Single‐Molecule Dendritic MRI Nanoprobes Reveal the Size‐Dependent Tumor Entrance

The tumor entrance of drug delivery systems, including therapeutic proteins and nanomedicine, plays an essential role in affecting the treatment outcome. Nanoparticle size is a critical but contradictory factor in making a trade‐off among blood circulation, tumor accumulation, and penetration. Here, this work designs a series of single‐molecule gadolinium (Gd)‐based magnetic resonance imaging (MRI) nanoprobes with well‐defined sizes to precisely explore the size‐dependent tumor entrance in vivo. The MRI nanoprobes obtained by divergent synthesis contain a core molecule of macrocyclic Gd(III)‐chelate and different layers of dendritic lysine units, mimicking globular protein. This work finds that the r1 relaxivity and MR imaging signals increase with the nanoparticle size. The nanoprobe with a lower limit of critical size threshold ≈8.0 nm achieves superior tumor accumulation and penetration. These single‐molecule MRI nanoprobes can be served to precisely examine the size‐related nanoparticle‐biological interactions. A size series of well‐defined MRI nanoprobes is synthesized to investigate the size‐dependent tumor accumulation and penetration. It is found a critical size threshold ≈8 nm that the larger nanoprobes could have prolonged blood circulation, better tumor filtration, and increased tumor accumulation. The results may guide the development of dendrimer‐based nanomedicine and other drug‐delivery systems.