Optimization of an Injectable Hydrogel Depot System for the Controlled Release of Retinal-Targeted Hybrid Nanoparticles

Abstract

A drawback in the development of treatments that can reach the retina is the presence of barriers in the eye that restrain compounds from reaching the target. Intravitreal injections hold promise for retinal delivery, but the natural defenses in the vitreous can rapidly degrade or eliminate therapeutic molecules. Injectable hydrogel implants, which act as a reservoir, can allow for long-term drug delivery with a single injection into the eye, but still suffer due to the fast clearance of the released drugs when traversing the vitreous and random diffusion that leads to lower pharmaceutic efficacy. A combination with HA-covered nanoparticles, which can be released from the gel and more readily pass through the vitreous to increase the delivery of therapeutic agents to the retina, represents an advanced and elegant way to overcome some of the limitations in eye drug delivery. In this article, we developed hybrid PLGA-Dotap NPs that, due to their hyaluronic acid coating, can improve in vivo distribution throughout the vitreous and delivery to retinal cells. Moreover, a hydrogel implant was developed to act as a depot for the hybrid NPs to better control and slow their release. These results are a first step to improve the treatment of retinal diseases by protecting and transporting the therapeutic treatment across the vitreous and to improve treatment options by creating a depot system for long-term treatments.

Comprehensive Ocular and Systemic Safety Evaluation of Polysialic Acid-Decorated Immune Modulating Therapeutic Nanoparticles (PolySia-NPs) to Support Entry into First-in-Human Clinical Trials

“…The evaluation of PolySia-NPs for intravitreal administration has also been evaluated in the setting of drug delivery to the retina [ 27 , 28 , 29 , 30 ]. Fenofibrate (peroxisome proliferator-activated receptor alpha (PPAR) agonist)-encapsulated PLGA nanoparticles and blank PLGA NP were tested intravitreally in streptozocin-induced diabetic rats, laser-induced choroidal neovascularization, and very low-density lipoprotein receptor knockout (Vldlr −/−) mice, and no toxicity to retinal structure and function was noted [ 31 ].…”

“…There was also no effect on retinal function as measured by electroretinogram, like the negative findings when fenofibrate-containing nanoparticles were injected intravitreally and eyes were examined by ERG [ 31 ]. Intravitreal PLGA has been shown pre-clinically in nanoparticles and clinically in a PLGA-dexamethasone eluting implant to be safe and non-toxic [ 29 , 32 ].…”

On the other end of the line: Extracellular vesicle-mediated communication in glaucoma

“…Specifically in the eye, IVT injected fluorescently-labeled EVs were cleared from the vitreous, yet were retained in the RGCs in vivo , with a retention time between 6 and 14 days ( Mathew et al, 2021 ). A possible approach to increase the retention time of the IVT injected EVs, could be to incorporate the EVs in hydrogel implants which, by acting as reservoirs in the vitreous humor, may ensure a prolonged EV release and an increased therapeutic window with a single injection into the eye ( Ilochonwu et al, 2020 ; Ottonelli et al, 2022 ). Finally, it is still unclear which EV cargo component is responsible for the therapeutic effects observed in the above-mentioned studies, and many of them do not explore the precise cellular target.…”

Hydrogels in Ophthalmology: Novel Strategies for Overcoming Therapeutic Challenges

“…The co-polymerization of hydrophilic and hydrophobic components is typically observed in Pluronic triblocks as well, also known as poloxamers. Pluronic F-127 (i.e., poloxamer 407) has been widely explored for IVT ocular drug delivery [ 62 , 63 , 64 , 65 ]. The triblock consists of a central hydrophobic PPG flanked on either side by hydrophilic PEG blocks [ 62 ].…”

“…The triblock consists of a central hydrophobic PPG flanked on either side by hydrophilic PEG blocks [ 62 ]. When combined with HA, two groups have recently observed positive results, with excellent injectability, abundant localization to the retinal tissue, good cell bioavailability, and controlled release with a superior anti-angiogenic effect when compared to ranibizumab suspension over 12 weeks [ 62 , 64 ]. They also showed that drug-in-liposome-in-hydrogel delivery was an option for those drugs that are not compliant with the hydrogel properties, such as flurbiprofen, a nonsteroidal anti-inflammatory drug (NSAID) for macular edema, thus expanding potential uses [ 63 ].…”