The Critical Role of Aromatic-Aromatic Drug-Polymer Interactions to Provide Nanomedicines Containing Chloroquine: A Simple Proposal to Provide High Encapsulation, High Stability, and Prolonged Drug Release

Abstract

Background: Chloroquine (CQ) is a drug commonly used to treat malaria. CQ has also gained interest for the treatment of other chronic diseases such as arthritis, lupus, cancer, diabetes, atherosclerosis, and dermatomyositis, among others. Since CQ is hydrophilic and low molecular-weight, attractive interactions with polymers in aqueous medium are weaker than with water, so that low encapsulation together with uncontrolled and fast release is observed. Importantly, a long-term administration of CQ is suggested, thus the development of formulations with controlled and prolonged release is desirable. Results: Here we propose the use of aromatic interactions between the cationic CQ and the FDA approved polymer poly(sodium 4-styrenesulfonate) (PSS) for the formation and stabilization of nanoparticles (NPs). The strategy consists on the simple mixture of two aqueous solutions containing the oppositelly charged molecules. UV-vis and NMR spectroscopy evidence intimate aromatic-aromatic interactions between CQ and PSS. CQ/PSS molar ratios from 0.2 to 0.5 allow obtaining NPs with spherical shape, size in the range of 170-410 nm, zeta potential from -18 to -45 mV, and particles number in the range of 0.9 - 6.6 x 1010 NPs/mL. Selected NPs (CQ/PSS molar ratio 0.4) are stable to wide variations in ionic strength (0-200 mM), pH (2-10) and temperature (20-50 °C). In addition, CQ/polymer 0.4 was also tested but with the absence of the aromatic group in the polymer, and providing smaller (70 nm), lower-concentrated (6.1 x 109 NPs/mL), and unstable particles, confirming the key role of the aromatic group. Furthermore, CQ/PSS NPs are stable during months and can be converted to a reconstitutable powder. Importantly, the selected NPs (CQ/PSS 0.4) show full drug association efficiency (100 %), very high drug loading (49 %), very high yield (89 %), and evidencing a drug entrapment/release governed by kinetic associations (≈99 %). Finally, release studies evidence a controlled and prolonged delivery. Conclusions: Considering the potential uses of CQ for chronic diseases, and the simplicity and efficiency of our proposal, it could be considered as a valuable alternative to developed nanomedicines. In addition, this strategy could be used for other drugs and polymers showing similar characteristics to CQ and PSS.