Targeted delivery of metastasis-specific tumour homing TMTP1 peptide to non-small-cell lung cancer (NSCLC) using inhalable hybrid Nano-assemblies

Lung cancer is one of the most fatal malignancies, with the highest death rates (~19%), of which NSCLC type, contributes to ~85%. In the search for new treatments, antimicrobial peptides have received much attention due to their propensity for selective destruction of cancer cells. In the current study, we evaluated the efficacy of metastasis-specific tumour-homing-TMTP1peptide against lung cancer using inhalable hybrid-nano-assemblies of PEG–PLGA-copolymer as a carrier for pulmonary delivery which was assessed for aerodynamic and physicochemical properties, along with peptide-release profile, physical stability, cellular uptake & biocompatibility, generation of reactive-oxygen-species, cell migration, autophagic flux, and apoptotic cell death in A549 lung cancer cells. Optimization of inhaled dose, lung retention, and efficacy studies was conducted to evaluate the formulation in NNK (Nicotine-derived nitrosamine ketone) induced tumour-bearing lung cancer, murine model. After inhalation, the formulation with nano-scale physiognomies showed good lung deposition, retention, and metabolic stability. The inhalable-nano-assemblies have shown enhanced generation of reactive-oxygen-species with increased autophagy-flux and apoptotic-cell death. Pre-clinical animal trials show substantial tumour regression by inhalable-TMTP1-based-nano-formulation with limited side effects. Our results on metastasis targeting and tumour-homing peptide TMTP1 exhibit effective tumour targeting and tumour-killing efficacy and provide a reference for the development of new therapeutics for NSCLC.