Abstract
Traumatic brain injury (TBI) is a major cause of disability and death among children and young adults in the United States, yet there are currently no treatments that improve the long-term brain health of patients. One promising therapeutic for TBI is brain-derived neurotrophic factor (BDNF), a protein that promotes neurogenesis and neuron survival. However, outstanding challenges to the systemic delivery of BDNF are its instability in blood, poor transport into the brain, and short half-life in circulation and brain tissue. Here, BDNF is encapsulated into an engineered, biodegradable porous silicon nanoparticle (pSiNP) in order to deliver bioactive BDNF to injured brain tissue after TBI. The pSiNP carrier is modified with the targeting ligand CAQK, a peptide that binds to extracellular matrix components upregulated after TBI. The protein cargo retains bioactivity after release from the pSiNP carrier, and systemic administration of the CAQK-modified pSiNPs results in effective delivery of the protein cargo to injured brain regions in a mouse model of TBI. When administered after injury, the CAQK-targeted pSiNP delivery system for BDNF reduces lesion volumes compared to free BDNF, supporting the hypothesis that pSiNPs mediate therapeutic protein delivery after systemic administration to improve outcomes in TBI.
| Original language | English |
|---|---|
| Pages (from-to) | 1685-1697 |
| Number of pages | 13 |
| Journal | Bioconjugate Chemistry |
| Volume | 33 |
| Issue number | 9 |
| DOIs | |
| State | Published - Sep 21 2022 |
Bibliographical note
Publisher Copyright:© 2022 American Chemical Society.
Funding
This work was supported by the National Institutes of Health (NIH) Director\u2019s New Innovator Award (Number DP2 NS111507); by the National Science Foundation (NSF) through the University of California, San Diego Materials Research Science and Engineering Center (UCSD MRSEC, award number DMR-2011924); and by the NIH (R01 AI132413). This work was performed in part at the San Diego Nanotechnology Infrastructure (SDNI) of the University of California, San Diego, a member of the National Nanotechnology Coordinated Infrastructure, which is supported by the NSF (grant ECCS-1542148). The authors acknowledge the use of facilities and instrumentation supported by NSF through the University of California, San Diego Materials Research Science and Engineering Center (award number DMR-2011924). The authors would also like to thank the University of California, San Diego\u2500Cellular and Molecular Medicine Electron Microscopy Core (UCSD-CMM-EM Core, RRID: SCR_022039), for equipment access and technical assistance. The UCSD-CMM-EM Core is supported in part by the NIH (Award number S10OD023527).
| Funders | Funder number |
|---|---|
| Director’s New Innovator Award | |
| National Institutes of Health (NIH) | |
| Materials Research Science and Engineering Center, University of California, San Diego | |
| UCSD MRSEC | R01 AI132413, DMR-2011924 |
| U.S. Department of Energy Chinese Academy of Sciences Guangzhou Municipal Science and Technology Project Oak Ridge National Laboratory Extreme Science and Engineering Discovery Environment National Science Foundation National Energy Research Scientific Computing Center National Natural Science Foundation of China | 2011924, 1542148 |
| Institute of Neurological Disorders and Stroke National Advisory Neurological Disorders and Stroke Council | DP2NS111507 |
| Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases | R01AI132413 |
| NIH Office of the Director | S10OD023527 |
| University of California San Diego Health | ECCS-1542148, S10OD023527 |
ASJC Scopus subject areas
- Biotechnology
- Bioengineering
- Biomedical Engineering
- Pharmacology
- Pharmaceutical Science
- Organic Chemistry