Laboratories of Neuroimmunology, Department of Symptom Research, Division of Internal Medicine, The University of Texas, M.D. Anderson Cancer Center, 6565 MD Anderson Blvd., Houston, TX, 77030, USA.
Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, Hufelandstr. 55, Essen, D-45147, Germany.
Adv Healthc Mater. 2022 Apr;11(8):e2102153. doi: 10.1002/adhm.202102153. Epub 2022 Jan 27.
Cognitive deficits (chemobrain) and peripheral neuropathy occur in ∼75% of patients treated for cancer with chemotherapy and persist long-term in >30% of survivors. Without preventive or curative interventions and with increasing survivorship rates, the population debilitated by these neurotoxicities is rising. Platinum-based chemotherapeutics, including cisplatin, induce neuronal mitochondrial defects leading to chemobrain and neuropathic pain. This study investigates the capacity of nasally administered mesenchymal stem cell-derived mitochondria coated with dextran-triphenylphosphonium polymer (coated mitochondria) to reverse these neurotoxicities. Nasally administered coated mitochondria are rapidly detectable in macrophages in the brain meninges but do not reach the brain parenchyma. The coated mitochondria change expression of >2400 genes regulating immune, neuronal, endocrine and vascular pathways in the meninges of mice treated with cisplatin. Nasal administration of coated mitochondria reverses cisplatin-induced cognitive deficits and resolves neuropathic pain at a >55-times lower dose compared to uncoated mitochondria. Reversal of these neuropathologies is associated with resolution of cisplatin-induced deficits in myelination, synaptosomal mitochondrial integrity and neurogenesis. These findings demonstrate that nasally administered coated mitochondria promote resolution of chemobrain and peripheral neuropathy, thereby identifying a novel facile strategy for clinical application of mitochondrial donation and treating central and peripheral nervous system pathologies by targeting the brain meninges.
认知缺陷（化疗脑）和周围神经病变发生在接受化疗治疗癌症的患者中约 75%，且>30%的幸存者长期持续存在。由于缺乏预防或治疗干预措施以及幸存者人数不断增加，受这些神经毒性影响的人群正在增加。包括顺铂在内的铂类化疗药物会导致神经元线粒体缺陷，从而引发化疗脑和神经性疼痛。本研究调查了经葡聚糖-三苯基膦聚合物包被的鼻内给予的间充质干细胞衍生的线粒体（包被线粒体）逆转这些神经毒性的能力。包被线粒体经鼻给予后，可在脑膜中的巨噬细胞中快速检测到，但不会到达脑实质。包被线粒体改变了 2400 多个基因的表达，这些基因调节接受顺铂治疗的小鼠的免疫、神经元、内分泌和血管途径。与未包被线粒体相比，鼻内给予包被线粒体可逆转顺铂引起的认知缺陷，并解决神经性疼痛，其剂量低 55 倍以上。这些神经病理学的逆转与顺铂引起的髓鞘形成、突触体线粒体完整性和神经发生缺陷的解决相关。这些发现表明，经鼻给予的包被线粒体可促进化疗脑和周围神经病变的缓解，从而确定了一种通过靶向脑膜来实现线粒体捐赠的临床应用和治疗中枢及周围神经系统病变的新的简便策略。
