Project Portugal 2030

Summary

The SUPERATE project embodies two main objectives: (i) to engineer NPs featuring super-diffusive transport in intestinal mucus, and (ii) to demonstrate their potential as feasible carriers for biopharmaceuticals, namely therapeutic peptides. Insulin and T1DM will be used as model peptide and disease, respectively, for establishing general proof-of-concept for the previous objective. It is expected that, in addition to commonly advocated advantageous features of nanocarriers (e.g., active payload protection, improved epithelial permeability), super-diffusive behavior may further enhance insulin transport in mucus. The proposed work includes the fabrication and physicochemical characterization of nanosystems featuring asymmetric surface chemistry that allows conferring self-propelling properties (Supporting Fig. 1). Anisotropic NPs will be designed to feature an overall mucus-inert PEG coating that is counterpointed by a distinctive domain allowing self-propulsion. NPs will be screened in vitro for transport in healthy intestinal mucus obtained from pigs or mucus surrogates, and for GIT distribution and retention upon gavage or intra-intestinal administration to mice. Demonstration of the utility of super-diffusive NPs as oral carriers for insulin will be pursued by using a T1DM mouse model. It is anticipated that the SUPERATE project leads to the development of super-diffusive insulin-loaded NPs with enhanced bioavailability and hypoglycemic effects as compared to matched “conventional” mucoadhesive and mucodiffusive NPs. The experimental tasks of the SUPERATE project intend to provide answers – defined as specific aims – to the following questions: (1) Can we engineer anisotropic NPs that potentially possess super-diffusive properties? (Task 1); (2) Can anisotropic NPs feature super-diffusive transport in intestinal mucus? (Task 2); (3) Can super-diffusive NPs display distinct distribution and/or retention in the GIT when administered orally, namely as compared to mucoadhesive and mucodiffusive NPs? (Task 3); (4) Can super-diffusive NPs improve the bioavailability and therapeutic outcome of insulin when used as oral carriers for the management of T1DM, namely as compared to mucoadhesive and mucodiffusive NPs? (Task 4). Each task is built on intermediate goals (expected outcomes) that will ultimately contribute to the success of the project. Despite comprising single and well-defined units, tasks will be conducted in a dynamic and interconnected fashion, providing not only solid ground for subsequent stages, but also valuable feedback for iterations. This aspect of the project will be particularly prominent during Task 1 and Task 2. We expect at the end of the project that at least one formulation of super-diffusive nanocarriers can be shown effective in improving the bioavailability and pharmacological activity of insulin, namely as compared to mucoadhesive and mucodiffusive NPs. This should be obtained at EU technology readiness level 4, viz. validated in laboratory environment, and on-track to start initial clinical testing. Intellectual property protection of relevant technology will be procured by patent filing, while progress into the next steps of development will be considered by seeking clinical and industrial partners. The potential economic and healthcare impact of the outputs from the SUPERATE project are predictably high.