Current treatments for wet age-related macular degeneration (wAMD) include the use of vascular endothelial growth factor (VEGF) inhibitors and the use of photodynamic therapy (PDT).¹ Combination of these therapies may offer significant improvements in visual acuity but safety concerns remain.^1,2 Researchers from the University of Hong Kong Faculty of Medicine (HKUMed) reported the development of a novel and minimally invasive approach to wAMD treatment, by intravenously administering a photoactivatable nanosystem and irradiating the diseased eyes.¹

AMD is the leading cause of blindness for people aged 50 in the developed world.³ Of these, wAMD represents 20% of reported cases and accounts for 90% of acute vision loss cases.³ Inhibition of angiogenesis with VEGF inhibitors is the current first-line treatment of wAMD, but its effect is partially mitigated by pericytes which protect established vessels.¹ Alternative treatments like photodynamic therapy (PDT) have also been used to occlude new vessels.¹ Through the production of reactive oxygen species (ROS), PDT can selectively damage the endothelium and destroy polypoidal lesions in the vessels resulting in thrombosis. However, its long-term effectiveness might be compromised by compensatory VEGF upregulation.¹ Previous attempts at combining VEGF inhibition with PDT have shown significant improvement in visual acuity over VEGF inhibition alone (p=0.012).² Yet, there remain concerns of safety with monthly invasive intravitreal injections which may lead to intraocular adverse events and low patient compliance.¹

To address this unmet need, a novel drug delivery method using a photoactivable nanosystem (Di-DAS-VER NPs) has been developed.¹ This drug system consists of 3 components including a photosensitizer named verteporfin (VER), an amphiphilic lipid (DSPE-PEG₂₀₀₀), and a ROS-sensitive dimeric prodrug of dasitinib (Di-DAS) which is a Src kinase inhibitor.¹ The nanosystem is activated via exposure to 690nm laser irradiation through the transparent ocular cavity.¹ Without red-light exposure in normal tissues, the inactive prodrug is expected to stay inactive in circulation after intravenous administration.¹ Upon activation in the ocular cavity, VER generates ROS which simultaneously facilitates PDT and cleaves the Di-DAS into its active form.¹

In this study, the feasibility of the nanosystem in vivo was investigated with a series of murine experiments that looked into choroidal neovascularization (CNV), a hallmark of wAMD progression.^1,3 Rodents with CNV were intravenously administered with Di-DAS-VER NPs, followed by 690nm laser irradiation to the eyes at 1 hour post-injection.¹ Choroidal tissues were harvested 2 hours after irradiation, and revealed that DAS concentration was 5 times higher in irradiated choroidal tissues compared to unirradiated eyes (2,000ng/g vs. 400ng/g tissue; p<0.0001), whereas DAS concentration in the major organs remained low (433ng/g-1,400ng/g tissue), indicating specific DAS release in pathological tissue upon red-light irradiation.¹ The average CNV area was also markedly decreased in the group treated with Di-DAS-VER NPs resulting in an area of approximately 6% area relative to those treated with saline (2.5x10³mm² vs. 40.0x10³mm²; p<0.0001).¹ The mean maximum CNV thickness was also reduced at (24.4 vs. 52.2mm; p<0.0001).¹

Other murine studies regarding the efficacy of Di-DAS-VER NPs revealed that it led to a significant reduction in neovascular leakage (p<0.0001) with a lower average leakage intensity of 38.6% compared to saline treatment at 87.1% at 5 days post-injection.¹ Patients treated with Di-DAS-VER NPs also had predominately lower-grade lesions (grade I-III) compared with those treated with saline (96.4% vs. 37.5%; p<0.0001), with no significant pathological leakage.¹ Diminished angiogenic signaling along with vascular occlusion was also observed.¹

Biosafety was also evaluated for Di-DAS-VER NPs.¹ No signs of ocular side-effects such as clouding, ulceration, and hemorrhage were reported.¹ No additional toxicity over the saline control was reported at the tight junctions of the retinal pigment epithelium.¹ Temperature elevation with irradiation was negligible without thermal damage to the eyes.¹ Electroretinogram (ERG) assessments also suggested that both groups retained similar visual functions.¹ Lastly, all measured biochemical parameters of the liver and the kidneys were comparable between groups.¹ Altogether, the prodrug-based nanosystem was deemed safe in vivo.¹

In summary, this study has shown the viability of Di-DAS-VER NPs in murine models.¹ Intravenous administration of Di-DAS-VER NPs with red-light irradiation may effectively and safely enable PDT-induced vascular occlusion and DAS-induced CNV suppression.¹