Size-dependent lymphatic delivery of Gd-based MRI contrast agents: insights from in vivo studies

Lymphatic transport is strongly influenced by the hydrodynamic size of delivered agents, yet comparisons across distinct material platforms remain limited. This work investigates this principle using a selection of Gd-based MRI contrast agents that span a wide size range and key material platforms: a small molecule Gd-DTPA, a macromolecular polymer PAA-Gd, and a nanocrystal NaGdF₄@PEG. The results reveal a clear size-dominated delivery rule: agents with hydrodynamic diameters below 10 nm efficiently enter lymphatic vessels for nodal accumulation, whereas larger nanoparticles (>20 nm) are largely excluded from lymphatic vessels and instead rely on interstitial transport. This distinct pharmacokinetic behavior was visualized through dynamic contrast-enhanced (DCE) MRI and T₁-weighted imaging (T₁WI) and validated by chlorophosphonazo III (CPN III) staining. Furthermore, subcutaneous tumor models were employed to probe the interplay between lymphatic transport and tumor microenvironments. This work moves the field forward by providing a framework to guide the design of lymphatic delivery drugs, turning material-specific observations into universal, size-informed design principles applicable across diverse platforms.