Nano-based drug delivery systems: Targeting to corticospinal tract neurons for controlled release of therapeutics

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May-23

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Abstract

Central nervous system (CNS) damage leads to persistent loss of cognition, sensation, and motor control, and affecting approximately millions of patients. Retention or regain of function could be improved by therapies encouraging axon regeneration. However, therapeutic effectiveness is challenged by limited CNS axon regeneration, limited CNS accessibility due to the blood-brain barrier (BBB), and inefficient targeting to specific neurons due to CNS cellular diversity. We suggest using surface functionalized nanoparticles (SFNPs) to specifically target particular neurons and deliver regeneration-encouraging drugs in a remotely actuation-able and controlled manner. We have developed fluorescently labeled polyethylene glycol (PEG) copolymer nanoparticles surface functionalized with amino (N150, 150 nm diameter) or carboxyl (C150 and C750, 150 nm and 750 nm diameters, respectively) functional groups. Here, we attached brain-derived neurotrophic factor (BDNF) using peptide bonding to the surface functional groups and assessed the amount and stability of BDNF derivatization, targeting to corticospinal tract (CST) upper motor neurons, and promotion of outgrowth of neuronal processes from release of the outgrowth promoting therapeutic, C3 transferase. Each SFNP construct stably bound between 68.2 and 74.7% of the initial amount of BDNF. About 40.7% of the N150 and 42% of C150 SFNPs either not derizatized or derivatized with BDNF traversed a continuous monolayer of brain microvascular endothelial cells (BBMVECs, an in-vitro BBB model) within four hours, while fewer C750 (24%) crossed the barrier in the same time frame. Cell type specific immunolabeling showed that N150 and C150, and to a lesser extent C750, BDNF-SFNPs were preferentially internalized into CST neurons compared to astrocytes, oligodendrocytes, or microglia. BDNF-SFNP released C3 transferase increased several measures of neurite outgrowth in CST neurons compared to SFNPs without BDNF derivatization. We conclude that the N150 and C150 BDNF-SFNPs efficiently cross a BBB model, are preferentially endocytosed by CST neurons, and release imbibed C3 transferase to increase process outgrowth. The C750 construct less efficiently crossed the in-vitro BBB, but their greater BDNF binding and C3 transferase carrying capacity may support comparable axon regeneration compared to the smaller constructs. Thus, collectively, all three BDNF-SFNP constructs hold promise for clinical use in treating neurotraumatic and neurodegenerative conditions.

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Nano-based drug delivery system

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