Tuladhar Anup, Obermeyer Jaclyn M, Payne Samantha L, Siu Ricky C W, Zand Sohrab, Morshead Cindi M, Shoichet Molly S
Institute of Biomaterials and Biomedical Engineering, University of Toronto, 164 College Street, Toronto, ON, M5S 3G9, Canada; Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, 160 College Street, Toronto, ON, M5S 3E1, Canada.
Institute of Biomaterials and Biomedical Engineering, University of Toronto, 164 College Street, Toronto, ON, M5S 3G9, Canada; Department of Chemical Engineering and Applied Chemistry, University of Toronto, 200 College Street, Toronto, ON, M5S 3E5, Canada; Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, 160 College Street, Toronto, ON, M5S 3E1, Canada.
Biomaterials. 2020 Mar;235:119794. doi: 10.1016/j.biomaterials.2020.119794. Epub 2020 Jan 16.
Therapeutic delivery to the brain is limited by the blood-brain barrier and is exacerbated by off-target effects associated with systemic delivery, thereby precluding many potential therapies from even being tested. Given the systemic side effects of cyclosporine and erythropoietin, systemic administration would be precluded in the context of stroke, leaving only the possibility of local delivery. We wondered if direct delivery to the brain would allow new reparative therapeutics, such as these, to be identified for stroke. Using a rodent model of stroke, we employed an injectable drug delivery hydrogel strategy to circumvent the blood-brain barrier and thereby achieved, for the first time, local and sustained co-release to the brain of cyclosporine and erythropoietin. Both drugs diffused to the sub-cortical neural stem and progenitor cell (NSPC) niche and were present in the brain for at least 32 days post-stroke. Each drug had a different outcome on brain tissue: cyclosporine increased plasticity in the striatum while erythropoietin stimulated endogenous NSPCs. Only their co-delivery, but not either drug alone, accelerated functional recovery and improved tissue repair. This platform opens avenues for hitherto untested therapeutic combinations to promote regeneration and repair after stroke.
向大脑的治疗性给药受到血脑屏障的限制，并且与全身给药相关的脱靶效应会加剧这种限制，从而使许多潜在疗法甚至无法进行测试。鉴于环孢素和促红细胞生成素的全身副作用，在中风的情况下不能进行全身给药，只剩下局部给药的可能性。我们想知道直接向大脑给药是否能让针对中风的新的修复性疗法得以确定，比如上述这些疗法。我们使用中风的啮齿动物模型，采用可注射药物递送水凝胶策略来绕过血脑屏障，从而首次实现了环孢素和促红细胞生成素在大脑中的局部和持续共释放。两种药物都扩散到皮质下神经干细胞和祖细胞（NSPC）生态位，并且在中风后至少32天内在大脑中存在。每种药物对脑组织都有不同的影响：环孢素增加纹状体的可塑性，而促红细胞生成素刺激内源性NSPC。只有它们共同给药，而不是单独使用任何一种药物，才能加速功能恢复并改善组织修复。这个平台为促进中风后再生和修复的迄今未经测试的治疗组合开辟了道路。
