Covalent conjugation of anticancer drugs to targeting carriers (e.g., antibodies
or small molecules) capable of selectively binding to tumor-specific antigens, is
emerging as a successful strategy to overcome the drawbacks of traditional chemotherapy.
Due to its overexpression on blood vessels of human tumors, αvβ3 integrin is one
of the most studied receptors of tumor-targeted therapeutics: several peptides and peptidomimetics,
bearing the RGD (Arg-Gly-Asp) recognition sequence, have been developed
as integrin ligands and linked to different anticancer drugs. The resulting integrin-
targeted small molecule-drug conjugates (SMDCs) are able to release the cytotoxic agents upon cleavage of a linker
under specific conditions (i.e., hydrolysis, enzymatic action or reduction). Despite the significant efforts made in this
field, αvβ3 integrin-targeted SMDCs are still far from the clinic. In this review, we survey this approach with a special focus
on the different linkers employed and the reported biological activities in vitro and in vivo.