Resonance Acoustic Mixing-Enabled Non-covalent Loading of Cy7 for Enhanced Solubility, Stability, and Fluorescent Imaging Performance

Near-infrared dye Cy7 is widely used as a fluorescent imaging probe but suffers from poor aqueous solubility, low stability, and limited bioavailability, which restricts its clinical translation. Here, we report a mechanochemical resonance mixing approach to construct noncovalent solid dispersions of Cy7 with poly(amidoamine) (PAMAM) dendrimers. Systematic optimization of milling parameters and drug/excipient ratios yielded Cy7-PAMAM dispersions with a 1000-fold increase in solubility and >98% retention rate. Physicochemical characterizations (FT-IR, DSC, XRD, SEM, and TEM) confirmed the amorphization of Cy7 and the formation of hydrogen-bonding and ionic interactions with PAMAM, resulting in stable nanoscale dispersions. Compared to raw Cy7, the Cy7-PAMAM formulation exhibited enhanced fluorescence quantum yield, improved thermal and photostability, and reduced photobleaching. Dissolution and permeability assays revealed rapid release (>85% within 120 min) and ~10-fold higher mucosal penetration. Pharmacokinetic studies in rats demonstrated a 10-fold increase in oral bioavailability, along with elevated plasma levels and accelerated metabolism. Importantly, when integrated into a kidney-targeted nanoparticle platform (ibuprofen-modified Polygonatum sibiricum polysaccharide, IBU-PSP), Cy7-PAMAM enabled precise renal imaging with 3.8-fold higher accumulation and prolonged retention, while minimizing off-target signals in liver and heart. Molecular docking analysis supported the mechanistic role of hydrogen bonding and steric stabilization in Cy7-PAMAM assembly. Collectively, this study establishes a robust and scalable strategy for noncovalent solubilization of hydrophobic fluorophores, offering a promising formulation strategy to advance cyanine-based bioimaging agents with improved in vivo efficacy.