Mitochondrial function declines with age, and one of the effects of this decline is an increased production of oxidizing molecules. Delivering antioxidants specifically to mitochondria has shown some ability to modestly slow aging in animal models, and has demonstrated its worth in the treatment of a few conditions characterized by excessive oxidative stress.
Efforts to develop mitochondrially targeted antioxidants to date have largely involved small molecules, and a limited number of classes of such molecules, those capable of localizing themselves to the mitochondria, have been established to date. Given a delivery system like lipid nanoparticles (LNPs) capable of targeting mitochondria, however, one can consider many different payloads. A broader selection of antioxidants, for a start, but there are many forms of protein therapy and gene therapy that one might want to send to mitochondria, given the means to do so.
Today's open access paper is focused on the liver as a target for LNP-delivered antioxidant therapy, as LNPs tend to end up in the liver, like most injected compounds or therapies. It is, however, possible to build LNPs that have very different biodistribution characteristics, either more broadly distributed throughout the body, or much more localized to specific tissues other than the liver. We should expect to see steady innovation on this front given initial demonstrations of the ability to target the delivery of LNP payloads to the mitochondria.
Mitochondria function as hubs for the integration and control of metabolic and immune systems by communicating with other organelles to maintain their individual functions and provide energy and signals. This organelle produces reactive oxygen species (ROS) in the electron transport chain that produces adenosine triphosphate (ATP). ROS production is regulated by oxidoreductases and antioxidant pathways, and moderate levels of ROS that play a role in signal transmission, cell survival, apoptosis, differentiation, and the activation of the immune system.
However, when mitochondria are unable to maintain homeostasis due to external stimulation, they generate excessive levels of ROS, thus inducing oxidative damage. Increased oxidative stress leads to mitochondrial dysfunction, resulting in premature ageing and the development of various diseases. On this point, the delivery of antioxidant molecules to mitochondria would be a useful type of therapeutic strategy.
Delivering a drug or other molecule to mitochondria needs to reach the target organ, be taken up by cells and then transferred to an organelle. The use of lipid nanoparticles (LNPs) for lipid-based drug delivery have the potential to overcome these challenges. Coenzyme Q10 (CoQ10) is a well-known antioxidant molecule and also acts as an essential coenzyme for ATP production in mitochondria. We previously reported on a method for preparing a CoQ10-MITO-Porter, a mitochondria-targeted LNP encapsulating CoQ10, using a microfluidic device. The procedure had a high degree of reproducibility and could be scaled up.
This study reports on an attempt to establish a system for delivering an antioxidant molecule CoQ10 to mitochondria and the validation of its therapeutic efficacy in a model of acetaminophen liver injury caused by oxidative stress in mitochondria. A CoQ10-MITO-Porter, a mitochondrial targeting lipid nanoparticle (LNP) containing encapsulated CoQ10, was prepared using a microfluidic device. It was essential to include polyethylene glycol (PEG) in the lipid composition of this LNP to ensure stability of the CoQ10, since it is relatively insoluble in water.
Based on transmission electron microscope observations and small angle X-ray scattering measurements, the CoQ10-MITO-Porter was estimated to be a 50nm spherical particle without a regular layer structure. The use of the CoQ10-MITO-Porter improved liver function and reduced tissue injury, suggesting that it exerted a therapeutic effect on APAP liver injury.