Abstract
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(v)β(3) 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.