Long-Acting, Multi-Targeted Nanomedicine: Addressing Unmet Medical Need in Acute Lung Injury

Acute lung injury (ALI) associated with sepsis and acute respiratory distress syndrome (ARDS) is a leading cause of death of critically ill patients in U.S. Our understanding of the pathobiology and mechanisms underlying ALI is increasing as a result of basic research and advances in molecular biology. Unfortunately, morbidity and mortality from ALI and ARDS still remains unacceptably high (30-40%). The major reason underlying lag in improvement in outcome is the lack of novel and specific therapies for ALI and ARDS. To begin to address this issue, we developed novel long-acting biocompatible and biodegradable phospholipid micelles (size, similar to 15 nm) to inhibit triggering receptor expressed on myeloid cells 1 (TREM-1), reactive oxygen species and Hsp90, key effectors thought to underlie ALI, in vivo. Realizing short half-life of peptide drugs (minutes) hampers their clinical use, we invented micellar TREM-1 peptide and glucagon-like peptide-1 (7-36) amide (GLP-1) where each peptide drug is stabilized in its active form (a-helix) and its bioactivity is prolonged for hours in vivo. Likewise, water-insolubility of 17-allylamino-17-demethoxygeldanamycin (17-AAG), a selective Hps90 inhibitor, constrains its use in humans. Accordingly, self-association of 17-AAG with these micelles overcomes this limitation while at the same time increasing its stability and bioavailability. These long-acting micellar nanomedicines provide significant advancement in the treatment of experimental of ALI which could then be extended to critically ill patients.