Enhanced Quercetin Encapsulation through Charge Density and Amphiphilicity Tuning in Cationic Triblock Micelles

This study presents an optimized strategy to improve the bioavailability and stability of quercetin (QR), a hydrophobic antioxidant, through the development of a series of branched cationic triblock micelles, poly(ethylene glycol)-block-[poly(4-vinylpyridine)-graft-poly(ε-caprolactone)] named (PEG)13-(P4VP+140-PCLn)Q%, with controlled charge density (Q%) and PCL oligomer chain length (n). The colloidal stability and encapsulation efficiency of these micelles were not dictated by charge density or hydrophilic–hydrophobic balance alone but rather by their synergistic interplay. By fine-tuning both parameters, the micelles achieved optimal stability and drug release properties. The customized synthesis process-RAFT polymerization of 4-vinylpyridine (4VP) with a (PEG)-based macro-RAFT agent, followed by quaternization with chloride-functionalized PCL (Cl-PCLn), allowed precise modulation of these factors, demonstrating that the balance between electrostatic and hydrophobic interactions is critical for achieving robust micellar structures with high drug-loading capacity and controlled release behavior. The (PEG)13-(P4VP+140-PCL3)75% micelles with higher charge density and minimal chain length of PCL exhibited high encapsulation efficiency (88%) and sustained QR release, with over 94% antioxidant activity retention. The results confirmed the formation of stable micelles with a critical aggregation concentration (C.A.C.) of 0.34 mg/L, making them ideal for physiological applications. In vitro genotoxicity assays demonstrated an inverse relationship between charge density and DNA interaction, with (PEG) shielding mitigating genotoxic effects. Acute toxicity studies showed that the treatments were well-tolerated, and in vitro degradation studies indicated effective polymer breakdown in acidic conditions at 37 °C, with a 60% reduction in molecular weight after 6 days. Overall, these findings highlight the critical role of optimizing charge density and hydrophilic–hydrophobic balance in the design of nanocarriers for hydrophobic drugs. Specifically, the research demonstrates the effectiveness of optimized cationic triblock micelles in addressing the limitations of conventional quercetin delivery systems, providing valuable insights for the development of safe and efficient targeted therapeutic applications.