Abstract

Nanomedicines containing the aromatic drug chloroquine and the polymer poly(sodium 4-styrenesulfonate) have been theoretically designed and experimentally synthesized following the simple mixture of two aqueous solutions containing the drug and the polymer, respectively. Theoretical calculations show higher binding energy between both the aromatic polymer and chloroquine, and a higher tendency to release water from their hydration spheres, as compared to the binding between the drug and the aliphatic polymer poly(sodium vinyl sulfonate). MD simulations show the spontaneous formation of stable structures of 10 nm of average diameter, even combining short polymer chains, highly diluted reactants, and short reaction time (in the range of mu s). Rapid mixture of the liquids in a stopped flow equipment shows nanoparticle formation in the range of tenths of seconds. Equilibration studies in the range of minutes evidence spheroidal nanoparticles with almost quantitative association efficiency, 48.6 % of drug loading, size of 170 - 410 nm, low polydispersity (PdI = 0.25 - 0.47), and negative zeta potential (-18 - -45 mV). They provide drug release for 30 days, and are stable to NaCl exposure, pH gradient, several temperature values, and long-term storage. Furthermore, we demonstrate scaling up of the nanomedicine production upon increasing the reaction volume. Our studies demonstrate that these highly loaded drug nanoparticles are based on the occurrence of site -specific short-range interactions between the drug and the aromatic excipient such as pi-stacking. In the absence of the aromatic group in the polymer, weak interactions and unstable formulations are evidenced, both theoretically and experimentally. The combination of the selected theoretical and experimental tools could promote the efficient production of drug / polyelectrolyte formulations with therapeutical applications. The chosen components could be considered as potential medicines or as model components to design, develop, characterize, and scale up medicines comprising other combinations of drugs and polymers.