Targeted liposomal antioxidant and anti-inflammatory therapy for liver ischemic reperfusion injury
Ana Margarida Ferreira-Silva (PhD fellow sponsored by the PRC) - The Research Institute for Medicines (iMed.ULisboa) and BioNanoSciences/Drug Delivery and Immunotherapy (BioNanoSci)
Our project focuses on liver reperfusion injury, which is a severe pathology with a very high unmet therapeutic need as patients in whom a liver transplantation fails do not have any treatment option left. The high-level objective of our project is to improve the outcome of liver transplantation by using intravenous liposome therapy after transplantation to target two important pathologic pathways in liver perfusion ischemic injury: oxidative stress and inflammation.1)2)3)4)5) Liposomes offer the unique opportunity to load anti-inflammatory drugs in the interior while using the phospholipid bilayer for the encapsulation of anti-oxidant lipophilic compounds including phospholipids composed of polyunsaturated fatty acids (PUFAs). The importance of both pathways for the irreversible damage resulting from the pathology will be investigated and the usefulness of targeting either pathway will be assessed. Also, the required timing of therapeutically interfering in these pathways will need to be clarified, as oxidative stress and inflammation may not occur in parallel.
The main deliverable and outcome of this project is one or two investigational lead products that can be furthered to level of clinical readiness by working on GMP manufacturing, stability and safety assessment.
Benefit for the community
The improvement of clinical outcomes after liver surgery is crucial to the success of the procedure. In 2015, the number of liver transplants in Portugal was around 450 cases in a total of 830 organ transplant. The development of new medicinal products able to decrease ischemia/reperfusion injury with a single administration during the procedure is potentially of high social and economic impact. It is also important to clarify key pathways contributing to oxidative-stress and inflammation during liver surgery, establish a basis for an understanding of its modulation of inflammatory mechanisms during ischemia/reperfusion injury, and to relate biomarkers and the progress of the disease.
Molecular pathways in protecting the liver from ischaemia/reperfusion injury: A 2015 update
Clin. Sci.(Lond.) 129, 345-362
Hepatic ischemia-reperfusion injury in liver transplant setting: mechanisms and protective strategies
J. Biomed. Res. 33, 221-234
Gene Silencing using siRNA for Preventing Liver Ischaemia-Reperfusion Injury
Curr. Pharm. Des. 24, 2692-2700
Therapeutic activity of superoxide dismutase-containing enzymosomes on rat liver ischaemia-reperfusion injury followed by magnetic resonance microscopy
Eur. J. Pharm. Sci. 109; 464-471
Superoxide dismutase enzymosomes: carrier capacity optimization, in vivo behaviour and therapeutic activity
Pharm. Res. 32, 91-102