Highly Retina-Permeating and Long-Acting Resveratrol/Metformin Nanotherapeutics for Enhanced Treatment of Macular Degeneration

The development of therapeutics for effective treatments of retinal diseases is significantly constrained by various biological barriers. We herein report a nanomedicine strategy to develop nanotherapeutics featured with not only high retinal permeability but also sustained bioactive delivery. Specifically, the nanotherapeutics are rationally designed via aminolysis of resveratrol-encapsulated polycaprolactone nanoparticles (R@PCL NPs), followed by the formation of amide linkages with carboxyl-terminated transacting activator of transcription cell penetrating peptide (T) and metformin (M). The R@PCL-T/M NP nanotherapeutics are demonstrated in vitro to possess persistent drug release profiles, good ocular biocompatibility, and potent bioactive activities for targeting prevailing risk factors associated with retinal diseases. In vivo studies indicate that single-dose intravitreal administration of the R@PCL-T/M NPs can effectively improve retinal permeability (& SIM;15-fold increase), prevent loss of endogenous antioxidants, and suppress the growth of abnormal vessels in the retina with macular degeneration for 56 days. This high treatment efficacy can be ascribed to the enhanced retinal permeability of the nanotherapeutics in conjunction with the sustained pharmacological activity of the dual drugs (R and M) in the retinal pigment epithelial region. These findings show a great promise for the development of pharmacological nanoformulations capable of targeting the retina and thereby treating complex posterior segment diseases with improved efficacies.

Automated summary

We developed a nanomedicine strategy to create nanotherapeutics with high retinal permeability and sustained bioactive delivery. The nanotherapeutics were designed through aminolysis of resveratrol-encapsulated polycaprolactone nanoparticles, followed by the formation of amide linkages with a transacting activator of transcription cell penetrating peptide and metformin. In vitro and in vivo studies demonstrated the effectiveness of the nanotherapeutics in improving retinal permeability and targeting retinal diseases.