Exenatide-Modified Deferoxamine-Based Nanoparticles Ameliorates Neurological Deficits in Parkinson’s Disease Mice

Yiming Huang,1,* Xinran Wang,1,* Wenjing Li,1,* Feng Yue,1,2 Miao Wang,1 Feifan Zhou1,2 1State Key Laboratory of Digital Medical Engineering, School of Biomedical Engineering, Hainan University, Sanya, People’s Republic of China; 2One Health Institute, Hainan University, Haikou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Miao Wang; Feifan Zhou, Email wangm@hainanu.edu.cn; zhouff@hainanu.edu.cnPurpose: To avoid the biotoxicity and poor bioavailability of deferoxamine mesylate (DFO), an iron chelation for the treatment of Parkinson’s disease (PD), a self-oriented DFO nanoparticle functionalized with Exendin-4 was developed, which can be targeted delivered into the lesion brain area to achieve synergistic effects against PD by iron chelation and inflammatory suppression.Methods: The self-oriented DFO nanoparticles (Ex-4@DFO NPs) were synthesized by double emulsion technique, and characterized in terms of the particle size, morphology and DFO encapsulation efficiency. The cellular internalization, biocompatibility and cytoprotection of NPs were assessed on BV-2 and SH-SY5Y cells. The brain targeting and therapeutic effect of NPs were investigated in MPTP-induced PD mice by near-infrared II fluorescence imaging and immunofluorescence staining, as well as mobility behavioral tests.Results: Ex-4@DFO NPs with a particle size of about 100 nm, showed great biocompatibility and cytoprotection in vitro, which inhibited the decrease of mitochondrial membrane potential of SH-SY5Y cells and the release of inflammatory factors of BV-2 cells. In MPTP-induced PD mice, Ex-4@DFO NPs could penetrate the BBB into brain, and significantly mitigate the loss of dopaminergic neurons and inflammation in the substantia nigra, finally alleviate the mobility deficits.Conclusion: This self-oriented nanosystem not only improved the biocompatibility of DFO, but also enhanced therapeutic effects synergistically by ameliorating neuronal damage and neuroinflammation, showing a potential therapeutic strategy for PD. Keywords: Parkinson’s disease, deferoxamine mesylate, Exendin-4, nanoparticle system, brain targeting