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    Pulmonary surfactant and drug delivery: Vehiculization, release and targeting of surfactant/tacrolimus formulations

    Year: 2021

    Journal: J. Control. Release, Volume 329, JAN 10, page 205–222

    Authors: Hidalgo, Alberto; Garcia-Mouton, Cristina; Autilio, Chiara; Carravilla, Pablo; Orellana, Guillermo; Islam, Mohammad N.; Bhattacharya, Jahar; Bhattacharya, Sunita; Cruz, Antonio; Perez-Gil, Jesus

    Organizations: Spanish Ministry of Science, Universities and Innovation [RTI2018-094564-B-I00, RTI2018-096410B-C22]; Regional Government of Madrid [P2018/NMT-4389]; US National Institutes of Health [HL36024, HL57556]; University of the Basque Country [DOCREC18/01]; Basque Government [POS_2018_1_0066, IT1196-19]

    Keywords: Interfacial delivery; Drug delivery; Pulmonary surfactant; Airways; Respiratory surface; Air-liquid interfaces

    This work explores the potential for strategizing pulmonary surfactant (PS) for drug delivery over the respiratory air-liquid interface: the interfacial delivery. The efficacy of PS- and interface-assisted drug vehiculization was determined both in vitro and in vivo using a native purified porcine PS combined with the hydrophobic anti-inflammatory drug Tacrolimus (TAC), a calcineurin inhibitor. In vitro assays were conducted in a novel double surface balance setup designed to emulate compression-expansion dynamics applied to interfacially connected drug donor and recipient compartments. In this setup, PS transported TAC efficiently over air-liquid interfaces, with compression/expansion breathing-like dynamics enhancing rapid interface-assisted diffusion and drug release. The efficacy of PS-assisted TAC vehiculization was also evaluated in vivo in a mouse model of lipopolysaccharide (LPS)-induced acute lung injury (ALI). In anesthetized mice, TAC combined with PS was intra-nasally (i.n) instilled prior administering i.n. LPS. PS/TAC pre-treatment caused greater TAC internalization into a higher number of lung cells obtained from bronchoalveolar lavages (BAL) than TAC pre-treatment alone. Additionally, the PS/TAC combination but not TAC or PS alone attenuated the LPS-induced pro-inflammatory effects reducing cells and proteins in BAL fluid. These findings indicated that PS-mediated increase in TAC uptake blunted the pro-injurious effects of LPS, suggesting a synergistic anti-inflammatory effect of PS/drug formulations. These in vitro and in vivo results establish the potential utility of PS to open novel effective delivery strategies for inhaled drugs.
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