Proteins hold enormous promise to treat chronic conditions and irreversible injuries, for example, human growth hormone is encapsulated in tiny polymeric particles and used to treat children with stunted growth. In order to avoid repeated injections or daily pills, researchers use complicated strategies both to deliver proteins to their site of action, and to ensure they’re released over a long enough period of time to have a beneficial effect. This has long been a major challenge for protein-based therapies, especially because proteins are large and often fragile molecules.
For decades, biomedical engineers have painstakingly encapsulated proteins in nanoparticles to control their release, yet challenges such as low-loading, poor encapsulation efficiency, and loss of protein activity limit clinical translation. Now, a research team from the University of Toronto shows 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; they state their technique is a potential game-changer for the treatment of chronic illnesses or injuries that often require multiple injections or daily pills. The opensource study is published in the journal Science Advances.
Previous studies show that as 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. Poly(lactic-co-glycolic acid) (PLGA) is widely used for encapsulation because of its biocompatibility, biodegradability, wide range of degradation rates, and long clinical history. However, PLGA protein formulations often suffer from low-encapsulation efficiency and low-protein loading. Skipping encapsulation altogether means fewer denatured proteins, making for more consistent protein therapeutics that are easier to make and store. The current study shows that to get the desired controlled release, proteins only need to be alongside the PLGA nanoparticles, not inside them.
The current study mixes the proteins and nanoparticles in a Jello-like substance called a hydrogel, which keeps them localized when injected at the site of injury. Results show that the positively charged proteins and negatively charged nanoparticles naturally stick together. Data findings show that as the nanoparticles break down they make the solution more acidic, weakening the attraction and letting the proteins break free.
Results show that manipulating the pH of the solution and the size and number of nanoparticles, the release of bioactive proteins can be controlled. The group state that this has already changed and simplified the protein release strategies that they are pursuing in pre-clinical models of disease in the brain and spinal cord.
The team surmise that their findings show the therapeutic protein NT3, a factor that promotes the growth of nerve cells, can be slowly released when unencapsulated and just mixed into a Jello-like substance, that also contained nanoparticles. For the future, the researchers state that their technique stands to improve reliability and fabrication process for treatments involving conditions such as spinal cord damage and stroke.
Source: University of Toronto