Co-loading of Levodopa and Curcumin Using Brain-targeted Protocells as a Drug Delivery System for Improving the Efficacy of Parkinson's Disease

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 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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Co-loading of Levodopa and Curcumin Using Brain-targeted Protocells as a Drug Delivery System for Improving the Efficacy of Parkinson's Disease

10.21203/rs.3.rs-26742/v2 ◽

2020 ◽

Author(s):

wenkai zhou ◽

Chang Liu ◽

Feifei Yu ◽

Xia Niu ◽

Xiaomei Wang ◽

...

Keyword(s):

Parkinson’S Disease ◽

Drug Delivery ◽

Parkinson's Disease ◽

Mouse Model ◽

Inner Core ◽

Cell Model ◽

Mesoporous Silica Nanoparticles ◽

Brain Targeting ◽

Delivery Platform ◽

A Cell

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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Co-loading of Levodopa and Curcumin Using Brain-targeted Protocells for Improving the Efficacy of Parkinson's Disease

10.21203/rs.3.rs-131164/v1 ◽

2021 ◽

Author(s):

Wenkai Zhou ◽

Chang Liu ◽

Feifei Yu ◽

Xia Niu ◽

Xiaomei Wang ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Inner Core ◽

Cell Model ◽

Mesoporous Silica Nanoparticles ◽

Brain Targeting ◽

Delivery Platform ◽

The Central Nervous System ◽

Nanoparticle System ◽

Clinical Drug

Abstract Parkinson's disease (PD), one of the most common movement and neurodegenerative disorders, is challenging to treat. 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 (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 spherical morphology, and can be used to co-load levodopa and curcumin efficiently; the combination of curcumin and levodopa alleviates the apoptosis of PD cells, decreases the expression of a-synuclein and increase the expression of tyrosine hydroxylase in SH-SY5Y cells as compared to single drug; the binary-drug loaded lf-protocells ameliorate oxidative stress and mitochondrial dysfunction as compared to combination of free drugs; lf-protocells improve significantly the distribution in brain compared with unmodified protocells; binary-drug loaded lf-protocells have better performance of motor function in mouse than unmodified protocells and combination of free drugs. In conclusion, binary-drug loaded lf-protocells show better therapeutic efficacy in both cell model and mouse model of PD than combination of free drugs 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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Rational Design of Thermosensitive Hydrogel to Deliver Nanocrystals with Intranasal Administration for Brain Targeting in Parkinson’s Disease

Research ◽

10.34133/2021/9812523 ◽

2021 ◽

Vol 2021 ◽

pp. 1-13

Author(s):

Yun Tan ◽

Yao Liu ◽

Yujing Liu ◽

Rui Ma ◽

Jingshan Luo ◽

...

Keyword(s):

Parkinson’S Disease ◽

Drug Delivery ◽

Parkinson's Disease ◽

Mitochondrial Dysfunction ◽

Nasal Cavity ◽

Dopaminergic Neurons ◽

Rational Design ◽

Brain Targeting ◽

Solution Temperature ◽

Delivery Platform

Mitochondrial dysfunction is commonly detected in individuals suffering from Parkinson’s disease (PD), presenting within the form of excessive reactive oxygen species (ROS) generation as well as energy metabolism. Overcoming this dysfunction within brain tissues is an effective approach to treat PD, while unluckily, the blood-brain barrier (BBB) substantially impedes intracerebral drug delivery. In an effort to improve the delivery of efficacious therapeutic drugs to the brain, a drug delivery platform hydrogel (MAG-NCs@Gel) was designed by complexing magnolol (MAG)-nanocrystals (MAG-NCs) into the noninvasive thermosensitive poly(N-isopropylacrylamide) (PNIPAM) with self-gelation. The as-prepared MAG-NCs@Gel exhibited obvious improvements in drug solubility, the duration of residence with the nasal cavity, and the efficiency of brain targeting, respectively. Above all, continuous intranasal MAG-NCs@Gel delivery enabled MAG to cross the BBB and enter dopaminergic neurons, thereby effectively alleviating the symptoms of MPTP-induced PD. Taking advantage of the lower critical solution temperature (LCST) behavior of this delivery platform increases its viscoelasticity in nasal cavity, thus improving the efficiency of MAG-NCs transit across the BBB. As such, MAG-NCs@Gel represented an effective delivery platform capable of normalizing ROS and adenosine triphosphate (ATP) in the mitochondria of dopaminergic neurons, consequently reversing the mitochondrial dysfunction and enhancing the behavioral skills of PD mice without adversely affecting normal tissues.

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Liposomes: Novel Drug Delivery Approach for Targeting Parkinson’s Disease

Current Pharmaceutical Design ◽

10.2174/1381612826666200128145124 ◽

2020 ◽

Vol 26 (37) ◽

pp. 4721-4737 ◽

Cited By ~ 4

Author(s):

Bhumika Kumar ◽

Mukesh Pandey ◽

Faheem H. Pottoo ◽

Faizana Fayaz ◽

Anjali Sharma ◽

...

Keyword(s):

Parkinson’S Disease ◽

Drug Delivery ◽

Parkinson's Disease ◽

Side Effects ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Brain Targeting ◽

Neural Cells ◽

Blood Brain ◽

The Brain

Parkinson’s disease is one of the most severe progressive neurodegenerative disorders, having a mortifying effect on the health of millions of people around the globe. The neural cells producing dopamine in the substantia nigra of the brain die out. This leads to symptoms like hypokinesia, rigidity, bradykinesia, and rest tremor. Parkinsonism cannot be cured, but the symptoms can be reduced with the intervention of medicinal drugs, surgical treatments, and physical therapies. Delivering drugs to the brain for treating Parkinson’s disease is very challenging. The blood-brain barrier acts as a highly selective semi-permeable barrier, which refrains the drug from reaching the brain. Conventional drug delivery systems used for Parkinson’s disease do not readily cross the blood barrier and further lead to several side-effects. Recent advancements in drug delivery technologies have facilitated drug delivery to the brain without flooding the bloodstream and by directly targeting the neurons. In the era of Nanotherapeutics, liposomes are an efficient drug delivery option for brain targeting. Liposomes facilitate the passage of drugs across the blood-brain barrier, enhances the efficacy of the drugs, and minimize the side effects related to it. The review aims at providing a broad updated view of the liposomes, which can be used for targeting Parkinson’s disease.

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