Co-Delivery of D-LAK Antimicrobial Peptide and Capreomycin as Inhaled Powder Formulation to Combat Drug-Resistant Tuberculosis

INTRODUCTION: The emergence of multidrug-resistant (MDR) Mycobacterium tuberculosis (Mtb) posed a severe challenge to tuberculosis (TB) management. The treatment of MDR-TB involves second-line anti-TB agents, most of which are injectable and highly toxic. Previous metabolomics study of the Mtb membrane revealed that two antimicrobial peptides, D-LAK120-A and D-LAK120-HP13, can potentiate the efficacy of capreomycin against mycobacteria. AIMS: As both capreomycin and peptides are not orally available, this study aimed to formulate combined formulations of capreomycin and D-LAK peptides as inhalable dry powder by spray drying. METHODS AND RESULTS: A total of 16 formulations were prepared with different levels of drug content and capreomycin to peptide ratios. A good production yield of over 60% (w/w) was achieved in most formulations. The co-spray dried particles exhibited spherical shape with a smooth surface and contained low residual moisture of below 2%. Both capreomycin and D-LAK peptides were enriched at the surface of the particles. The aerosol performance of the formulations was evaluated with Next Generation Impactor (NGI) coupled with Breezhaler®. While no significant difference was observed in terms of emitted fraction (EF) and fine particle fraction (FPF) among the different formulations, lowering the flow rate from 90 L/min to 60 L/min could reduce the impaction at the throat and improve the FPF to over 50%. CONCLUSIONS: Overall, this study showed the feasibility of producing co-spray dried formulation of capreomycin and antimicrobial peptides for pulmonary delivery. Future study on their antibacterial effect is warranted

Synthetic KL4 peptide as new carrier of siRNA therapeutics for pulmonary delivery

Poster PresentationSmall interfering RNA (siRNA) has great potential for the treatment of various respiratory diseases through RNA interference (RNAi), but their clinical application is hindered by the lack of a safe and effective pulmonary delivery system. KL4 peptide is a synthetic amphipathic peptide that was previously developed to mimic the function of pulmonary surfactant protein B (SP-B). Its potential as siRNA carrier for pulmonary delivery was examined in this study. The cationic KL4 peptide was able to bind with siRNA to form complexes at 15:1 ratio (peptide to siRNA weight ratio) or above. It also mediated efficient gene silencing on lung epithelial cells, with 20:1 ratio as the optimal ratio for siRNA transfection. Furthermore, the KL4/siRNA complexes were not toxic at concentrations used for transfection in vitro. The study shows that KL4 peptide appears to be a promising candidate for siRNA delivery. Further investigation on animal study and work on aerosol formulation are required to develop KL4 peptide as siRNA carrier for clinical application