Neurodegenerative disorders like Alzheimer's or Parkinson's are difficult to treat because drugs must be able to cross the blood–brain barrier. As a result, the doses given must be high, and only a small fraction reaches the brain, resulting in serious systemic adverse effects.
In a recent study by postdoctoral researcher Jean-Michel Rabanel, under the supervision of Professor Charles Ramassamy, at the Institut national de la recherche scientifique (NRS), are developing optimized polymer-coated nanoparticles to increase their permeability across this blood-brain barrier and consequently enhancing the delivery of encapsulated drugs in the brain.
For drug nanocarrier surface coating, zwitterion polymers with high antifouling properties have been proposed as credible alternatives to polyethylene glycol (PEG). PEG coating flaws, such as immunological reactions and insufficient protein repellency, are thought to be resolved by zwitterionic polymers.
The team demonstrated the effectiveness of a specific polymer PMPC-coated nanoparticles (NPs). These molecules are neutral overall, and have an equal number of positive and negative charges to mimic the molecules on the cell's surface. The researchers compared the characteristics of two polymer coatings on the polylactic acid (PLA) nanoparticles, a biocompatible material easily cleared by the body.
The first coating, consisting of polyethylene glycol (PEG), as tested on zebrafish, allows for virtual real-time visualisation of nanoparticle dispersion due to its transparent body. Under the same conditions, the second coating consisting of zwitterionic polymer was compared.
The endothelium's uptake of NPs has a significant impact on their pharmacokinetics and biodistribution. The data on NP biodistribution in zebrafish larvae showed that, regardless of their shell composition, NPs preferentially accumulate in low blood flow regions, particularly in tortuous capillaries with flow rates at least an order of magnitude lower than those found in straight capillaries such as arterioles.
It was demonstrated that the zwitterionic polymer, which is more biocompatible in theory since it is similar to molecules on the cell's surface, had greater access to the brain using this sort of experiment. It is, however, absorbed more quickly by blood vessel walls, which lowers the time it takes for blood to circulate.
Although PEG remains the most attractive coating polymer with respect to the bloodstream and blood circulation time, researchers pointed out that a mixture of both polymers could be considered to leverage the benefits of each. Aside from their similar size and surface potential, a side-by-side assessment of PEG- and PMPC-coated NPs revealed significant differences in vitro and in vivo for the first time. Surprisingly, PMPC coating was shown to improve protein binding. According to the researchers, it is an interesting avenue for delivering drugs directly to the brain thereby improving the treatment for neurodegenerative diseases.
Reference:
Jean-Michel Rabanel et al, Nanoparticle shell structural cues drive in vitro transport properties, tissue distribution and brain accessibility in zebrafish, Biomaterials (2021).
Journal information: Biomaterials
Blog by Pravajja Vaddikar
Comments