Development of peptide-drug conjugates with a caged enzymatic cleavage site for improved drug delivery

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Brain tumors such as glioblastoma are one of the most deadly cancer types. The treatment of this highly invasive cancer is limited due to the bad blood brain barrier permeability of many chemotherapeutics. To overcome this issue and the generation of side-effects as a result of low cancer cell selectivity, peptide-drug conjugates are often used. It has been shown that specific peptide sequences, derived from nature, can cross the blood brain barrier. Furthermore, certain peptides bind with high affinity and selectivity to receptors that are overexpressed in the membrane of cancer cells. These promising features will be utilized in a conjugate, consisting of a blood brain barrier shuttle, a peptidic receptor ligand and a chemotherapeutic agent. The resulting Trojan horse is envisioned to carry the drug across the blood brain barrier and to selectively treat cancer by shuttling the drug inside tumor cells. To further increase the selectivity, an enzymatically cleavable peptide linker will be introduced to the conjugate. Specific enzymes are involved in tumor growth, which means that they are secreted in high levels at the malignant site. If the peptide linker is cleaved by such a specific enzyme, the drug will be released to act mostly at a location where the tumor is growing and migrating. To stabilize this linker in the blood, the enzymatic cleavage site shall be temporally caged (protected) by a novel mechanism that relies on the Diels-Alder reaction with inverse electron demand. The synthesis and in vitro testing of these multifunctional constructs will help to improve permeability and selectivity of drug-conjugates. Furthermore, it is planned to establish and optimize the application of caging an enzymatic cleavage site, which can contribute to the development of a novel prodrug-method.