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Abstract Parkinson's disease (PD), one of the most common movement and neurodegenerative disorders, is challenging to treat, partly because the blood-brain barrier blocks passage of most drugs. Levodopa is a common clinical drug for controlling the symptoms of PD, but it only replenishes the missing dopamine, can’t protect dopaminergic neurons. While curcumin as a neuroprotective agent has been reported for treatment of PD. Herein, we present a novel organic-inorganic composite nanoparticle with brain targeting (denoted as lf-protocells) for co-delivery of levodopa and curcumin, and demonstrate its attractive use as a biocompatible platform for PD treatment. The nanoparticle system is comprised of a lactoferrin (lf) modified lipid bilayer (LB) containing curcumin as its outer membrane and mesoporous silica nanoparticles (MSNs) containing levodopa as its supporting inner core. Our studies illustrate that the lf-protocells have a size of about 180 nm and spherical morphology, and can be used to co-load levodopa and curcumin efficiently. Further, a cell model and a mouse model induced by rotenone (Rot) and MPTP respectively are used to investigate the effects of binary-drug loaded lf-protocells on PD. Our results demonstrate that the combination of curcumin and levodopa alleviate the apoptosis of PD cells, enhance the cell viability as compared to levodopa used alone; levodopa together with curcumin also efficiently decrease the expression of a-synuclein, increase the expression of tyrosine hydroxylase in SH-SY5Y cells, and transform more levodopa into dopamine for supplement the loss of the brain. Moreover, the resulting binary-drug loaded lf-protocells ameliorate oxidative stress and mitochondrial dysfunction as compared to combination of free drugs. In addition, testing in a mouse model indicate that lf-protocells can improve significantly the motor function and distribution in brain compared with unmodified protocells. In conclusion, binary-drug loaded lf-protocells show much better therapeutic efficacy in both the cell model and the mouse model of PD than single free drug and lower toxicity than bare MSNs. These results suggest that lf-protocells can be used as a promising drug delivery platform for targeted therapy against PD and other diseases of the central nervous system.
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