Fig. 2

Illustration of in vivo delivery and tumor penetration of iRGD-PPCD and RCD-PPCD. iRGD cyclopeptide (iRGDyC) was bound to PAMAM dendrimer with DOX by an acid-sensitive cis-aconityl linkage (PEG-PAMAM-cisaconityl DOX, PPCD), producing an iRGD–PPCD conjugate. The iRGD–PPCD conjugate is proteolytically cleaved by the proteinase on the cell surface to generate a C-terminal PPCDCRGDK sequence capable of binding to neuropilin-1 and providing a transport pathway out of the blood vessels and through the extracellular tumor tissue. In contrast, RGD–PPCD only accumulates around the tumor blood vessels by binding to alpha v integrins and shows poor penetration ability in the tumor parenchyma