Abstract
Targeted Nanoparticles to Mitigate Radiation‐Induced Blood‐Brain Barrier Disruption and Cognitive Impairment
The FASEB journal, Vol.36(S1), p.n/a
05/2022
DOI: 10.1096/fasebj.2022.36.S1.L8026
Abstract
Background
Up to 90% of brain cancer survivors develop radiation‐induced cognitive dysfunction following treatment. Damage to neurovascular endothelium contributes to cognitive decline through increased blood‐brain barrier (BBB) permeability. In our preliminary studies of endothelial cells (ECs) and mice, increased mitochondrial reactive oxygen species (mtROS), inducing heightened mitochondrial DNA (mtDNA) damage and release as cell‐free DNA are detected following irradiation (IR). This cell‐free mtDNA is known to activate Toll‐like receptor 9 (TLR9), triggering an immune response and further ROS. These endothelial responses are prevented with TLR9 inhibition and mtROS scavenging, suggesting a key role for TLR9 in sustained IR‐induced endothelial damage and dysfunction.
Here, we posit that specific inhibition of TLR9 in cerebral ECs during radiation treatment will prevent subsequent BBB permeability and cognitive decline. Thus, the objective of this study is to examine the role of TLR9 in IR‐induced cognitive decline using TLR‐specific loaded nanoparticles (NP).
Methods and Results
To target TLR9 in irradiated ECs, poly (lactic‐co‐glycolic acid)‐based NP coated with cyclic Arg‐Gly‐Asp (cRGD)‐peptide were designed and loaded with TLR9 inhibitor (ODN‐2088, 2.23ug/mg particle). cRGD‐peptide is a ligand for integrin αvβ3, which is highly expressed in ECs post‐IR. cRGD‐NP loaded with coumarin‐6 were used to first evaluate specificity in vitro and in vivo. ECs 24h post‐IR (4 Gy) displayed higher fluorescence than non‐IR, indicating selective uptake. Moreover, in C57Bl6 mice 24h post unilateral cerebral IR (12Gy) with cRGD‐NP, uptake accumulated in endothelium of the IR hemisphere.
Mice were administered NP‐ODN‐2088 or empty NP (3mg injection) and subjected to IR as described above. 30 days post‐IR, they were tested for memory and learning ability using the Novel Object Recognition test. IR induced a significant impairment in the memory ability of empty NP treated mice compared to NP‐ODN‐2088. BBB permeability was analyzed in the same mice 30 days post‐IR with immunohistochemistry using anti‐mouse IgG. Significant BBB permeability was detected in the IR hemisphere of empty NP mice compared to the non‐IR hemisphere. However, the IR hemisphere of NP‐ODN‐2088 mice showed attenuated permeability compared to empty NP treated mice.
Conclusion
Inhibition of TLR9 in irradiated ECs was observed to protect against BBB disruption and cognitive decline. These data support a pathway of radiation‐induced endotheliopathy through which TLR9 activation links vascular mitochondrial injury to neuropathology. Currently there are no pharmacological options for treating radiation‐induced normal tissue injury and targeting TLR9 poses a promising strategy.
Details
- Title: Subtitle
- Targeted Nanoparticles to Mitigate Radiation‐Induced Blood‐Brain Barrier Disruption and Cognitive Impairment
- Creators
- Nathanial R Lindsey - University of IowaKanawat Witwatchaitawee - University of IowaLinette Leng - University of IowaAliasger Salem - University of IowaIsabella M Grumbach - University of IowaKarima Ait-Aissa - University of Iowa
- Resource Type
- Abstract
- Publication Details
- The FASEB journal, Vol.36(S1), p.n/a
- DOI
- 10.1096/fasebj.2022.36.S1.L8026
- ISSN
- 0892-6638
- eISSN
- 1530-6860
- Publisher
- The Federation of American Societies for Experimental Biology
- Number of pages
- 1
- Grant note
- AHA (2021CDA 853499) NIH (R01 EY 031544‐02; I01 BX000163‐12)
- Language
- English
- Date published
- 05/2022
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Pharmaceutical Sciences and Experimental Therapeutics; Cardiovascular Medicine; Radiation Oncology; Craniofacial Anomalies Research Center; Dental Research; Chemical and Biochemical Engineering; Internal Medicine
- Record Identifier
- 9984231973402771
Metrics
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