Dendrimer-based Delivery of Peptides and Antibodies for Choroidal Neovascularization
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Date
2022-12-02
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Johns Hopkins University
Abstract
Biomolecular drugs are the cornerstone of modern medicine, but their indiscriminate targeting of broad biological processes has devastating effects on disease treatment and quality of life. Biologics are a relatively new and potent class of drugs that can target specific cellular processes and may cure previously incurable diseases. However, delivery issues, such as rapid degradation, instability under physiological conditions, and difficulty achieving cell-specific absorption, have hampered the clinical translation of biologic drugs. In recent years, dendrimer-based therapeutics have demonstrated the efficacy of the platform in delivering small molecule drugs to reactive macrophages in models of ocular inflammation and neuroinflammation. Herein, we have developed dendrimer-conjugation that improved the systemic administration of otherwise rapidly cleared biologic drugs, offering alternative routes of administration to reduce patient discomfort and increase accessibility in regions with limited medical resources. Initially, we demonstrated that the dendrimer-conjugation of short peptides not only withstood in vitro enzymatic degradation, but also localized to sites of ocular inflammation upon systemic delivery, thereby inhibiting the progression of choroidal neovascularization.
Second, we conjugate dendrimer with the antibody Aflibercept (EYLEA), which binds to vascular endothelial growth factor (VEGF) and inhibits the neovascularization process in AMD. Although we did not detect the reduction of VEGF intracellularly and extracellularly through in vitro cell experiments, through in vivo experiments, we established a choroid neovascularization (CNV) mouse model and administered drugs into the vitreous, and discovered that Dendrimer-conjugated EYLEA significantly decreased CNV area. Thus, we validated its effectiveness to some degree.
In the presented studies, we have demonstrated that dendrimer conjugation can overcome many of the delivery obstacles encountered by biopharmaceuticals and can therefore be used to accelerate the clinical translation of these potent substances.
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Keywords
Dendrimer, Choroid Neovascularization