(230d) A Microfluidic Platform for Aerosol and Nanoparticle Drug and Gene Delivery

Pulmonary drug administration requires the direct delivery of drug formulations into the deep lung region in the form of inhaled particles or droplets, providing a distinct advantage over other methods for the treatment of respiratory diseases: the drug can be delivered directly to the site of inflammation, thus reducing the need for systemic exposure and the possibility of adverse effects. Nevertheless, it is difficult to produce aerosol droplets of a drug solution within a narrow polydisperse size range between 1 and 5 µm to achieve maximum deposition in the lower pulmonary tract and alveoli. We first demonstrate the use of surface acoustic wave (SAW) microfluidic atomization as an efficient means to generate aerosols containing the short-acting β₂-agonist salbutamol for the treatment of asthma. The 2.84 μm mean diameter of the aerosol droplets produced lies well within the optimum size range. This is subsequently confirmed using a twin-stage impinger in vitro lung model, in which we observe that approximately 70% to 80% of the drug is deposited within the lung; such lung dose efficiencies are considerably higher than those possible through currently available metered dose inhalers and nebulizers. Thus, even with a modest power range of around 1 W, which is a tenth of that required with ultrasonic nebulizers, the SAW atomization technology provides a viable and efficient generic nebulization platform for drug delivery via the pulmonary route. In addition, the potential for the platform to be used for non-viral gene delivery is demonstrated through high levels of gene expression observed in Western blot analysis of the COS-7 cells transfected with post-atomised plasmid DNA encoded with a merozoite surface protein 4/5, which is a potential malaria vaccine candidate. This is subsequently verified through the expression of yellow fluorescent protein in lung sections of Swiss mice following intratracheal instillation of the plasmid DNA containing the protein. Further, we show that the technology is a very rapid, efficient and straightforward means for the synthesis of biodegradable polymeric particles with dimensions down to 100 nm within which therapeutic molecules such as nucleic acids, proteins and peptides can be encapsulated. Finally, the ability to synthesize multiple coatings of polyelectrolyte layers encapsulating these biomolecules is demonstrated using sequential atomization-suspension steps as a fast and efficient alternative to conventional layer-by-layer polyelectrolyte assembly. These multilayer nanocapsules offer the exciting possibility for tuning the drug release profile for controlled delivery over a prolonged period or for targeting the delivery to a specific location within the body. In all of the above, the control offered over the aerosol/particle size, the possibility for flexible and multilayer encapsulation, the low power requirement, the high delivery efficiency, and the miniaturization of the system altogether suggest that the proposed SAW atomization platform represents an attractive alternative to current nebulizers and inhalers, which we envisage could constitute next-generation devices that revolutionize pulmonary drug and gene delivery for needle-free vaccination or for the treatment of various diseases in the near future.