University at Buffalo, SUNY, Pharmaceutical Sciences, H526 Hochstetter Hall, Buffalo 14260, USA.
Drug Deliv. 2011 May;18(4):246-54. doi: 10.3109/10717544.2010.536269. Epub 2010 Nov 30.
Replacement therapy using recombinant factor VIII (rFVIII) is currently the most common therapy for hemophilia A, a bleeding disorder caused by the deficiency of FVIII. However, 15-30% of patients develop inhibitory antibodies against administered rFVIII, which complicates the therapy. Encapsulation or association of protein with lipidic structures can reduce this immune response. Previous studies developed and characterized rFVIII-containing phosphatidylserine (PS) cochleate cylinders using biophysical techniques. It was hypothesized that these structures may provide a reduction in immunogenicity while avoiding the rapid clearance by the reticuloendothelial system (RES) previously observed with liposomal vesicles of similar composition. This study investigated in vivo behavior of the cochleates containing rFVIII including immunogenicity and pharmacokinetics in hemophilia A mice. The rFVIII-cochleate complex significantly reduced the level of inhibitory antibody developed against rFVIII following intravenous (i.v.) administration. Pharmacokinetic modeling allowed assessment of in vivo release kinetics. Cochleates acted as a delayed release delivery vehicle with an input peak of cochleates showed limited RES uptake and associated rFVIII displayed a similar disposition to the free protein upon release from the structure. Incomplete disassociation from the complex limits systemic availability of the protein. Further formulation efforts are warranted to regulate the rate and extent of release of rFVIII from cochleate complexes.
使用重组因子 VIII（rFVIII）进行替代疗法是目前治疗血友病 A 的最常见方法，血友病 A 是一种由 FVIII 缺乏引起的出血性疾病。然而，15-30%的患者会对给予的 rFVIII 产生抑制性抗体，这使得治疗变得复杂。蛋白质与脂质结构的包封或结合可以减少这种免疫反应。先前的研究使用生物物理技术开发并表征了含有磷脂酰丝氨酸（PS）的 rFVIII 螺旋管。假设这些结构可能会降低免疫原性，同时避免以前观察到的具有类似组成的脂质体囊泡的快速清除。本研究调查了含有 rFVIII 的螺旋管的体内行为，包括在血友病 A 小鼠中的免疫原性和药代动力学。rFVIII-螺旋管复合物在静脉内（i.v.）给予后显著降低了针对 rFVIII 产生的抑制性抗体水平。药代动力学模型允许评估体内释放动力学。螺旋管作为延迟释放的给药载体，输入的螺旋管峰值显示出有限的 RES 摄取，并且在从结构中释放后，相关的 rFVIII 表现出与游离蛋白相似的处置。与复合物的不完全解离限制了蛋白质的全身可用性。需要进一步的制剂努力来调节 rFVIII 从螺旋管复合物中的释放速率和程度。
