Overcoming Treatment Challenges in Posterior Segment Diseases with Biodegradable Nano-Based Drug Delivery Systems

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TL;DR

This review summarizes biodegradable nano-based drug delivery systems (DDS) for posterior segment eye diseases, highlighting their ability to improve drug bioavailability, prolong residence time, and reduce injection frequency compared to conventional therapies. Key systems include PLGA nanoparticles, liposomes, hydrogels, and lipid nanocapsules, which have shown promise in preclinical models for conditions like age-related macular degeneration, diabetic retinopathy, and retinopathy of prematurity. The clinical significance lies in the potential to replace frequent intravitreal injections with sustained-release, biodegradable formulations, though translation to humans remains limited by anatomical differences and a lack of long-term safety data.

Full summary

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**Background:** Treatment of posterior segment eye diseases (e.g., age-related macular degeneration, diabetic retinopathy, retinitis pigmentosa) is hindered by anatomical barriers such as the tear film, cornea, blood–aqueous barrier, and blood–retinal barrier, which limit drug bioavailability. Conventional topical drops achieve only about 5% penetration, while intravitreal injections require frequent dosing and carry risks like endophthalmitis and retinal detachment. Biodegradable nano-based drug delivery systems (DDS) offer a solution by using nanosized, biocompatible polymers that degrade into safe by-products, enabling sustained release, improved penetration, and reduced toxicity.

**Methods:** This is a narrative review of preclinical and clinical studies published between 2017 and 2022. The authors searched for studies on biodegradable nano-based DDS for posterior segment diseases, including nanomicelles, liposomes, dispersed nanoparticles, dendrimers, hydrogels, nanosuspensions, nanoemulsions, and microneedles. They summarized findings from in vitro, ex vivo, and in vivo animal models, as well as early-phase clinical trials. Key polymers discussed include PLGA, chitosan, hyaluronic acid, polycaprolactone (PCL), and polyethylene glycol (PEG).

**Key Results:** - **Retinitis Pigmentosa:** PLGA microspheres co-delivering GDNF and TUDCA showed sustained release for at least 91 days in vitro. mPEG-cholane nanoparticles loaded with ML240 prolonged drug release over 10 days and provided photoreceptor protection for up to 21 days in retinal explants. Myriocin-loaded nanostructured lipid carriers (NLCs) decreased retinal sphingolipid levels in rabbit eyes after topical administration. - **Age-Related Macular Degeneration (AMD) and Choroidal Neovascularization (CNV):** Macrophage-disguised PLGA nanoparticles loaded with rapamycin suppressed neovascularization in a laser-induced CNV mouse model. Synthetic high-density lipoprotein (sHDL) nanoparticles delivering rapamycin achieved a 125-fold increase in drug aqueous concentration in rats. PCL nanoparticles co-delivering resveratrol and metformin provided sustained release for up to 56 days in a rat AMD model. PAMAM-coated liposomes containing berberine hydrochloride and chrysophanol improved cellular permeability and bioadhesion. - **Diabetic Retinopathy (DR):** PLGA nanoparticles delivering IL-12 had an encapsulation efficiency of ~34.7% and prolonged drug release, significantly decreasing retinal damage in a DR mouse model. PLGA-PEG lipid-polymer hybrid nanoparticles loaded with melatonin showed high encapsulation efficacy (79.8%) and sustained release for up to 8 days. Triamcinolone acetonide-loaded PCL/Pluronic F68 nanoparticles improved retinal thickness and vascular health in a DR rat model after topical administration. - **Diabetic Macular Edema (DME):** TA-loaded liposomes were safe and tolerable in a Phase 1 clinical assay and reduced central fovea thickness in DME patients. Chitosan-coated liposomes enhanced bioavailability and prolonged TA release in vivo. - **Anti-VEGF Agents:** Thermoresponsive hydrogels (e.g., mPEG-PLGA-BOX) delivered bevacizumab for 35 days in rabbits. PLGA microspheres in a PEG-PLLA-DA/NIPAAm hydrogel released aflibercept for 6 months in vitro and were as effective as bimonthly injections in a CNV rat model. PLGA nanoparticles loaded with bevacizumab increased antiangiogenic effects in oxygen-induced retinopathy (OIR) mice. Liposomes maintained bevacizumab release at therapeutic levels for 22 weeks in vivo. - **Retinopathy of Prematurity (ROP):** Lipid nanocapsules loaded with cyclosporin A decreased neovascularization by a factor of 6 in OIR mice. DOTAP cationic nanoemulsions with antisense oligonucleotide ODN17 inhibited 64% of vitreal neovascularization in ROP mice. Folic acid–chitosan-modified mesoporous silica nanoparticles delivering miRNA-223 inhibited retinal neovascularization by 52.6% compared to 26.1% with bevacizumab solution. - **Clinical Advancements:** Ozurdex® (dexamethasone PLGA implant) is the only FDA-approved biodegradable implant for posterior segment diseases, providing up to 4 months of sustained release. GB-102 (sunitinib maleate PLGA microparticles) is in Phase IIb trials for wet AMD, with durability for 6 months after a single injection. Pegaptanib sodium (Macugen®) is an approved PEG-conjugated aptamer for wet AMD.

**Clinical Implications:** Biodegradable nano-based DDS have the potential to revolutionize treatment of posterior segment diseases by reducing injection frequency, improving patient compliance, and minimizing side effects. However, translation from preclinical models to humans is limited by anatomical differences (e.g., rodent sclera is thicker, rabbit eyes have lower blinking rates) and the use of artificially induced disease models that may heal naturally. Future research should focus on larger animal models (rabbits, pigs, monkeys), long-term safety studies, and the development of targeted, stimuli-responsive systems. Interdisciplinary collaboration is essential to bring these systems to clinical practice.