Abstract
Miltefosine (MFS) is an alkylphosphocholine used for the local treatment of cutaneous metastases of breast cancer and oral therapy of visceral leishmaniasis. Recently, the drug was reported in in vitro and preclinical studies to exert significant activity against different developmental stages of schistosomiasis mansoni, a widespread chronic neglected tropical disease (NTD). This justified MFS repurposing as a potential antischistosomal drug. However, five consecutive daily 20 mg/kg doses were needed for the treatment of schistosomiasis mansoni in mice. The present study aims at enhancing MFS efficacy to allow for a single 20mg/kg oral dose therapy using a nanotechnological approach based on lipid nanocapsules (LNCs) as oral nanovectors. MFS was incorporated in LNCs both as membrane-active structural alkylphospholipid component and active antischistosomal agent. MFS-LNC formulations showed high entrapment efficiency (EE%), good colloidal properties, sustained release pattern and physical stability. Further, LNCs generally decreased MFS-induced erythrocyte hemolytic activity used as surrogate indicator of membrane activity. While MFS-free LNCs exerted no antischistosomal effect, statistically significant enhancement was observed with all MFS-LNC formulations. A maximum effect was achieved with MFS-LNCs incorporating CTAB as positive charge imparting agent or oleic acid as membrane permeabilizer. Reduction of worm load, ameliorated liver pathology and extensive damage of the worm tegument provided evidence for formulation-related efficacy enhancement. Non-compartmental analysis of pharmacokinetic data obtained in rats indicated independence of antischistosomal activity on systemic drug exposure, suggesting possible gut uptake of the stable LNCs and targeting of the fluke tegument which was verified by SEM. The study findings put forward MFS-LNCs as unique oral nanovectors combining the bioactivity of MFS and biopharmaceutical advantages of LNCs, allowing targeting via the oral route. From a clinical point of view, data suggest MFS-LNCs as a potential single dose oral nanomedicine for enhanced therapy of schistosomiasis mansoni and possibly other diseases.
Highlights
Neglected tropical diseases (NTDs) afflict more than one billion of the lowest income people in tropical and subtropical regions presenting an enormous global health and economic burden [1]
The present study aims at enhancing MFS efficacy to allow for a single 20mg/kg oral dose therapy using a nanotechnological approach based on lipid nanocapsules (LNCs) as oral nanovectors
Standard LNCs not containing additives were generally uniform with a mean diameter of58.7 nm
Summary
Neglected tropical diseases (NTDs) afflict more than one billion of the lowest income people in tropical and subtropical regions presenting an enormous global health and economic burden [1]. MFS was initially developed as antineoplastic agent but is currently used for the local treatment of cutaneous metastases of breast cancer. It has been repurposed with approval in India and more recently, the USA as the first and only oral drug for visceral leishmaniasis. Unlike praziquantel (PZQ), the mainstay for schistosomiasis control administered in a single oral dose, MFS had to be administered to infected mice in five successive 20mg/kg/day oral doses. This limits its potential clinical applicability as a PZQ alternative for mass chemotherapy. Overcoming the considerable limitations of PZQ such as poor solubility in water and absorption through the gastrointestinal tract (GIT), failure to prevent re-infection, reduced activity against juvenile worms and development of resistance [9, 10]justify research efforts for novel therapeutic and preventive approaches
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