Objective: This study aimed to design and validate a nanoparticle-based delivery system for rifampicin, with the objective of enhancing its therapeutic efficacy, improving brain targeting, and mitigating Parkinson’s disease (PD)-induced neuronal damage.

Background: PD is a chronic and debilitating neurodegenerative disorder, predominantly marked by the accumulation of misfolded α-synuclein (α-syn) proteins and the progressive degeneration of dopaminergic neurons. The development of sustainable and safe delivery systems for brain-targeted therapeutics is of paramount importance for achieving successful treatment outcomes in PD.

Method: A PEG-PLA polymer-based nanoparticle system, modified with 18F-FP-DTBZ, was constructed to encapsulate rifampicin. The physicochemical properties of the nanoparticles were characterized using dynamic light scattering and transmission electron microscopy. The specificity and cellular uptake of the nanoparticles were evaluated in SH-SY5Y cells using immunofluorescence. The in vivo efficacy was assessed in a PD mouse model induced by α-synuclein fibrils (PFFs). Behavioral tests evaluated motor function, cognitive function, and emotional disturbances. The distribution and effects of the nanoparticles were investigated using special staining and MRI. Western Blot and flow cytometry was used to verify the activation of protective pathways by rifampicin.

Results: The nanoparticles had a hydrodynamic diameter of 145.3±6.49 nm, PDI < 0.3, and zeta potential of 20.96±2.13 mV. In vitro, SH-SY5Y cells showed efficient nanoparticle uptake. The nanoparticles inhibited α-syn oligomerization, reduced RIP3/MLKL-driven necroptosis, and decreased apoptosis markers compared to PFF-induced group (p < 0.01). In vivo, nanodelivered rifampicin improved motor and cognitive metrics versus the PFF-induced group (p < 0.05). Nanoparticles accumulated in the substantia nigra, striatum, and hippocampus. Treatment significantly reduced α-syn aggregation and RIP3/MLKL-mediated necroptosis in these regions.

Conclusion: This novel rifampicin delivery system enhances drug bioavailability and targets key brain regions, offering a promising therapeutic approach for PD. It not only alleviates motor symptoms but also addresses non-motor aspects like cognitive and emotional impairments.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/targeted-brain-delivery-of-rifampicin-via-peg-pla-nanoparticles-a-promising-therapeutic-strategy-for-neuroprotection-and-disease-modification-in-parkinsonian-mouse-models/