EVPERS · Extracellular vesicles as a tool to predict drug clearance and improve precision pharmacotherapy
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2022-01-01 → 2023-12-31
- EU contribution
- €162,806
- Participants
- 1
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
Extracellular vesicles as a tool to predict drug clearance and improve precision pharmacotherapy
What is the problem/issue being addressed? Drug transporters of the ABC (ATP-binding cassette) family are membrane proteins expressed in epithelia of pharmaco-toxicological relevance (intestine, kidney, bile canaliculi, blood-brain-barrier). Due to their critical role in the efflux of a wide range of drugs, they constitute a major factor determining therapeutic efficacy and toxicity. The most studied member of the ABC family is the P-glycoprotein (P-gp). In addition, the relevance of multidrug resistance-associated protein 2 (MRP2) and breast cancer resistance protein (BCRP) is also well-acknowledged. The expression and activity of ABC transporters are highly variable between individuals. Several factors (e.g. drugs, hormones, diet) lead to major changes in the transporter expression and, therefore, in drug pharmacokinetics. So far, extraction of biopsies would be the only option to measure ABC transporter expression in relevant tissues. However, due to its invasive character, this is neither performed routinely, nor in those cases where serious side effects could be expected due to inappropriate dosing. Extracellular vesicles (EVs) are nanoparticles released by all cell types of the organism. They carry proteins, RNA and lipids, the array of these components frequently reflecting the conditions of the cell of origin. The presence of EVs from a wide range of tissues in the blood allows a minimally invasive access to these nanoparticles. However, the limited amount of EV material requires advanced analytical methods (e.g., liquid chromatography coupled to tandem mass spectrometry, UPLC-MS/MS). So far, it is not known whether EVs constitute a good surrogate for changes in the protein levels of ABC transporters. Why is it important for society? Drug pharmacokinetics is one of the pillars determining the efficacy and safety of a therapy. An incorrect dosing might have, in some cases, fatal consequences. So far, there is no analytical strategy available to estimate the expression of ABC transporters or their changes before or during a treatment. Analyzing the potential of EVs as dynamic surrogates for ABC transporter expression can deliver useful knowledge towards developing biomarkers of drug clearance. What are the overall objectives? The general objective of this project was to investigate the potential of the ABC transporter-cargo in EVs as a biomarker of drug efflux. For this purpose, a UPLC-MS/MS method shall be developed and validated. This method shall be used to quantify the expression of ABC transporters in different types of models (i.e. primary and immortalized cells, cell lines) under treatment with different modulators. This way, the dynamic association between ABC transporter expression and activity in the cells of origin and in the EVs shall be investigated. Finally, the potential of EVs to assess cell-specific ABC transporter expression in a multicellular system (i.e. organoids) shall be investigated.
Data: CORDIS, © European Union
Project objective
Drug transporters of the ATP-binding cassette (ABC) family (e.g., P-gp, MRP2 and BCRP) promote the intestinal, biliary and urinary excretion of a wide range of drugs and, thus, determine their bioavailability, therapeutic efficacy and toxicity. Transporter expression is highly variable between individuals and within the same individual. This may result in enormous differences in the plasma concentration of a drug, which for drugs with a narrow therapeutic index may result in life-threatening situations. Extraction of biopsies would be the only option to measure transporter expression in tissues and adapt the therapeutic strategy. However, this is not performed due to its invasive character. Extracellular vesicles (EVs) are nanoparticles released by all cells of the organism. Their cargo (proteins, RNA and lipids) is frequently a dynamic fingerprint of the cell. The presence of EVs from different tissues in blood and urine allows for an easy access. The aim of this project is to evaluate if the amount of ABC transporters in EVs from blood and urine can be used to specifically predict the transporter expression at the tissues of origin under basal and induced conditions, as well as to predict in vivo drug pharmacokinetics. Following work packages (WP) are proposed: WP I: EVs as dynamic surrogate for ABC expression in vitro and ex vivo. I.I. Validation of an analytical protocol for the quantification of ABC transporters in EVs, I.II. Correlation between ABC expression in biopsies and in EVs from the same specimens, I.III. Correlation between expression of ABCs in EVs from primary cells and the expression and activity of ABCs in the cells of origin under basal and induced conditions. WP II: EVs as biomarker for drug pharmacokinetics. II.I. Optimization of the immunopurification of circulating hepatic-, intestinal- and renal EVs, II.II. Correlation of ABC transporter expression in EVs with the pharmacokinetics of an ABC model substrate under basal and induced conditions.
Original text from CORDIS.
Participants
- UNIVERSITATSKLINIKUM HEIDELBERG · HeidelbergCoordinatorGermany
Links
Data: CORDIS, © European Union