Tartu Ulikool

Our recent work has uncovered that tumor-homing peptides that penetrate deep into extravascular tumor tissue contain both a tumor-specific homing sequence and a tissue-penetrating and cell-internalizing C-end Rule (CendR) motif. The CendR element in the tumor-penetrating peptides (TPP) is cryptic and proteolytically activated at the target site. It is not necessary to couple a cargo to the TPP for tumor-selective delivery; free TPP activates a bulk transport pathway in the tumor which carries a co-injected drug or nanoparticle through the vascular wall and deep into the tumor tissue. This application proposes studies to provide detailed understanding of the tissue penetration process that is triggered by TPP. Specifically, we propose: (i) to identify TPP of novel specificities (specific to non-angiogenic tumors and to selected normal organs) using in vivo phage display and de novo design; (ii) to define the molecular pathway of the CendR-induced transport; (iii) to optimize the ability of the peptides to selectively increase tissue permeability; (iv) to validate selected peptide-drug combinations in preclinical treatment and imaging studies. These studies are important for development of CendR-TPP drug targeting platform and lay foundation for the translation of the technology into clinical applications.