Background
Macrophages and folate receptor in rheumatoid arthritis
Activated macrophages have been identified as key mediators in inflammatory diseases like rheumatoid arthritis. Prolonged inflammatory states can last for weeks, months or even years. Macrophages may display distinctive markers of activation and maturation depending on the type of activation, the immune cells involved, state of differentiation, type of aggression and the tissue where this all takes place.
Folate receptor β (FRβ), whose expression is selectively elevated in synovial macrophages on rheumatoid arthritis, has been used as a target for immunotherapy in a number of clinical situations, such as autoimmunity and inflammation.
Activated macrophages have been identified as key mediators in inflammatory diseases like rheumatoid arthritis. Prolonged inflammatory states can last for weeks, months or even years. Macrophages may display distinctive markers of activation and maturation depending on the type of activation, the immune cells involved, state of differentiation, type of aggression and the tissue where this all takes place.
Folate receptor β (FRβ), whose expression is selectively elevated in synovial macrophages on rheumatoid arthritis, has been used as a target for immunotherapy in a number of clinical situations, such as autoimmunity and inflammation.
Proposed modes of intervention with folate-based liposomes (FBL) in inflammation behind rheumatoid arthritis.
Current treatment for rheumatoid arthritis
The goal of the treatment of rheumatoid arthritis is both to alleviate the symptoms and to prevent destruction of the joints and the resulting handicap. The drugs currently being used are often ineffective in one of those two aspects and frequently present harmful side effects that can even lead to the death of the patient. The most important and most common adverse events of the disease-modifying anti-rheumatic drugs (DMARDs) relate to liver and bone marrow toxicity (e.g. azathioprine), renal toxicity (e.g. cyclosporine), pneumonitis and liver steatosis (methotrexate), allergic skin reactions (e.g. gold salts), autoimmunity (e.g. minocycline) and infections (azathioprine, cyclosporine).
Methotrexate (MTX)
Many rheumatologists consider MTX to be the most important and useful DMARD, despite its potential toxicity and possible depression of the bone marrow or interference with liver bioprocesses leading to hepatitis and impaired liver function. MTX is commonly administered once a week and is supplied in excess. However, through rapid elimination mechanisms, it is largely removed from the body over 1 to 2 days with the first 24 hours, being associated with side-effects including lethargy and nausea. This initial high loading dose is considered necessary to fully bind target sites and to obtain an effect. The bulk of applied MTX is normally not delivered to the target sites but instead is taken up by the main metabolic organs (liver, spleen, and kidney) where it exerts a general metabolic suppression effect which is felt by patients as lack of energy and nausea. This particular side effect is reported most frequently by women (ca. 75% of reports). In a sub-set of patients (ca. 25%) the gut eventually reacts to oral MTX therapy (MTX is an inhibitor of epithelial replication, essential for the gut lining) and treatment needs to be replaced by injectable forms of MTX. The injectable forms have a lower impact on the gut but a stronger initial effect on the liver and central organs, which forces most patients to rest after the application. These effects are due to MTX being rapidly removed from the blood stream by the central organs meaning that adequate doses for exposure to arthritic lesions in the limbs are associated with excess exposure in the central organs.
The goal of the treatment of rheumatoid arthritis is both to alleviate the symptoms and to prevent destruction of the joints and the resulting handicap. The drugs currently being used are often ineffective in one of those two aspects and frequently present harmful side effects that can even lead to the death of the patient. The most important and most common adverse events of the disease-modifying anti-rheumatic drugs (DMARDs) relate to liver and bone marrow toxicity (e.g. azathioprine), renal toxicity (e.g. cyclosporine), pneumonitis and liver steatosis (methotrexate), allergic skin reactions (e.g. gold salts), autoimmunity (e.g. minocycline) and infections (azathioprine, cyclosporine).
Methotrexate (MTX)
Many rheumatologists consider MTX to be the most important and useful DMARD, despite its potential toxicity and possible depression of the bone marrow or interference with liver bioprocesses leading to hepatitis and impaired liver function. MTX is commonly administered once a week and is supplied in excess. However, through rapid elimination mechanisms, it is largely removed from the body over 1 to 2 days with the first 24 hours, being associated with side-effects including lethargy and nausea. This initial high loading dose is considered necessary to fully bind target sites and to obtain an effect. The bulk of applied MTX is normally not delivered to the target sites but instead is taken up by the main metabolic organs (liver, spleen, and kidney) where it exerts a general metabolic suppression effect which is felt by patients as lack of energy and nausea. This particular side effect is reported most frequently by women (ca. 75% of reports). In a sub-set of patients (ca. 25%) the gut eventually reacts to oral MTX therapy (MTX is an inhibitor of epithelial replication, essential for the gut lining) and treatment needs to be replaced by injectable forms of MTX. The injectable forms have a lower impact on the gut but a stronger initial effect on the liver and central organs, which forces most patients to rest after the application. These effects are due to MTX being rapidly removed from the blood stream by the central organs meaning that adequate doses for exposure to arthritic lesions in the limbs are associated with excess exposure in the central organs.
Concept and approach
FOLSMART proposes the application of liposomes with an FA-peptide linker, encapsulating MTX
During NANOFOL project, we rationally designed a bifunctional peptide that serves as FA linker and anchor. The peptide is derived from the neck domain of pulmonary surfactant-associated protein D (SP-D). The new FBL developed during NANOFOL represents a very promising tool for the treatment of chronic inflammatory diseases such as RA.
In contrast to free MTX, the FBL is selectively retained in plasma and through the larger size of the liposomes it is not subjected to immediate absorption and filtering by the main organs. This means that the FBL can circulate to its peripheral target tissue and bound there instead of being non-selectively absorbed by other parts of the body. Our data show that the vehicle is a promising means of delivering MTX to a target organ.
During NANOFOL project, we rationally designed a bifunctional peptide that serves as FA linker and anchor. The peptide is derived from the neck domain of pulmonary surfactant-associated protein D (SP-D). The new FBL developed during NANOFOL represents a very promising tool for the treatment of chronic inflammatory diseases such as RA.
In contrast to free MTX, the FBL is selectively retained in plasma and through the larger size of the liposomes it is not subjected to immediate absorption and filtering by the main organs. This means that the FBL can circulate to its peripheral target tissue and bound there instead of being non-selectively absorbed by other parts of the body. Our data show that the vehicle is a promising means of delivering MTX to a target organ.
Work packages
The FOLSMART project will combine expertise in nanotechnologies, biology, chemistry, materials science, biotechnology, engineering, medical and pharmaceutical sciences creating a multidisciplinary context that is expected to generate a cost effective alternative for the treatment of rheumatoid arthritis.
The FOLSMART project will combine expertise in nanotechnologies, biology, chemistry, materials science, biotechnology, engineering, medical and pharmaceutical sciences creating a multidisciplinary context that is expected to generate a cost effective alternative for the treatment of rheumatoid arthritis.
FOLSMART strategy for cost efficient treatment of rheumatoid arthritis.
| 18M Publishable Summary.pdf |
Project co-funded by the European Commission within the Horizon 2020 research and innovation programme under Grant Agreement No. 68335.