Synthesis of novel conjugates based on a functionalized cyclo[DKP-isoDGR] integrin ligand and potent cytotoxic agents

Targeted drug delivery is a growing-interest field in cancer therapy as a strategy for overcoming the systemic cytotoxicity associated to traditional chemotherapy. One important approach in this research area is represented by the small molecule-drug conjugates (SMDCs), where the drug-targeting is performed by a low molecular weight ligand (peptide, vitamin or peptidomimetic) connected to a potent warhead through a stable linker. This PhD thesis describes the synthesis and biological evaluation of novel SMDCs containing the functionalized cyclo[DKP-isoDGR] integrin ligand developed by our research group and potent cytotoxic drugs (α-amanitin, MMAE and MMAF) combined via different linkers and spacers. The conjugates were evaluated for their binding affinity to the isolated αvβ3 receptor and for their antiproliferative activity on cancer cell lines with different levels of αVβ3 expression in order to study the efficacy of the cyclo[DKP-isoDGR] integrin ligand as a vector for tumor drug-delivery.