Walther Frans J, Gupta Monik, Lipp Michael M, Chan Holly, Krzewick John, Gordon Larry M, Waring Alan J
Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, 90502, USA.
Acorda Therapeutics Inc., Chelsea, Massachusetts, 02150, USA.
Gates Open Res. 2019 Mar 14;3:6. doi: 10.12688/gatesopenres.12899.2. eCollection 2019.
: The development of synthetic lung surfactant for preterm infants has focused on peptide analogues of native surfactant proteins B and C (SP-B and SP-C). Non-invasive respiratory support with nasal continuous positive airway pressure (nCPAP) may benefit from synthetic surfactant for aerosol delivery. : A total of three dry powder (DP) surfactants, consisting of phospholipids and the SP-B analogue Super Mini-B (SMB), and one negative control DP surfactant without SMB, were produced with the Acorda Therapeutics ARCUS® Pulmonary Dry Powder Technology. Structure of the DP surfactants was compared with FTIR spectroscopy, surface activity with captive bubble surfactometry, and activity in surfactant-deficient adult rabbits and preterm lambs. In the animal experiments, intratracheal (IT) aerosol delivery was compared with surfactant aerosolization during nCPAP support. Surfactant dosage was 100 mg/kg of lipids and aerosolization was performed using a low flow inhaler. FTIR spectra of the three DP surfactants each showed secondary structures compatible with peptide folding as an α-helix hairpin, similar to that previously noted for surface-active SMB in other lipids. The DP surfactants with SMB demonstrated surface activity <1 mN/m. Oxygenation and lung function increased quickly after IT aerosolization of DP surfactant in both surfactant-deficient rabbits and preterm lambs, similar to improvements seen with clinical surfactant. The response to nCPAP aerosol delivery of DP surfactant was about 50% of IT aerosol delivery, but could be boosted with a second dose in the preterm lambs. Aerosol delivery of DP synthetic surfactant during non-invasive respiratory support with nCPAP significantly improved oxygenation and lung function in surfactant-deficient animals and this response could be enhanced by giving a second dose. Aerosol delivery of DP synthetic lung surfactant has potential for clinical applications.
针对早产儿的合成肺表面活性剂的研发主要集中在天然表面活性蛋白B和C（SP - B和SP - C）的肽类似物上。经鼻持续气道正压通气（nCPAP）的无创呼吸支持可能受益于用于气雾剂递送的合成表面活性剂。
使用Acorda Therapeutics公司的ARCUS®肺部干粉技术制备了三种由磷脂和SP - B类似物超级迷你B（SMB）组成的干粉（DP）表面活性剂，以及一种不含SMB的阴性对照DP表面活性剂。通过傅里叶变换红外光谱（FTIR）对DP表面活性剂的结构进行了比较，用俘获气泡表面张力测定法对其表面活性进行了比较，并在缺乏表面活性剂的成年兔和早产羔羊中对其活性进行了比较。在动物实验中，将气管内（IT）气雾剂递送与nCPAP支持期间的表面活性剂雾化进行了比较。表面活性剂剂量为100mg/kg脂质，并使用低流量吸入器进行雾化。三种DP表面活性剂的FTIR光谱均显示出与作为α - 螺旋发夹的肽折叠兼容的二级结构，类似于先前在其他脂质中观察到的具有表面活性的SMB。含有SMB的DP表面活性剂表现出<1mN/m的表面活性。在缺乏表面活性剂的兔子和早产羔羊中，IT雾化DP表面活性剂后，氧合和肺功能迅速改善，类似于临床表面活性剂所见的改善。对DP表面活性剂nCPAP气雾剂递送的反应约为IT气雾剂递送的50%，但在早产羔羊中第二次给药可增强该反应。在nCPAP无创呼吸支持期间，DP合成表面活性剂的气雾剂递送显著改善了缺乏表面活性剂动物的氧合和肺功能，并且通过给予第二次剂量可增强这种反应。DP合成肺表面活性剂的气雾剂递送具有临床应用潜力。
