Hybrid Nano-in-Micro systems for lung delivery of Host Defence Peptides (HDP) as adjunct therapeutics for Pulmonary TB

 Ankur Sharma and Rahul K Verma

 Institute of Nano Science and Technology (Government of India), Phase-10, Mohali-160062 INDIA 

Summary

Pulmonary tuberculosis (TB) is a leading killer worldwide and multi drug resistant (MDR) tuberculosis is reaching epidemic proportions. More innovations in TB therapeutics need to be pursued to combat this fatal threat. Host Defense peptides (HDP) possess wide-ranging antimicrobial activity and effective against pathogenic mycobacterium in in-vitro studies. For precise lung deposition and effective delivery of therapeutic HDP, respirable hybrid Nano-in-Micro (NIM) nanoformulation has developed and extensively investigated for pulmonary tuberculosis therapy. We developed and aerodynamically characterized inhalable hybrid Nano-in-Micro (NIM) delivery systems containing HHC-10 with/without standard anti-TB drug (Isoniazid) to provide sustained delivery of peptides to lungs and alveolar macrophages. HHC-10 loaded PLGA nanoparticles were prepared double emulsion solvent evaporation method, which was further processed into micron-sized Nano-in-Micro system using Spray Freeze technology (SFD). The efficacy of NIM in mycobacterium infected macrophage cell-lines and animal model was determined. Further, mechanistic studies were carried out in macrophage cell lines.Micron-sized inhalable nano-assemblies “Nano-in-Micro system (NIM) platform (5.2±1.34mm) with nano-scale (324.8±13.56nm) features was developed to improve the delivery of HHC-10 to lungs and enhance its stability. The MMAD, GSD and Fine Particle fraction (FPF_<4.6 μm) of emitted dose of HHC-10-NIM (2.35 ± 0.10 µm, 1.58 ± 0.03% µm and 72.38 ± 3.05%). The activity of NIM containing HHC-10 against intracellular Mycobacteria was discernible in a dose and time dependent manner without significant toxicity. NIM containing HDP may provide an unconventional novel approach for sustained delivery of peptide and may represent a novel paradigm in TB therapy.