Conjugates of Cryptophycin and RGD or isoDGR Peptidomimetics for Targeted Drug Delivery

RGD‐cryptophycin and isoDGR‐cryptophycin conjugates were synthetized by combining peptidomimetic integrin ligands and cryptophycin, a highly potent tubulin‐binding antimitotic agent across lysosomally cleavable Val‐Ala or uncleavable linkers. The conjugates were able to effectively inhibit binding of biotinylated vitronectin to integrin α(v)β(3), showing a binding affinity in the same range as that of the free ligands. The antiproliferative activity of the novel conjugates was evaluated on human melanoma cells M21 and M21‐L with different expression levels of integrin α(v)β(3), showing nanomolar potency of all four compounds against both cell lines. Conjugates containing uncleavable linker show reduced activity compared to the corresponding cleavable conjugates, indicating efficient intracellular drug release in the case of cryptophycin‐based SMDCs. However, no significant correlation between the in vitro biological activity of the conjugates and the integrin α(v)β(3) expression level was observed, which is presumably due to a non‐integrin‐mediated uptake. This reveals the complexity of effective and selective α(v)β(3) integrin‐mediated drug delivery.