Hari R Desu1, Laura A Thoma2, George C Wood3. 1. Intera Healthcare, IKP Knowledge Park, Genome Valley, Shameerpet, Hyderabad, TS, 500101, India. hari@inpcs.onmicrosoft.com. 2. Plough Center for Sterile Drug Delivery Systems, College of Pharmacy, The University of Tennessee Health Science Center, Memphis, Tennessee, USA. 3. Department of Pharmaceutical Sciences, The University of Tennessee Health Science Center, Memphis, Tennessee, USA.
Abstract
PURPOSE: Acute lung injury (ALI) is a fatal syndrome in critically ill patients. It is characterized by lung edema and inflammation. Numerous pro-inflammatory mediators are released into alveoli. Among them, interleukin-1beta (IL-1β) causes an increase in solute permeability across the alveolar-capillary barrier leading to edema. It activates key effector cells (alveolar epithelial and endothelial cells) releasing inflammatory chemokines and cytokines. The purpose of the study was to demonstrate that nebulized liposomes inhibit ALI in vivo. METHODS: In vivo ALI model was simulated through intra-tracheal instillation of IL-1β solution (100 μg/mL in PBS, pH 7.2, 200 μL) in male Sprague-Dawley rats. Various formulations were tested in ALI induced rats. These formulations include plain liposomes (PL), methylprednisolone sodium succinate solution (MPS solution), cRGD-peptide grafted liposomes (LcRGD) and methylprednisolone sodium succinate encapsulated and cRGD-peptide grafted liposomes (MPS-LcRGD). Formulations were nebulized in vivo in rats using micro-pump nebulizer. RESULTS: Liposome formulations exhibited higher levels of drug concentration in lungs. The physicochemical parameters demonstrated that the liposome formulations were stable. On the basis of aerodynamic droplet-size, nebulized formulations were estimated to deposit in different regions of respiratory tract, especially alveolar region, Among the formulations, MPS-LcRGD caused significant reduction of edema, neutrophil infiltration and inflammation biochemical marker levels. CONCLUSION: From the results, it can be inferred that nebulization of targeted liposomes had facilitated spatial and temporal modulation of drug delivery resulting in alleviation of ALI.
PURPOSE:Acute lung injury (ALI) is a fatal syndrome in critically illpatients. It is characterized by lung edema and inflammation. Numerous pro-inflammatory mediators are released into alveoli. Among them, interleukin-1beta (IL-1β) causes an increase in solute permeability across the alveolar-capillary barrier leading to edema. It activates key effector cells (alveolar epithelial and endothelial cells) releasing inflammatory chemokines and cytokines. The purpose of the study was to demonstrate that nebulized liposomes inhibit ALI in vivo. METHODS: In vivo ALI model was simulated through intra-tracheal instillation of IL-1β solution (100 μg/mL in PBS, pH 7.2, 200 μL) in male Sprague-Dawley rats. Various formulations were tested in ALI induced rats. These formulations include plain liposomes (PL), methylprednisolone sodium succinate solution (MPS solution), cRGD-peptide grafted liposomes (LcRGD) and methylprednisolone sodium succinate encapsulated and cRGD-peptide grafted liposomes (MPS-LcRGD). Formulations were nebulized in vivo in rats using micro-pump nebulizer. RESULTS: Liposome formulations exhibited higher levels of drug concentration in lungs. The physicochemical parameters demonstrated that the liposome formulations were stable. On the basis of aerodynamic droplet-size, nebulized formulations were estimated to deposit in different regions of respiratory tract, especially alveolar region, Among the formulations, MPS-LcRGD caused significant reduction of edema, neutrophil infiltration and inflammation biochemical marker levels. CONCLUSION: From the results, it can be inferred that nebulization of targeted liposomes had facilitated spatial and temporal modulation of drug delivery resulting in alleviation of ALI.
Entities:
Keywords:
drug delivery; formulation; inflammation; liposome; nebulization
Authors: Bonny B Drago; Dai Kimura; Cynthia R Rovnaghi; Andreas Schwingshackl; Mark Rayburn; G Umberto Meduri; Kanwaljeet J S Anand Journal: Pediatr Crit Care Med Date: 2015-03 Impact factor: 3.624