Department of Pediatrics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA.
Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, 1124 W Carson Street, Torrance, CA, 90502-2006, USA.
Respir Res. 2022 Apr 4;23(1):78. doi: 10.1186/s12931-022-02007-8.
Dry powder (DP) synthetic lung surfactant may be an effective means of noninvasive delivery of surfactant therapy to premature infants supported with nasal continuous positive airway pressure (nCPAP) in low-resource settings.
Four experimental DP surfactant formulations consisting of 70% of phospholipids (DPPC:POPG 7:3), 3% Super Mini-B (SMB) or its sulfur-free derivate B-YL as SP-B peptide mimic, 25% of lactose or trehalose as excipient, and 2% of NaCl were formulated using spray drying. In vitro surface activity was confirmed with captive bubble surfactometry. Surfactant particle size was determined with a cascade impactor and inhaled dose was quantified using a spontaneously breathing premature lamb lung model supported with CPAP. In vivo surfactant efficacy was demonstrated in three studies. First, oxygenation and lung compliance were monitored after intratracheal instillation of resuspended DP surfactant in intubated, ventilated, lavaged, surfactant-deficient juvenile rabbits. In dose-response studies, ventilated, lavaged, surfactant-deficient rabbits received 30, 60, 120 or 240 mg/kg of DP B-YL:Lactose or B-YL:Trehalose surfactant by aerosol delivery with a low flow aerosol chamber via their endotracheal tube. Noninvasive aerosolization of DP B-YL:Trehalose surfactant via nasal prongs was tested in spontaneous breathing premature lambs supported with nCPAP. Intratracheal administration of 200 mg/kg of Curosurf, a liquid porcine surfactant, was used as a positive control.
Mass median aerosol diameter was 3.6 μm with a geometric standard deviation of 1.8. All four experimental surfactants demonstrated high surface efficacy of intratracheal instillation of a bolus of ~ 100 mg/kg of surfactant with improvement of oxygenation and lung compliance. In the dose-response studies, rabbits received incremental doses of DP B-YL:Lactose or B-YL:Trehalose surfactant intratracheally and showed an optimal response in oxygenation and lung function at a dose of 120-240 mg/kg. Aerosol delivery via nasal prongs of 1 or 2 doses of ~ 100 mg/kg of B-YL:Trehalose surfactant to premature lambs supported with nCPAP resulted in stabilization of spontaneous breathing and oxygenation and lung volumes comparable to the positive control.
These studies confirm the clinical potential of DP synthetic lung surfactant with B-YL peptide as a SP-B mimic to alleviate surfactant deficiency when delivered as a liquid bolus or as an aerosol.
干粉（DP）合成肺表面活性剂可能是一种有效的非侵入性递送方法，可将表面活性剂治疗递送给在资源匮乏环境中接受鼻持续气道正压通气（nCPAP）支持的早产儿。
使用喷雾干燥法制备了 4 种实验性 DP 表面活性剂配方，其中包含 70%的磷脂（DPPC：POPG 7：3）、3%的超级迷你-B（SMB）或其无硫衍生物 B-YL 作为 SP-B 肽模拟物、25%的乳糖或海藻糖作为赋形剂，以及 2%的 NaCl。使用俘获气泡表面张力计确认体外表面活性。使用级联冲击器测定表面活性剂颗粒大小，并使用 CPAP 支持的自主呼吸早产羔羊模型定量吸入剂量。在 3 项研究中证明了体内表面活性剂的疗效。首先，在插管、通气、灌洗、表面活性剂缺乏的幼年兔中经气管内滴注重悬 DP 表面活性剂后，监测氧合和肺顺应性。在剂量反应研究中，通气、灌洗、表面活性剂缺乏的兔通过低流量气溶胶室经气管内管接受 30、60、120 或 240mg/kg DP B-YL：Lactose 或 DP B-YL：Trehalose 表面活性剂的气溶胶给药。通过 nCPAP 支持的自主呼吸早产羔羊的鼻腔插管测试 DP B-YL：Trehalose 表面活性剂的非侵入性气溶胶化。气管内给予 200mg/kg 的 Curosurf（一种液体猪肺表面活性剂）作为阳性对照。
质量中值气溶胶直径为 3.6μm，几何标准偏差为 1.8。所有 4 种实验性表面活性剂均显示出经气管内推注约 100mg/kg 表面活性剂的高表面活性，改善了氧合和肺顺应性。在剂量反应研究中，兔经气管内给予递增剂量的 DP B-YL：Lactose 或 DP B-YL：Trehalose 表面活性剂，并在 120-240mg/kg 剂量时表现出最佳的氧合和肺功能反应。通过 nCPAP 支持的早产羔羊的鼻腔插管给予 1 或 2 剂约 100mg/kg 的 B-YL：Trehalose 表面活性剂的气溶胶给药导致自主呼吸稳定，氧合和肺容积与阳性对照相当。
这些研究证实了含有 B-YL 肽作为 SP-B 模拟物的 DP 合成肺表面活性剂在作为液体推注或气溶胶给药时缓解表面活性剂缺乏的临床潜力。
