This thesis is part of the development and evaluation of nanomedicines potentially able toovercome unfavorable biopharmaceutical properties of amphotericin B (AmB), a highlyeffective molecule used for the treatment of systemic fungal infections and leishmaniasis, butdifficult to formulate efficiently, whatever the route of delivery. It is believed that thishydrophobic molecule suffers from severe limitations due to its pronounced tendency toaggregate under physiological conditions. The first part of the thesis was driven on thehypothesis that the degree of aggregation of AmB could have a strong impact on some of itspharmacokinetics properties. For this purpose albumin has been used to produce controlledcomplexes between albumin and AmB in order to control AmB aggregation states. Themorphological characteristics of the resulting colloidal objects have been carefullycharacterized by UV-Vis spectroscopy and circular dichroism. Furthermore, the impact ofaggregation state on both the intestinal permeability and a possibly expected recognition ofthe aggregates by the immunological system were investigated. The second part of this workwas focused on the development of micro- and nanocarriers intended to overcome theabsorption barrier raised against AmB after oral delivery. For this purpose, AmB was loadedinto micro- and nanoemulsions to evaluate a possible permeability enhancement effectthrough the intestinal membrane, which was evaluated in ratas using the Ussing chambermodel. No detectable permeation was seen in any of the experimental conditions. However,the electrophysiological data showed tissue viability losses due to the strong toxicity of AmB,that were dependent on the aggregation state of AmB when in contact with the tissue. It wasalso concluded from detailed permeation experiments in healthy tissues that paracellular andtranscellular routes were likely to be only marginal pathways when oral absorption areobserved in vivo, as reported in the literature. The likeness of other possible absorptionpathways, including Peyer's patches capture and lymphatic pathway implication foraggregated particles has been discussed. Finally, another particulate system intended forcolonic delivery and based on xylan, a natural and enzymatically degradable biopolymer, hasbeen investigated. Xylan is a polysaccharide present in grains, cereals and angiosperm plantsthat is specifically degraded on colon region, by the microbiota. An original processconsisting in a water-in-water emulsion of xylan in presence of PEG followed by acrosslinking phase using trisodium trimetaphosphate has been developed, making possible the production of xylan-based biocompatible micro- and nanospheres ranging from 380 nm to4.5 μm, depending on the parameters in the process. This eco-friendly process is free ofharmful solvents and has potential application for the delivery of AmB at the colonic level.
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