Inhalable microspheres with hierarchical pore size for tuning the release of biotherapeutics in lungs

Abstract

A series of customized inhalable mono-dispersed poly-L-lactide microspheres (PLA-MS) having hierarchical pore structures with either open or closed porosity were synthesized by double emulsion solvent evaporation method using various molar concentrations of porogens. We have presented a simple method for large scale, reproducible synthesis of hierarchically porous PLA-MS, controlling 3D morphologies with well-ordered porosity ranging from ∼2.5 to 850 nm. The prepared PLA-MS were characterized in terms of size, morphology, porosity, cellular uptake using particle size analysis, scanning electron microscopy, Brunauer-Emmett-Teller (BET) and confocal microscopy respectively. We explored, how tailoring the pore size and surface properties of micro-matrix would improve the aerodynamic properties, cellular uptake and release of the bio-therapeutic molecules of variable size. Porous PLA-MS with geometric size 5–10 μm and lower Mass Median Aerodynamic diameter (MMAD) (≤3 μm) shown to aerosolize well, evade macrophages phagocytosis and deposit in deep lungs. These results demonstrated that the type of porogens rather the concentration was more important in generating MS of variable porosity. The in-vitro release profiles of four model-biotherapeutics of significantly different molecular size, from MS of different porosities were investigated up to ∼6 days, their release patterns were found to be significantly different on a chronological basis. It is noteworthy observation that in-vitro cellular phagocytosis of MS is also governed by variable porosity of MS. Our findings shed light on the possible influence of size and porosity of MS on the lung deposition, cellular uptake and sustained delivery of a size-range of biotherapeutics. This approach of tuning porous structures of PLA-MS could be suitable to develop promising inhalable delivery systems.