Journal
ADVANCED HEALTHCARE MATERIALS
Volume 11, Issue 8, Pages -Publisher
WILEY
DOI: 10.1002/adhm.202102153
Keywords
chemotherapy; cognition; encapsulation; intranasal; meninges; pain; stem cells
Funding
- NIH [RO1CA208371, RO1CA227064]
- MD Anderson Cancer Center Core Grant [NIH P30CA016672]
- Houston Methodist Research Institute
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This study investigates the capacity of nasally administered coated mitochondria to reverse cognitive deficits and peripheral neuropathy induced by chemotherapy. The findings demonstrate that nasal administration of coated mitochondria can promote the resolution of these neurotoxicities, identifying a novel strategy for treating central and peripheral nervous system pathologies.
Cognitive deficits (chemobrain) and peripheral neuropathy occur in similar to 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.
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