20 research outputs found
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
siRNA Versus miRNA as Therapeutics for Gene Silencing
Discovered a little over two decades ago, small interfering RNAs (siRNAs) and microRNAs (miRNAs) are noncoding RNAs with important roles in gene regulation. They have recently been investigated as novel classes of therapeutic agents for the treatment of a wide range of disorders including cancers and infections. Clinical trials of siRNA- and miRNA-based drugs have already been initiated. siRNAs and miRNAs share many similarities, both are short duplex RNA molecules that exert gene silencing effects at the post-transcriptional level by targeting messenger RNA (mRNA), yet their mechanisms of action and clinical applications are distinct. The major difference between siRNAs and miRNAs is that the former are highly specific with only one mRNA target, whereas the latter have multiple targets. The therapeutic approaches of siRNAs and miRNAs are therefore very different. Hence, this review provides a comparison between therapeutic siRNAs and miRNAs in terms of their mechanisms of action, physicochemical properties, delivery, and clinical applications. Moreover, the challenges in developing both classes of RNA as therapeutics are also discussed.published_or_final_versio
Storage stability of lysostaphin solution and its pulmonary delivery
Methicillin-resistant Staphylococcus aureus (MRSA) has become a leading causative pathogen of nosocomial pneumonia with an alarming in-hospital mortality rate of 30%. Last resort antibiotic, vancomycin, has been increasingly used to treat MRSA infections, but the rapid emergence of vancomycin-resistant strains urges the development of alternative treatment strategies against MRSA-associated pneumonia. The bacteriolytic enzyme, lysostaphin, targeting the cell wall peptidoglycan of S. aureus, has been considered as a promising alternative for MRSA infections. Its proteinaceous nature is likely benefit from direct delivery to the lungs, but the challenges for successful pulmonary delivery of lysostaphin lying on a suitable inhalation device and a formulation with sufficient storage stability. In this study, the applicability of a vibrating mesh nebulizer (Aerogen Solo®) and a soft mist inhaler (Respimat®) was investigated. Both devices were capable of aerosolizing lysostaphin solution into inhalable droplets and caused minimum antibacterial activity loss. In addition, lysostaphin stabilized with phosphate-buffered saline and 0.1% Tween 80 was proved to have acceptable stability for at least 12 months when stored at 4 °C. These promising data encourage further clinical development of lysostaphin for management of MRSA-associated lung infections. Graphical abstract: [Figure not available: see fulltext.] Lysostaphin had insignificant activity loss after aerosol generation by a vibrating mesh nebulizer and a soft mist inhaler.Most of the lysostaphin aerosols generated by the vibrating mesh nebulizer and soft mist inhaler are inhalable.The vibrating mesh nebulizer and soft mist inhaler are suitable device for pulmonary delivery of lysostaphin
Design of dry powder formulations of pH responsive peptide/plasmid DNA complexes for pulmonary delivery
Poster Presentation: no. 13PS50Respiratory diseases are substantial public health problems around the world. Recently, nucleic acid was developed as a potential therapeutic strategy to tackle a series of lung diseases. Delivery still poses one of the major challenges for their clinical application. pH responsive peptides containing either histidine or derivatives of 2,3-diaminopropionic acid (Dap) can mediate effective DNA transfection in lung epithelial cells with the latter remaining effective even in the presence of lung surfactant containing bronchoalveolar fluid (BALF), which make them promising vectors for delivering therapeutic nucleic acid to the airways .....published_or_final_versio
Spray freeze drying of small nucleic acids as inhaled powder for pulmonary delivery
published_or_final_versio
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