Alzheimer's Research Center, Regions Hospital, HealthPartners Research Foundation, Saint Paul, MN 55105, USA.
Drug Deliv. 2012 Apr;19(3):149-54. doi: 10.3109/10717544.2012.657720. Epub 2012 Feb 22.
Growth differentiation factor 5 (GDF5), in addition to its role in bone and joint development, protects dopaminergic (DA) neurons from degeneration, and is a potential therapeutic agent for Parkinson's disease. Its large size and insolubility at physiologic pH are obstacles for drug administration to the central nervous system (CNS) in humans.
In this study, formulations to deliver GDF5 to the brain using intranasal (IN) administration were developed.
IN administration of GDF5 in acidic buffer, 20 mM sodium acetate (NaAc) at pH 4.25, was performed in rats. Also, a lipid microemulsion (LME) comprised of olive oil and phosphatidylserine (PS) was used to formulate GDF5 at neutral pH for IN administration. Tissue concentrations of GDF5 were determined by both gamma counting and enzyme-linked immunosorbent assay (ELISA).
IN administration of GDF5 in acidic buffers bypassed the blood-brain barrier (BBB), resulting in delivery to the brain with limited systemic exposure. IN administration of GDF5-LME increased drug targeting to the midbrain eightfold when compared to IN administration of GDF5 in acidic buffer.
This study is the first to show that GDF5 can be formulated at neutral pH and can be directly delivered to the CNS via IN administration, with biologically relevant concentrations in the midbrain where it may be used to treat Parkinson's disease.
生长分化因子 5（GDF5）除了在骨骼和关节发育中发挥作用外，还能保护多巴胺能（DA）神经元免受变性，是治疗帕金森病的潜在治疗药物。其体积大，在生理 pH 值下不溶解，这是将其递送至人类中枢神经系统（CNS）的药物制剂的障碍。
本研究旨在开发通过鼻内（IN）给药将 GDF5 递送至大脑的制剂。
在大鼠中进行了 GDF5 在酸性缓冲液（pH 4.25 的 20mM 醋酸钠（NaAc））中的 IN 给药。此外，还使用了由橄榄油和磷脂酰丝氨酸（PS）组成的脂质微乳液（LME），将 GDF5 配制为中性 pH 值，用于 IN 给药。通过伽马计数和酶联免疫吸附测定（ELISA）测定组织中 GDF5 的浓度。
在酸性缓冲液中进行 IN 给药可绕过血脑屏障（BBB），从而将药物递送至大脑，同时全身暴露有限。与 IN 给予酸性缓冲液中的 GDF5 相比，IN 给予 GDF5-LME 可将药物靶向中脑增加八倍。
本研究首次表明，GDF5 可以在中性 pH 值下进行配制，并可以通过 IN 给药直接递送至 CNS，在其中脑中具有生物学相关浓度，可用于治疗帕金森病。
