NEWS & PERSPECTIVE

Photoactivatable nanosystem combining PDT and VEGF inhibition: A potentially safe and effective intravenous wAMD therapy

20 Feb 2024

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

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