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Dual Functionalized Liposomes for Selective Delivery of Poorly Soluble Drugs to Inflamed Brain Regions

2022; Multidisciplinary Digital Publishing Institute; Volume: 14; Issue: 11 Linguagem: Inglês

10.3390/pharmaceutics14112402

1999-4923

Sabrina Giofrè, Antonio Renda, Silvia Sesana, Beatrice Formicola, Barbara Vergani, Biagio Eugenio Leone, Vanna Denti, Giuseppe Paglia, Serena Groppuso, Valentina Romeo, Luca Muzio, Andrea Balboni, Andrea Menegon, Antonia I. Antoniou, Arianna Amenta, Daniele Passarella, Pierfausto Seneci, Sara Pellegrino, Francesca Re,

Nanoparticle-Based Drug Delivery

Dual functionalized liposomes were developed to cross the blood−brain barrier (BBB) and to release their cargo in a pathological matrix metalloproteinase (MMP)-rich microenvironment. Liposomes were surface-functionalized with a modified peptide deriving from the receptor-binding domain of apolipoprotein E (mApoE), known to promote cargo delivery to the brain across the BBB in vitro and in vivo; and with an MMP-sensitive moiety for an MMP-triggered drug release. Different MMP-sensitive peptides were functionalized at both ends with hydrophobic stearate tails to yield MMP-sensitive lipopeptides (MSLPs), which were assembled into mApoE liposomes. The resulting bi-functional liposomes (i) displayed a < 180 nm diameter with a negative ζ-potential; (ii) were able to cross an in vitro BBB model with an endothelial permeability of 3 ± 1 × 10−5 cm/min; (iii) when exposed to functional MMP2 or 9, efficiently released an encapsulated fluorescein dye; (iv) showed high biocompatibility when tested in neuronal cultures; and (v) when loaded with glibenclamide, a drug candidate with poor aqueous solubility, reduced the release of proinflammatory cytokines from activated microglial cells.