Scientists have developed a nanoparticle drug delivery system designed to enhance brain delivery of levodopa, the mainstay treatment for Parkinson’s disease, while also lowering a type of cellular damage called oxidative stress that’s implicated in the neurodegenerative condition.
The system was able to improve motor function in a mouse model of Parkinson’s while easing oxidative stress and protecting nerve cells against damage.
“This drug delivery system … presents a promising platform for more effective PD [Parkinson’s disease] therapy with [levodopa], holding great potential for advancements in neurology and PD treatment,” the researchers wrote.
The study, “Improving treatment for Parkinson’s disease: Harnessing photothermal and phagocytosis-driven delivery of levodopa nanocarriers across the blood-brain barrier,” was published in the Asian Journal of Pharmaceutical Sciences.
Parkinson’s disease is characterized by the progressive loss of dopaminergic neurons, or nerve cells that produce a brain signaling chemical called dopamine. A major treatment challenge is in getting therapies into brain tissue. That’s because the brain is protected by a selective membrane called the blood-brain barrier (BBB) that’s designed to keep potentially harmful substances in circulation out.
Nanoparticle drug delivery
Levodopa, the cornerstone of Parkinson’s treatment, is a precursor molecule that’s converted to dopamine in the body. While levodopa can cross the BBB, dopamine cannot. When circulating enzymes break levodopa down in the body too soon, the treatment limited in its ability to reach the brain and have a therapeutic effect. That’s why it is usually given with other medications, such as carbidopa or benserazide, that prevent its breakdown and help it more efficiently reach the brain.
Another caveat to this approach is that the levodopa metabolism can exacerbate a type of cellular damage called oxidative stress that’s implicated in Parkinson’s neurodegeneration. With oxidative stress, there are too many toxic reactive oxygen species (ROS) molecules and not enough antioxidants to counterbalance them.
To help overcome some of these treatment challenges in Parkinson’s, researchers developed a specialized nanocarrier designed to help deliver levodopa across the BBB while also reducing ROS levels.
First, levodopa was loaded into a large molecule to protect it from degradation by circulating enzymes. It was linked together with bonds that are sensitive to ROS, and will therefore break down and release levodopa in the presence of ROS.
This medication-loaded capsule was then wrapped around a gold nanorod, which has properties that will help enhance BBB permeability. The entire delivery system was then coated in angiopep-2, a molecule able to bind to proteins on the BBB and facilitate brain entry.
Addressing disease’s underlying causes
The idea is that the encapsulated levodopa will be safely and effectively transported to the brain, where it will be released in response to elevated ROS levels and converted into therapeutic dopamine. The release of the ROS-sensitive bonds is also expected to lower toxic ROS levels.
“This approach more effectively addresses the underlying causes of Parkinson’s disease, such as oxidative stress … offering a new promising avenue for potentially slowing disease progression and improving the quality of life for patients,” the researchers wrote.
In a series of lab experiments, the scientists showed that their nanoparticles worked as intended and were capable of crossing the BBB, lowering oxidative stress, and offering neuroprotection.
The treatment did not seem to cause any toxicity to healthy tissues or induce any unwanted immune responses in mice when given directly into the bloodstream.
Scientists found that using a beam of laser energy led to enhanced BBB permeability via the gold rods. After treatment, the BBB was able to recover.
In a mouse model of Parkinson’s, this laser-nanoparticle combination led to significant improvements in motor function relative to untreated mice. Standard levodopa with benserazide also had motor benefits, while levodopa alone did not.
Both the nanoparticles and levodopa/benserazide led to significant increases in levels of dopamine and its metabolites, whereas only the nanoparticle treatments led to reductions in markers of oxidative stress. They were also able to reduce dopaminergic neuron damage in brain tissue.
“In summary, the significant accumulation of [levodopa] and its metabolites in the brain, coupled with the reduced oxidative stress levels, suggests that this administration method can more effectively accomplish dopamine supplementation and enhance the microenvironment in the brains of Parkinsonian mice,” the researchers wrote. “This highlights its potential for clinical development and applicability in treating other brain diseases.”
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