Π-Π stacking stabilized polymeric micelles for hydrophobic drug delivery in the treatment of leishmaniasis

Abstract

Current control strategies for leishmaniases − a group of diseases caused by protozoan parasites of the genus Leishmania − rely on chemotherapy, which is often associated with significant drawbacks, including severe side effects and limited drug efficacy. The public health impact of leishmaniases underscores the urgent need for new therapeutic approaches. Quinoline-(1H)-imines have emerged as promising lead compounds for antileishmanial drug development, however, their poor aqueous solubility poses a significant challenge to therapeutic application. To address this problem in the present study quinoline-(1H)-imines were loaded into polymeric micelles (PMs) composed of block copolymer of methoxy poly(ethylene glycol)-b-poly(N-2-benzoyloxypropyl methacrylamide) [mPEG-b-p(HPMAm-Bz)]. These PMs are known to establish noncovalent π-π stacking interactions between the aromatic rings of the p(HPMAm-Bz) block and those of the drug molecules, contributing to the loading of drug cargo in their hydrophobic cores, which can effectively enhanced retention of hydrophobic drugs. Encapsulation of quinoline-(1H)-imines in PMs resulted in comparable antileishmanial efficacy to the free drugs (IC50 ≈ 1–2 µM), while significantly reducing toxicity toward primary macrophages in vitro (CC50 > 20–50 µM versus < 9 µM for the free drugs). Additionally, in a murine model of visceral leishmaniasis, the micellar formulation facilitated targeted drug accumulation in organs typically affected by the disease, reaching concentrations of approximately 2 µg in the liver, 0.4 µg in the spleen and 0.015 µg in the bone marrow after 24 h. In contrast, the free drug was either undetectable or present in markedly lower concentrations. These findings highlight the potential of mPEG-b-p(HPMAm-Bz) micelles as a promising strategy to enhance solubility of poorly water-soluble drugs and as a safe delivery system for antileishmanial therapy.