DENDRIMER TRANSPORT PROPERTIES: MODULATIONS THROUGH SURFACE MODIFICATIONS WITH SUGARS
Embargo until
2024-05-01
Date
2020-03-12
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Johns Hopkins University
Abstract
Hydroxyl-terminated polyamidoamine (PAMAM) dendrimers have an intrinsic capability to target activated microglia, and are currently undergoing clinical translation. These dendrimers have the unique ability to enter the inflamed brain, perfuse freely through tissue, and localize only within diseased cells. I begin this thesis by further defining the dendrimer’s ability to cross the impaired blood-brain barrier and the transport mechanisms that allow it to access and localize within activated microglia in a neonatal rabbit model of cerebral palsy.
From there, we sought to control and modify the transport properties of the dendrimer. We conjugated mannose sugar to the surface of the dendrimer in an effort to target alternatively activated macrophages in the brain. I found that the conjugation of mannose gave the dendrimer an ability to enter cells specifically through mannose receptor-mediated endocytosis, which resulted in localization in alternatively activated macrophages in a neonatal rabbit model of cerebral palsy upon systemic administration.
An outcome from the study of mannosylation was robust uptake of the dendrimer in the liver, which it had not accessed without mannose sugar. Building off this result, we synthesized a galactose-conjugated dendrimer and found that the addition of this sugar targeting ligand again changed how the dendrimer interacted with cells, internalizing in hepatocytes through multivalent binding to the asialoglycoprotein receptor. I demonstrated that uptake was specific to hepatocytes, leading to application in a mouse model of severe acetaminophen poisoning induced liver failure. Delivery of N-acetyl cysteine via the galactosylated dendrimer provided therapeutic benefits unattainable with free drug treatment.
We then set forth to develop a novel hepatocyte-targeting dendrimer inspired by characteristics of the galactosylated PAMAM dendrimer. G2-Gal24-OH96 dendrimer was synthesized from 24 molecules of galactose, expressing 96 surface hydroxyl groups. I showed in vitro that it has improved cellular localization over the PAMAM dendrimer, resulting in rapid uptake by the liver in vivo. G2-Gal24-OH96 distributed throughout the liver, localizing in > 80% of hepatocytes. Lastly, I verified that G2-Gal24-OH96 maintains its liver targeting capabilities in models of both hepatic necrosis and hepatic fibrosis, laying the groundwork for development of the next generation of hepatocyte-targeting nanotherapeutics.
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Keywords
Nanomedicine, nanoparticle, dendrimer, neuroscience, liver, drug delivery, sugar receptors, targeted delivery