Discovery of Novel Multifunctional Molecules for Synergistic Theranostics Based on Vascular Normalization Targets

Tumor vascular abnormalities can reduce drug and oxygen delivery and induce tumor resistance. However, it has recently been found that a few antiangiogenic drugs can achieve significant efficacy when combined with chemoradiotherapy, which is contrary to the effect of antiangiogenic drugs in clearing blood vessels. The theory of vascular normalization, originating from clinical observations, has explained this paradox and has become a promising strategy to overcome the bottleneck of tumor treatment, but there is a lack of innovative drugs. Based on the previous identification of the novel vascular normalization target EphrinB2, a synergistic strategy, "vascular normalization─chemotherapy" was proposed. Based on the principle of twin drugs in drug design and the controlled release strategy, we found a new type of vascular normalization-chemotherapy twin drug based on the active molecule QDAU5, which showed good membrane permeability, strong stability, rapid toxic payload release characteristics, and strong inhibitory activity against colorectal tumors. The study further enriches the theory of vascular normalization and promotes its expansion into the field of new drug development.