Lipidic nanomedicines enhance Hinokitiol activity on human primary macrophages from Ferroportin disease patients

Iron overload disorders pose complex clinical challenges. Hinokitiol (HK) is a promising therapeutic candidate as it can shuttle iron across cell membranes and release sequestered intracellular iron, especially for conditions like Ferroportin Disease (FD), where phlebotomy and iron chelation are often inadequate or burdensome. However, HK's clinical utility is limited by its physical-chemical properties and biodistribution. In this study, we report the first evaluation of biodegradable and biocompatible Nanomedicines (NMeds) developed for the parenteral administration of HK. Polymeric and lipidic NMeds were evaluated, namely poly lactic-co-glycolide (PLGA), Cholesterol (Chol) NMeds, and Nanostructured Lipid Carriers (NLC). The optimization led to homogeneous NMeds with size < 300 nm and encapsulation efficiency up to 40 %, despite the small molecular weight and volatile nature of HK. Drug retention ability was assessed, allowing for the selection of 3 NMeds to be tested on iron-loaded macrophage model (J774 cell line) and human primary macrophages obtained from healthy blood donors and FD patient-bearing two different mutations. Data revealed that all HK-loaded NMeds are non-toxic and can accumulate in the cells, but most importantly they are more efficient than the free HK in reducing the intracellular iron pool. NLCs in particular showed the most promising behavior in terms of high efficacy and low toxicity. These results demonstrate that delivering HK via NMeds is preferable to administering free HK, representing the first step towards the development of a more efficient treatment of this currently challenging disease.