Synergistic π–π Stacking and Hydrogen Bonding of Doxorubicin Electrostatically Bound to Sodium Alginate Drive the Formation of Supramolecular Nanoparticles with Exceptional Drug Loading

Doxorubicin hydrochloride (DX) is a widely used chemotherapeutic agent whose severe side effects can be attenuated by suitably designing drug delivery systems. The complexation between DX and the biocompatible and biodegradable sodium alginate (ALG) results in the formation of DX@ALG nanoparticles under conditions where neither the drug nor the polymer tends to form nanoscopic structures. DX@ALG complex formation leads to the quenching of DX intrinsic fluorescence, and the drug shows chiroptical properties characteristic of supramolecular gels of DX. The association of DX and ALG into supramolecular nanoparticles takes place at low DX concentration and without salt addition. More than 99% of the moles of DX complexed with ALG form a gel-like phase, and DX@ALG nanoparticles show a high DX loading efficiency. Nanoparticle formation is revealed by Dynamic Light Scattering (DLS) and Atomic Force Microscopy (AFM). Quantum Mechanics (QM) calculations support the formation of supramolecular DX-ALG aggregates by π–π stacking and hydrogen bonds. DX@ALG nanoparticles have been fully characterized by several spectroscopic techniques. Preliminary in vitro evaluation of DX@ALG toxicity revealed an antiproliferative activity against selected cancer cell lines.