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An Assay to Detect Protection of the Retinal Vasculature from Diabetes-Related Death in Mice
Published on: January 12, 2024
ROS-pH Dual-Responsive Polydopamine Nanoparticles for Targeted Fasudil Delivery Ameliorate Multiple Pathologies in
Jiaqi Li1, Zheng Zhong1, Yuhe Tan1
1Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei Key Laboratory of Otolaryngologic and Ophthalmic Diseases, Wuhan, 430068, People's Republic of China.
Background:
The multifaceted pathogenesis of diabetic retinopathy (DR) involves numerous pathways, among which oxidative stress and Rho-associated kinase (ROCK) signaling are critically implicated. The failure of current anti-VEGF monotherapies to address these key pathological processes limits their efficacy. While the ROCK inhibitor Fasudil is a promising candidate, its clinical translation for DR is hindered by poor ocular retention and lack of target specificity.
Methods:
We engineered a reactive oxygen species (ROS)- and pH-dual responsive polydopamine nanoplatform (Fasudil@PDA) to deliver Fasudil while concurrently scavenging oxidative stressors.
Results:
The Fasudil@PDA nanoparticles achieved a high drug loading capacity of ~28%. The release kinetics were specifically engineered to be responsive to the DR microenvironment. Under high ROS conditions in vitro, the platform demonstrated a sustained and efficient release profile, achieving a cumulative release of 87.3% over 56 days - demonstrating remarkable longevity. Separately, the pH-responsive drug release capability was also confirmed under acidic conditions. The platform effectively neutralized multiple ROS species in vitro and significantly restored endothelial barrier integrity by inhibiting the ROCK/MLC pathway. In a laser-induced choroidal neovascularization model, a single injection suppressed pathological angiogenesis by 45%. In diabetic mice, the same treatment markedly reduced vascular leakage, attenuated neuroinflammation, and restored retinal function, with b-wave amplitudes recovering to near-normal levels.
Conclusion:
This study establishes a multi-faceted nanotherapeutic strategy that synergizes sustained, long-acting ROCK inhibition with innate antioxidant activity. Designed to be activated by the pathological cues of DR, including acidic pH and ROS, our approach precisely targets multiple pathological pathways, offering a promising and translatable paradigm for overcoming the limitations of current monotherapies.
Insights
This study developed a dual-responsive nanoplatform for diabetic retinopathy (DR) treatment, combining sustained ROCK inhibition with antioxidant activity to improve ocular retention and target multiple pathways.
Area of Science:
- Ophthalmology
- Nanotechnology
- Biomedical Engineering
Background:
- Diabetic retinopathy (DR) pathogenesis involves oxidative stress and Rho-associated kinase (ROCK) signaling.
- Current anti-VEGF therapies have limited efficacy due to failure to address these pathways.
- Fasudil, a ROCK inhibitor, shows promise but faces challenges in ocular delivery and specificity.
Purpose of the Study:
- To engineer a novel nanoplatform for sustained and targeted delivery of Fasudil in DR.
- To develop a system with dual responsiveness to reactive oxygen species (ROS) and pH.
- To combine ROCK inhibition with antioxidant properties for a multi-faceted therapeutic approach.
Main Methods:
- Engineered a polydopamine nanoplatform (Fasudil@PDA) responsive to ROS and pH.
- Achieved high drug loading (~28%) and characterized sustained Fasudil release in vitro (87.3% over 56 days).
- Evaluated ROS scavenging, endothelial barrier restoration, and in vivo efficacy in choroidal neovascularization and diabetic mouse models.
Main Results:
- Fasudil@PDA demonstrated sustained drug release in response to DR-associated ROS and acidic pH.
- The nanoplatform effectively neutralized ROS and restored endothelial barrier integrity by inhibiting the ROCK/MLC pathway.
- In vivo studies showed suppressed angiogenesis, reduced vascular leakage, neuroinflammation, and restored retinal function in diabetic mice.
Conclusions:
- Developed a multi-faceted nanotherapeutic strategy combining sustained ROCK inhibition and antioxidant activity.
- The nanoplatform is activated by DR pathological cues (pH, ROS), precisely targeting multiple pathways.
- This approach offers a promising and translatable paradigm to overcome limitations of current DR monotherapies.
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