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, that is poly (aspartic acid-co-lactide)-1,2-dipalmitoyl-sn-glycero-3-phospho ethanolamine (PAL-DPPE), which was prior synthesised and identified using FTIR and NMR. Liposomes were evaluated for particle size, encapsulation efficacy, drug loading and release study in addition to <i>in vitro</i> hydroxyapatite binding ability. To determine the anti-osteoporosis effect of liposomes, <i>in vivo</i> 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, receptor activator of nuclear factor kappa beta/osteoprotegerin ratio and other bone 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.