Bioconjugate approaches for the systemic delivery of proteins with the Feldan Shuttle

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The cell membrane is a biological barrier that can be difficult to cross, especially for proteins. Its polar exterior and non-polar interior effectively block diffusion of these molecules, which limits their ability to reach the interior of the cell. This is a major challenge for the delivery of therapeutic proteins, because many of these agents must reach the intracellular space to be active. Feldan Therapeutics Inc. has developed a library of cationic peptides (i.e., the Feldan Shuttle platform) to facilitate the delivery of proteins, protein complexes, and peptides (i.e., the Cargos) into the cell. Because no covalent bond is formed between the cargo and the Shuttle, and because of the large number of different peptide Shuttles within the library, this platform is suitable for promoting the intracellular delivery of many categories of Cargos. This has been demonstrated in both ex vivo as well as in pilot animal studies. However, this process is non-specific and will occur in the first cells encountered. While not an issue for the delivery of proteins into cell cultures, this non-specificity implies that cargo delivery will be restricted to the immediate area at the site of injection (i.e., inability to target diseased vs. healthy tissue). Moreover, while the lack of covalent bond between the Shuttle and the cargo protein is seen as advantageous for cell culture experiments, this is a major challenge in vivo, due to high dilution upon injection that would cause the Shuttle to become dissociated from the cargo protein. This project will build upon proof-of-concept findings already established by Prof. Gauthier and Feldan. The objectives are to further advance the design of a prototype Shuttle/PEG/Cargo bioconjugate to: i) Increase its circulation time in the body by temporarily deactivating its cell-penetrating properties; ii) Temporarily conjugate a Cargo protein to the Shuttle so that both components (the Feldan Shuttle and its Cargo) reach the targeted area in the body; iii) Achieve altered biodistribution in vivo compared to a physical mixture of Shuttle and Cargo. The foreseen development of the prototype will be iterative and will be guided by performance assessed in both cell culture and animal experiments in healthy mice.