Langston Melissa V, Ramprasad Mysore P, Kararli Tugrul T, Galluppi Gerald R, Katre Nandini V
SkyePharma Inc., 10450 Science Center Drive, San Diego, CA 92121, USA.
J Control Release. 2003 Apr 14;89(1):87-99. doi: 10.1016/s0168-3659(03)00073-7.
Myelopoietins (MPO) are novel chimeric growth factors containing IL-3 and G-CSF receptor agonists that enhance the biological properties of both cytokines. These cytokines, like many therapeutic proteins, clear rapidly from circulation and must be administered daily to provide efficacy. Therefore, a controlled and sustained delivery system comprised of a biocompatible and biodegradable matrix, would offer important therapeutic advantages in the clinic, such as significantly reducing dose frequency and providing efficacy without toxicity. We report here the encapsulation of Leridistim (a protein from the MPO family) in multivesicular liposomes (DepoFoam) for sustained delivery, and demonstrate that a single injection of DepoFoam-encapsulated Leridistim results in elevated neutrophil counts for 10 days, in contrast to only 2 days for un-encapsulated Leridistim. Moreover, varying the lipid content of the DepoFoam matrix modulated the duration of elevated neutrophils from 2-3 to 9-10 days. The encapsulated Leridistim was released in vivo from the multivesicular liposomes in a uniform manner, consistent with its pharmacodynamic duration. Finally, a reproducible pharmacodynamic effect was observed with several batches of a DepoLeridistim formulation, indicating consistency of the manufacturing process of the DepoFoam delivery system. The capability of altering the release rates by varying the lipid composition provides maximum flexibility for controlled delivery of cytokine therapeutics.
骨髓生成素（MPO）是一种新型嵌合生长因子，含有白细胞介素-3和粒细胞集落刺激因子受体激动剂，可增强这两种细胞因子的生物学特性。这些细胞因子与许多治疗性蛋白质一样，会迅速从循环中清除，必须每天给药才能发挥疗效。因此，由生物相容性和可生物降解基质组成的可控缓释系统在临床上将具有重要的治疗优势，例如显著降低给药频率并提供无毒的疗效。我们在此报告了将Leridistim（一种来自MPO家族的蛋白质）封装在多囊脂质体（DepoFoam）中以实现持续递送，并证明单次注射封装在DepoFoam中的Leridistim可使中性粒细胞计数升高10天，而未封装的Leridistim仅能使中性粒细胞计数升高2天。此外，改变DepoFoam基质的脂质含量可将中性粒细胞升高的持续时间从2 - 3天调节至9 - 10天。封装的Leridistim以均匀的方式从多囊脂质体中体内释放，与其药效学持续时间一致。最后，在几批DepoLeridistim制剂中观察到了可重复的药效学效应，表明DepoFoam递送系统制造过程的一致性。通过改变脂质组成来改变释放速率的能力为细胞因子治疗药物的可控递送提供了最大的灵活性。
