Innovative multidrug nanomedicines for myocardial ischemia reperfusion injuries treatment

Nano4Life project aims at developing new multidrug nanomedicines for the
treatment of myocardial ischemia reperfusion (I/R) injury, the underlying
pathological mechanism of acute myocardial infarction and a major cause of
heart failure and mortality in the world.
Several mechanisms contribute to I/R injury, including increased radical
oxygen species (ROS) formation, endothelial dysfunction, platelet
aggregation, inflammation and cell death.
Clinical delivery of antioxidants (against ROS) or adenosine (antiinflammatory
capacities and anti-platelet aggregation) is mitigated due to
the fact that these drugs do not easily penetrate the membrane of cells or
have poor stability and short half-life in plasma when administered through
conventional delivery modes.
We propose an innovative approach based on the chemical linkage of
active molecules (adenosine and antioxidants) to squalene, a natural
biocompatible lipid, which triggers the spontaneous self-assembly of
resulting bioconjugates into nanoparticles (NPs). This enables to
dramatically increase the drug payload of NPs and to avoid an uncontrolled
release.
These multidrug nanoparticles are expected to protect the active principles
from rapid uptake and degradation into blood. The accumulation of this
multidrug nanomedicine toward the ischemic area is expected to occur
through the enhanced permeability and retention (EPR) effect resulting from
the strong inflammatory processes present in ischemic tissue. The cell
uptake could also be mediated by the vLDL and LDL receptors (recognizing
squalene) upregulated on endothelial cells under ischemia.
It is expected that combining adenosine with antioxidant within the same
nanomedicine (multidrug NPs) will allow better therapeutic efficacy. In case
of success, the validation of the cardioprotective efficacy in the murine
model of cardiac ischemia/reperfusion, will open the way towards validation
in large animals (pigs) and envisage a future clinical application.