Development of linagliptin-loaded liposomes using aspartic acid conjugate for bone-targeted delivery to combat osteoporosis

Osteoporosis is a common metabolic bone disorder that requires new treatment strategies. Linagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor is a proven osteogenic agent in diabetes-linked bone loss. However, poor solubility, low oral bioavailability, and inadequate bone-targeting limit its use in osteoporosis. We have successfully developed the bone-targeted liposomes of linagliptin using an aspartic acid conjugate i.e., poly (aspartic acid-co-lactide)-1,2-dipalmitoyl-sn-glycero-3-phospho ethanolamine (PAL-DPPE), which was prior synthesized and identified using FTIR & NMR. Liposomes were evaluated for particle size, encapsulation efficacy, drug loading, and release study in addition to in vitro hydroxyapatite binding ability. To determine the anti-osteoporosis effect of liposomes, in vivo testing was performed in glucocorticoid-induced osteoporosis model in mice. Bone targeted liposomes of linagliptin having particle size of 281.7 nm and hydroxyapatite affinity of 89%, significantly improved the bone architecture parameters and bone mineral density in micro-computed tomography analysis. Further, these liposomes positively modulated sclerostin, bone morphogenetic protein-2, and receptor activator of nuclear factor kappa beta/osteoprotegerin ratio and showed favourable changes in other turnover biomarkers. The findings demonstrate that aspartic acid conjugate (PAL-DPPE) based bone targeted liposomes of linagliptin hold promise for the treatment of osteoporosis. Moreover, the possible mechanistic pathways involved here is Wnt and AMPK pathway.