Renal Clearable H-Dots Leveraging Ligand Complexation for Enhanced Active Tumor Targeting

The use of ligand conjugation onto nanoparticle surfaces as an active targeting strategy has gained significant attention in the pursuit of improving tumor-specific delivery and retention. However, the chemical conjugation of targeting moieties often induces alterations in the physicochemical properties of nanoparticles, including size, conformation, charge-to-mass ratio, and hydrophilicity/lipophilicity, resulting in unexpected biodistribution and pharmacokinetic profiles. Here, the enhanced active targeting efficiency achieved by integrating cyclic arginine–glycine–aspartic acid (cRGD) peptides onto ultrasmall nanocarrier H-dot while preserving its essential physicochemical and pharmacokinetic attributes is investigated. The resulting cRGD/H-dots demonstrate improved cellular uptake via integrin α_vβ₃ receptors, accompanied by negligible cytotoxicity. Notably, the active targeting efficacy of cRGD/H-dots compared to unmodified H-dots (1.2%ID/g, two-fold increase) is quantitatively evaluated, validated through fluorescence imaging and histological analysis. The findings highlight that cRGD/H-dots offer enhanced tumor targetability and prolonged tumoral retention while maintaining active renal clearance of unbound molecules.