(17b) Targeted Polyanhydride Nanoparticles to Combat Neurodegeneration | AIChE

(17b) Targeted Polyanhydride Nanoparticles to Combat Neurodegeneration


Schlichtmann, B. - Presenter, Iowa State University
Narasimhan, B., Iowa State University
Mallapragada, S., Iowa State University
Anantharam, V., Iowa State University
Kanthasamy, A., Iowa State University
Ghaisas, S., Iowa State University
Neurodegenerative diseases affect a large proportion of society; this burden is expected to worsen with the aging population. These diseases are characterized by a complex set of disorders that result in the inability to perform daily living activities. Numerous therapeutics can treat neurodegenerative disease, but hurdles in central nervous system (CNS) delivery impede therapeutic efficacy.

Targeted nano-carriers can improve the local bioavailability of therapeutics by targeting these hurdles and providing sustained release. Polyanhydride nanoparticles (NPs) are a particularly attractive nano-carrier option in the context of CNS delivery due to their surface-eroding characteristics and superior internalization properties. In this work, a polyanhydride chemistry containing 1,6-bis(p-carboxyphenoxy)hexane and sebacic acid (i.e., 20:80 CPH:SA) was functionalized with (3-carboxypropyl)-triphenylphosphonium, a derivative of triphenylphosphonium which can target mitochondria and the blood brain barrier (BBB). The development of this bulk functionalization method is important for surface-eroding NPs to enable the persistence of the targeting ligand with the NPs throughout degradation for effective targeting of the hurdles downstream of the BBB. Surface-functionalized ligands may not be able to target these hurdles because they would be released from the NP too quickly after the onset of degradation in the body.

Studies in a rat mesencephalic neuronal cell line, N27, demonstrated significantly enhanced internalization of these bulk-functionalized NPs compared to non-functionalized 20:80 CPH:SA NPs as evaluated by flow cytometry and confocal microscopy. The ability of functionalized, drug-encapsulated NPs to improve the protective capability of the antioxidant Mito-apocynin against oxidative stress was also evaluated. Protection against oxidative stress by Mito-apocynin-encapsulated functionalized NPs was observed after challenging N27 cells with hydrogen peroxide, a known oxidative stress-inducing agent. These NPs were also dose-sparing compared to free drug. Taken altogether, these studies indicate the promise of this functionalization method for polyanhydride NPs and lay the foundation for improving therapeutic delivery to the brain.


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