Dataset Information

Red Light-Triggered Anti-Angiogenic and Photodynamic Combination Therapy of Age-Related Macular Degeneration.

ABSTRACT: Choroidal neovascularization (CNV) is the key pathological event of wet age-related macular degeneration (wAMD) leading to irreversible vision loss. Currently, anti-angiogenic therapy with anti-vascular endothelial growth factor (VEGF) agents has become the standard treatment for wAMD, while it is still subject to several limitations, including the safety concerns of monthly intravitreal administration and insufficient efficacy for neovascular occlusion. Combined therapy with photodynamic therapy (PDT) and anti-angiogenic agents has emerged as a novel treatment paradigm. Herein, a novel and less-invasive approach is reported to achieve anti-angiogenic and photodynamic combination therapy of wAMD by intravenous administration of a photoactivatable nanosystem (Di-DAS-VER NPs). The nanosystem is self-assembled by reactive oxygen species (ROS)-sensitive dasatinib (DAS) prodrug and photosensitizer verteporfin (VER). After red-light irradiation to the diseased eyes, intraocular release of anti-angiogenic DAS is observed, together with selective neo-vessels occlusion by VER-generated ROS. Notably, Di-DAS-VER NPs demonstrates promising therapeutic efficacy against CNV with minimized systemic toxicity. The study enables an efficient intravenous wAMD therapy by integrating a photoactivation process with combinational therapeutics into one simple nanosystem.

SUBMITTER: Xu S

PROVIDER: S-EPMC10625062 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Red Light-Triggered Anti-Angiogenic and Photodynamic Combination Therapy of Age-Related Macular Degeneration.

Xu Shuting S Cui Kaixuan K Long Kaiqi K Li Jia J Fan Ni N Lam Wai-Ching WC Liang Xiaoling X Wang Weiping W

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20230914 31

Choroidal neovascularization (CNV) is the key pathological event of wet age-related macular degeneration (wAMD) leading to irreversible vision loss. Currently, anti-angiogenic therapy with anti-vascular endothelial growth factor (VEGF) agents has become the standard treatment for wAMD, while it is still subject to several limitations, including the safety concerns of monthly intravitreal administration and insufficient efficacy for neovascular occlusion. Combined therapy with photodynamic therap ...[more]

PMID: 37705491

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Project description:In light of the intriguing potential of anti-angiogenic approach in suppressing choroidal neovascularization, we attempted to elaborate synthetic gene delivery systems encapsulating anti-angiogenic plasmid DNA as alternatives of clinical antibody-based therapeutics. Herein, block copolymer of cyclic Arg-Gly-Asp-poly(ethylene glycol)-poly(lysine-thiol) [RGD-PEG-PLys(thiol)] with multifunctional components was tailored in manufacture of core-shell DNA delivery nanoparticulates. Note that the polycationic PLys segments were electrostatically complexed with anionic plasmid DNA into nanoscaled core, and the tethered biocompatible PEG segments presented as the spatial shell (minimizing non-specific reactions in biological milieu). Furthermore, the aforementioned self-assembly was introduced with redox-responsive disulfide crosslinking due to the thiol coupling. Hence, reversible stabilities, namely stable in extracellular milieu but susceptible to disassemble for liberation of the DNA payloads in intracellular reducing microenvironment, were verified to facilitate transcellular gene transportation. In addition, RGD was installed onto the surface of the proposed self-assemblies with aim of targeted accumulation and internalization into angiogenic endothelial cells given that RGD receptors were specifically overexpressed on their cytomembrane surface. The proposed anti-angiogenic DNA therapeutics were validated to exert efficient expression of anti-angiogenic proteins in endothelial cells and elicit potent inhibition of ocular neovasculature post intravitreous administration. Hence, the present study approved the potential of gene therapy in treatment of choroidal neovascularization. In light of sustainable gene expression properties of DNA therapeutics, our proposed synthetic gene delivery system inspired prosperous potentials in long-term treatment of choroidal neovascularization, which should be emphasized to develop further towards clinical translations.

Project description:PurposePhotodynamic therapy (PDT) using verteporfin was the first pharmacologic therapy for neovascular age-related macular degeneration and changed the treatment paradigm for a major, blinding disease. The experimental work in the nonhuman primate was essential in developing treatment parameters for verteporfin PDT that could successfully occlude choroidal neovascularization with limited injury to the neural retina. Early in the preclinical primate studies, we hypothesized that higher irradiances could be used for ocular PDT than had been used in dermatology and other applications, which typically utilized an irradiance of 150 to 200 mW/cm(2). We set out to test the feasibility of irradiances up to 1800 mW/cm(2).MethodsPDT was applied to normal monkey eyes using verteporfin/benzoporphyrin derivative (BPD) (2 mg/kg) mixed with low-density lipoprotein in DMSO, and 692-nm light, with a spot size 1250mum, fluence approximately 50 J/cm(2), and irradiance varying from 150 (treatment time, 6 minutes) to 1800 mW/cm(2) (treatment time, 30 seconds). Photocoagulation lesions were applied using 514-nm and 692-nm laser light without drug, with irradiance of 18,750 to 200,000 mW/cm(2) and spot size of 500 mum. Treatment effect was evaluated by fundus photography, angiography, and light and electron microscopy with collagen denaturation as a marker of thermal injury.ResultsVerteporfin/BPD PDT at irradiances of 150 to 1800 mW/cm(2) showed no collagen denaturation in contrast to photocoagulation lesions without dye (irradiance 10-fold and higher).ConclusionsVerteporfin PDT could safely be performed at higher irradiances, permitting a clinically practical therapy. Ultimately, clinical trials demonstrated that verteporfin PDT could limit moderate vision loss in neovascular age-related macular degeneration. Although anti-VEGF therapy has replaced PDT as a first-line therapy, PDT may still have a role, perhaps in combination therapies. Further investigations to optimize drug delivery and to better understand the molecular mechanisms of PDT effects in both choroidal neovascularization and retina will improve its application in macular diseases.

Project description:ImportanceLight pollution's impact on human health is increasingly recognized, but its link to exudative age-related macular degeneration (EAMD) remains unclear.ObjectiveTo investigate the association between exposure to outdoor artificial light at night (OALAN) and the risk of incident EAMD.Design, setting, and participantsIn this nationwide population-based case-control study, all individuals 50 years or older with newly diagnosed EAMD between January 1, 2010, and December 31, 2011, were identified with reference to the Korean National Health Insurance Service registration program database for rare and intractable diseases. Birth year- and sex-matched controls (with no EAMD diagnosis until 2020) were selected at a 1:30 ratio. Data were acquired from May 1 to December 31, 2021, and analyzed from June 1 to November 30, 2022.ExposuresMean levels of OALAN at participants' residential addresses during 2008 and 2009 were estimated using time-varying satellite data for a composite view of persistent nighttime illumination at an approximate scale of 1 km2.Main outcomes and measuresThe hazard ratios (HRs) and 95% CIs of the association between residential OALAN and risk of incident EAMD were determined based on maximum likelihood estimation after adjusting for sociodemographic characteristics, comorbidities, and area-level risk factors (ie, nighttime traffic noise and particulate matter of aerodynamic diameter ≤10 μm in each participant's administrative district of residence).ResultsA total of 126 418 participants were included in the analysis (mean [SD] age, 66.0 [7.9] years; 78 244 men [61.9%]). Of these, 4078 were patients with newly diagnosed EAMD and 122 340 were EAMD-free matched controls. In fully adjusted models, an IQR (55.8 nW/cm2/sr) increase in OALAN level was associated with an HR of 1.67 (95% CI, 1.56-1.78) for incident EAMD. The exposure-response curve demonstrated a nonlinear, concave upward slope becoming more pronounced at higher levels of light exposure (ie, at approximately 110 nW/cm2/sr). In a subgroup analysis, an IQR increase in OALAN was associated with increased risk of incident EAMD in urban areas (HR, 1.46 [95% CI, 1.33-1.61]) but not in rural areas (HR, 1.01 [95% CI, 0.84-1.22]).Conclusions and relevanceIn this nationwide population-based case-control study, higher levels of residential OALAN were associated with an increased risk of incident EAMD. Future studies with more detailed information on exposure, individual adaptive behaviors, and potential mediators are warranted.

Dataset Information

Red Light-Triggered Anti-Angiogenic and Photodynamic Combination Therapy of Age-Related Macular Degeneration.

Publications

Red Light-Triggered Anti-Angiogenic and Photodynamic Combination Therapy of Age-Related Macular Degeneration.

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