Miltefosine Lipid Nanocapsules for Single Dose Oral Treatment of Schistosomiasis Mansoni: A Preclinical Study

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.

Production of novel vitamin D3 loaded lipid nanocapsules for milk fortification

“…It was obvious that particles had approximately spherical shape. Similar particle shape was reported for miltefosine lipid nanocapsules by Eissa et al (2015). [28] The average sizes of nanocarriers in TEM image were in agreement with PCS results.…”

A single oral fixed-dose praziquantel-miltefosine nanocombination for effective control of experimental schistosomiasis mansoni

“…In addition, suckers and teguments of adult male schistosomes recovered from S. mansoni-infected mice in the higher dose nanocombination subgroup (Iab) showed deformed suckers as well as extensive tegumental damage in the form of peeling of tubercles, dis gurement of spines and appearance of subtegumental tissue (Fig. 3) supporting earlier observations for singly loaded PZQ LNCs [24] and MFS LNCs [16]. Suckers promote the attachment of schistosomes to blood vessels for the feeding process [1].…”

Development and in vitro evaluations of new decitabine nanocarriers for the treatment of acute myeloid leukemia

“…12 Lipophilic drugs have already been encapsulated into LNCs, such as paclitaxel, docetaxel, SN38, etoposide, hydroxytamoxifen, miltefosine, or a ferrocenyl complex. [12][13][14][15][16][17] Hydrophilic drugs, such as fondaparinux 18 or DNA and siRNA, 19,20 have also been encapsulated, and reverse micelles associated with LNCs containing doxorubicin hydrochloride or erlotinib hydrochloride have been developed. 21,22 Encapsulation into LNCs has modified the pharmacokinetic parameters of DNA when encapsulated in stealth LNCs, 20 or of miltefosine, an antischistosomal drug, by increasing its time to reach the maximal concentration and increasing its activity against Shistosoma mansoni.…”