SURFACE ENGINEERING OF SOLID LIPID NANOASSEMBLIES FOR INHALED INTRAMACROPHAGIC ANTI-TB THERAPY

For an inhaled tuberculosis (TB) treatment, antibiotic aerosolization has to be produced by using drugs in their solid state administered by means of Dry Powder Inhaler (DPI) devices. In this regard, untreated drugs generally fail to reach alveolar epithelium and penetrate alveolar macrophages (AM) as the primary site of the infection.1 Therefore, the urgency to treat TB disease effectively may be addressed with approaches consisting of micro- or nanoparticulate carriers redeveloping existing drugs to reach the intended goal.2, 3 Specific modifications of the particulate carrier surface by conjugation with molecules that can specifically bind the receptors (active targeting) are expected to boost the particle avidity to cells increasing accumulation and intracellular uptake. Macrophages possess mannose-specific membrane receptors (MR) that can recognize and facilitate the internalization of carriers bearing mannose residues. In particular, the infected AM have an overexpression of MR.4 In the present study, surface engineered Solid Lipid Nanoparticle assemblies (SLNas) were developed as potential carriers of rifampicin, a first choice antitubercular drug, intended to maximize drug concentration at the primary site of TB infection. To increase specificity for macrophages and internalization potential, SLNas surface was functionalized by a mannosylated derivative to induce AM active targeting. Biocompatible lipid components such as fatty acids and their derivatives, diglycerides and triglycerides were processed by means of the melt emulsifying technique using biocompatible surfactants (sodium taurocholate and methyl mannopyranoside). Mannosylated SLNas were examined for their intrinsic properties (size and size distribution, shape, surface charge, bulk and tap density, aerodynamic diameter, porosity, flowability, physical state of the components). Powder breathability in terms of Emitted Dose and Fine Particle Fraction was assayed by Next Generation Impactor (NGI). This information on powder interparticle adhesion and deaggregation ability influencing powder dispersion and deposition onto alveolar epithelia. SLNas mannosylation was investigated by means of X-ray Photoelectron Spectroscopy for Chemical Analysis and Energy Dispersive X-ray Analysis. Prototypes of SLNas in terms of successful functionalization, optimal breathability and chemico-physical stability, were examined for cytotoxicity by MTT test on murine macrophages J774 cell lines.