Polymeric Drug Delivery Systems. Biomater. Res. 2020, 24, 12. [Google Scholar] [CrossRef] [PubMed]
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