Adsorption may be rate-limiting for the release of positively charged proteins from PLGA np. (i) Initially, the protein is fully adsorbed to the negatively charged nanoparticle surface. (ii) As the nanoparticle begins to degrade, acidic components build up and decrease the local pH. (iii) At a certain threshold, the nanoparticle surface becomes neutral, weakening the electrostatic interactions with the positively charged proteins and initiating release.
It’s a potential game-changer for Rx of chronic illnesses or injuries that often require multiple injections or daily pills. For decades, biomedical engineers have been painstakingly encapsulating proteins in nanoparticles to control their release. Now, a research team led by Professor Molly Shoichet has shown that proteins can be released over several weeks, even months, without ever being encapsulated. In this case the team looked specifically at therapeutic proteins relevant to tissue regeneration after stroke and spinal cord injury.
“It was such a surprising and unexpected discovery,” said Dr Donaghue, who first found that therapeutic protein NT3, a factor that promotes the growth of nerve cells, was slowly released when just mixed into a Jello-like substance that also contained nanoparticles.
Proteins hold enormous promise to treat chronic conditions and irreversible injuries—for example, human growth hormone is encapsulated in these tiny polymeric particles, and used to treat children with stunted growth. Until now, investigators have been treating proteins the same way as small drug molecules and encapsulating them in polymeric nanoparticles, often made of a material called poly(lactic-co-glycolic acid) or PLGA.
As the nanoparticles break down, the drug molecules escape. The same process is true for proteins; however, the encapsulating process itself often damages or denatures some of the encapsulated proteins, rendering them useless for treatment. They now show that to get the desired controlled release, proteins only need to be alongside PLGA nanoparticles, not inside them. “We think that this could speed up the path for protein-based drugs to get to the clinic,” said Elliott Donaghue.
Method: Shoichet’s group mixes proteins and nanoparticles in hydrogel, which keeps them localized when injected at the site of injury. The +ve charged proteins and -ve nanoparticles stick together. As the nanoparticles break down they make the solution more acidic, weakening the attraction and letting the proteins break free.
“We are particularly excited to show long-term, controlled protein release by simply controlling the electrostatic interactions between proteins and polymeric nanobeads,” said Shoichet. “By manipulating the pH of the solution, the size and number of nanoparticles, we can control release of bioactive proteins. This has already changed and simplified the protein release strategies that we are pursuing in pre-clinical models of disease in the brain and spinal cord.”
Pakulska said, “Our next question is whether we can do the opposite—design a similar release system for positively charged nanoparticles and negatively charged proteins.”
http://advances.sciencemag.org/content/2/5/e1600519.full
http://phys.org/news/2016-05-simple-protein-nanoparticles-encapsulation.html
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