Development of a small molecule drug delivery vehicle for treatment of chronic pulmonary diseases
Lofton, Megan Christina
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Chronic pulmonary disorders, marked by excessive extracellular matrix deposition (ECM) or fibrosis, are the most resistant to present clinical therapies resulting in prognoses of 50% life expectancy three years from diagnosis. Inadequacies of current treatments may be attributable to limitations in non-invasive therapeutic administration modalities. However, with the use of polyketal microparticles (PKMs), a novel drug delivery vehicle, a myriad of therapeutic schemes may be explored. Polyketals are a new polymeric family characterized by tissue biocompatibility, rapid hydrolysis, and benign degradation byproducts making it attuned for pulmonary applications. Potential treatments such as siRNA, oligo nucleotides, enzymes and other biomolecules can be encapsulated within PKMs and administered non-invasively via inhalation. For this study, we selected a model therapeutic peptide, Ac-SDKP, with established anti-fibrotic properties as the load for PKMs. For lung dysfunctions accompanied by fibrotic scarring, Ac-SDKP possesses promise in restoring the normal ECM framework. To assess PKMs viability as a pulmonary drug delivery vehicle three objectives were initially defined: 1) Synthesize particles possessing aerodynamic properties conducive for aerosolization 2) Optimization of the therapeutic load, Ac-SDKP, in PKMs to levels that will translate to clinical dosing concentrations, and 3) Determine the biocompatibility of the PKMs in the lung. Optimization of the Ac-SKDP loading within PKMs and size analysis revealed that a solid in oil in water double emulsion particle synthesis technique produced the most ideal microspheres. Based on previous reports, the loading efficiency attained, when locally dispensed, should reach clinical dosing requirements. Synthesized particles were compatible with aerosolization criteria; i.e., diameters below 3 μm and low polydispersities. In addition, we evaluated PKM tissue biocompatibility using a murine lung model. Examination of bronchoalveolar lavage fluid demonstrated only a slight inflammatory response to intratracheal particle injections of PKMs whereas PLGA, a commonly used biomaterial, elicited a significantly higher response. Histological assessment of the lungs following particle injection verified PKMs biocompatibility superiority. In conclusion, small-diameter PKMs are a suitable delivery system for pulmonary drug delivery, capable of delivering small peptide therapeutics and evading the local inflammatory response. The present work will enable expansion of therapeutic avenues capable of combating chronic lung disease.