Periodic Reporting for period 4 - INTESTINANOS (Intestinal Lipoidal Nanostructures - A Lipid Bridge to Increased Drug Delivery)
Berichtszeitraum: 2020-03-01 bis 2020-08-31
In project 2 we designed an assay that simultaneously assess the importance of digestion of lipid-based formulations on absorption of the formulated drug. We chose to work with Caco-2 cells, the gold standard for permeability assessment, as the absorption membrane in the assay developed. This enable detection of both passive and active transporters and their role in absorption of drugs, excipients (and digestion products thereof) as well as naturally available bile components. The chamber-based system has proven to be in vivo predictive of performance of lipid-based formulations, and has recently also shown to be useful for evaluation and head-to-head comparisons with other advanced formulation strategies. We have also showed that the designed method can be used together with cheaper artificial membranes instead of Caco-2. This is very useful for compounds where absorption is not expected to be influenced by active transporters. Through an ERC PoC grant we are also exploring the possibility to scale down the method and make it useful for automated assays.
In project 3, we designed a virtual intestine suitable for characterization of drug solubilization and formulation performance when exposed to the intestinal fluid, and the role of interindividual variability on these processes. Here, the data generated in project 1 was fed into the simulations to base the virtual intestine on real data. We have designed the virtual intestine to enable studies of the fasted and fed state. MD simulation is the backbone. To allow us to produce simulations with a relative high speed, allowing the use of the virtual intestine for future screening projects, we decided to use the coarse grain methodology. This has a lower resolution than the all atom methodology, but allow us to study processes for a longer time and/or to study larger systems; all crucial for the study of the dynamics of the intestinal fluid. Till date the virtual intestine has been used to study partitioning, solubilization of drugs and excipients, interactions with degradation products and the role of intestinal bile micelles as drug shuttles to the intestinal membrane. However, the virtual intestine is highly useful to understand food and nutrients, or other settings where colloidal rearrangements are of interest.
INTESTINANOS has delivered over expectations based on the very ambitious research program rolled out. Till date 24 scientific papers have been published, and data have been presented at 50 conferences through oral presentations, several of which being keynotes. In addition to this, a much higher number of posters and webinars have been provided by the PI and enrolled young researchers. The results achieved are also the basis for several new applications for funding, including those submitted by tenure track assistant professors in my group. Till date, the ENA and the virtual intestine have played key roles in research projects included in the Swedish Drug Delivery Center, a competence center where Uppsala University collaborates with 15 industrial partners and for which the PI is the director. Further, the experimental and computational platforms make up the foundation for research projects supported by the Swedish Research Council and NordForsk.