Acute respiratory distress syndrome (ARDS) is an acute, diffuse, inflammatory lung injury in which many pathways have been firmly implicated, but drug therapy has universally failed in dozens of large clinical trials. Why have so many rationally chosen drugs failed in ARDS? From a pharmacology perspective, a clear reason is that of poor drug delivery, with very little drug reaching the inflamed alveoli. To solve this problem, we developed pulmonary endothelium-targeted liposomes (PELs). PELs are simply drug-loaded liposomes (~100 nanometer spherical lipid bilayers), that when injected intravenously concentrate strongly in the lungs. In this proposal, we will study a promising and novel lung-targeting strategy for PELs that we recently invented, called ?RBC-hitchhiking? (RH). In RH, PELs are passively adsorbed ex vivo onto red blood cells (RBCs) and then, upon IV injection, the RBCs squeeze through the pulmonary capillaries, transferring the liposomes to the capillary endothelium. RH PELs concentrate drugs in the lungs of mice >300x more than ?free drugs? (drugs delivered without targeting). Further, RH concentrates PELs in the lungs even more than the ?gold standard? in targeted drug delivery for the last 20 years, ?antibody-targeted? drug carriers, which in this case are PELs coated with antibodies that bind epitopes (e.g., PECAM) on the pulmonary endothelium6,7. RH has the major advantage that strong lung targeting does not require the PELs to be coated with targeting antibodies, which makes clinical translation much easier. In this proposal, we will focus on RH targeting of PELs, but will also compare RH to ?antibody-targeted PELs?, providing comparison to a gold standard, and a back-up targeting strategy. In this proposal, we will test PELs in 3 ways:
In Aim 1, we will determine the localization of PELs within the lungs of mice, in vivo, measuring PEL accumulation in healthy vs inflamed regions and various cell types. Our hypothesis is that both RH and antibody-targeting will concentrate PELs in the lungs, but the intra-pulmonary localization will be determined by details of the targeting strategy.
In Aim 2 we will assess the therapeutic effects of drug-loaded PELs, with the hypothesis that PELs will decrease the mass of drug required to ameliorate mouse models of ARDS. Finally, in Aim 3 we will determine how PELs distribute drugs within ex vivo human lungs, obtained from organ donors whose lungs were rejected for transplantation due to ARDS. These studies will move our drug delivery technologies closer to ARDS patients, while providing mechanistic insights into how targeted drug delivery actually works. The proposal also outlines the candidate's training plan in the unique field of pulmonary targeted drug delivery.
Acute respiratory distress syndrome (ARDS) is an inflammatory lung injury that annually afflicts 190,000 Americans, carries a mortality rate of 40%, and has no FDA-approved drug therapy. Therefore we developed a technology that utilizes red blood cells to carry drugs to the lungs, increasing the concentrations of the drugs in the lungs by >300-fold compared to conventional drug administration. In this proposal, we will study the mechanisms and efficacy of our drug targeting technology on models of ARDS, including live mice and ex vivo human lungs, which will move our technology closer to helping ARDS patients.
| Brenner, Jacob S; Kiseleva, Raisa Yu; Glassman, Patrick M et al. (2018) The new frontiers of the targeted interventions in the pulmonary vasculature: precision and safety (2017 Grover Conference Series). Pulm Circ 8:2045893217752329 |
