Hakami Abrar, Narasimhan Kaushik, Comini Giulia, Thiele Julian, Werner Carsten, Dowd Eilís, Newland Ben
School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK; Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
Pharmacology & Therapeutics and Galway Neuroscience Centre, University of Galway, H91 W5P7 Galway, Ireland.
J Control Release. 2024 May;369:404-419. doi: 10.1016/j.jconrel.2024.03.023. Epub 2024 Apr 4.
Neurotrophic growth factors such as glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) have been considered as potential therapeutic candidates for neurodegenerative disorders due to their important role in modulating the growth and survival of neurons. However, clinical translation remains elusive, as their large size hinders translocation across the blood-brain barrier (BBB), and their short half-life in vivo necessitates repeated administrations. Local delivery to the brain offers a potential route to the target site but requires a suitable drug-delivery system capable of releasing these proteins in a controlled and sustained manner. Herein, we develop a cryogel microcarrier delivery system which takes advantage of the heparin-binding properties of GDNF and BDNF, to reversibly bind/release these growth factors via electrostatic interactions. Droplet microfluidics and subzero temperature polymerization was used to create monodisperse cryogels with varying degrees of negative charge and an average diameter of 20 μm. By tailoring the inclusion of 3-sulfopropyl acrylate (SPA) as a negatively charged moiety, the release duration of these two growth factors could be adjusted to range from weeks to half a year. 80% SPA cryogels and 20% SPA cryogels were selected to load GDNF and BDNF respectively, for the subsequent biological studies. Cell culture studies demonstrated that these cryogel microcarriers were cytocompatible with neuronal and microglial cell lines, as well as primary neural cultures. Furthermore, in vivo studies confirmed their biocompatibility after administration into the brain, as well as their ability to deliver, retain and release GDNF and BDNF in the striatum. Overall, this study highlights the potential of using cryogel microcarriers for long-term delivery of neurotrophic growth factors to the brain for neurodegenerative disorder therapeutics.
神经营养生长因子，如胶质细胞系源性神经营养因子（GDNF）和脑源性神经营养因子（BDNF），因其在调节神经元生长和存活方面的重要作用，被视为神经退行性疾病的潜在治疗候选物。然而，临床转化仍然难以实现，因为它们的大分子尺寸阻碍了其穿过血脑屏障（BBB），并且它们在体内的半衰期短，需要重复给药。向脑内局部给药为到达靶位点提供了一条潜在途径，但需要一种能够以可控和持续方式释放这些蛋白质的合适药物递送系统。在此，我们开发了一种冷冻凝胶微载体递送系统，该系统利用GDNF和BDNF的肝素结合特性，通过静电相互作用可逆地结合/释放这些生长因子。采用液滴微流控和零下温度聚合方法制备了具有不同程度负电荷且平均直径为20μm的单分散冷冻凝胶。通过调整作为带负电荷部分的3-磺丙基丙烯酸酯（SPA）的含量，可以将这两种生长因子的释放持续时间调整为从数周至半年不等。分别选择80% SPA冷冻凝胶和20% SPA冷冻凝胶负载GDNF和BDNF，用于后续生物学研究。细胞培养研究表明，这些冷冻凝胶微载体与神经元和小胶质细胞系以及原代神经培养物具有细胞相容性。此外，体内研究证实了它们在脑内给药后的生物相容性，以及它们在纹状体中递送、保留和释放GDNF和BDNF的能力。总体而言，本研究突出了使用冷冻凝胶微载体向脑内长期递送神经营养生长因子用于神经退行性疾病治疗的潜力。
