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"Receptor-responsiveness", the change of receptors such as clustering after activation via ligand binding, attenuates the targeting efficiency of a receptor-mediated nanocarrier.Here, based on the validation of integrin αvβ3 clustering on B 16 cells and the molecular model computation of αvβ3 clustering, we design a tailored nanomedicine to respond to such "receptor-responsiveness" by modifying nanoparticles with a more compatible dimeric RGD molecule.Compared with the control, this nanocarrier demonstrates better targeted delivery to αvβ3 overexpressing tumors both in vitro and in vivo via an enhanced receptor-ligand across-talking.