- Protocol
- Published:
- Andy J. Chua ORCID: orcid.org/0000-0003-4796-77641,2,
- Valentina Di Francesco ORCID: orcid.org/0000-0003-4216-724X1,3,
- Anisha D’Souza ORCID: orcid.org/0000-0003-2457-671X1,3,
- Mansoor Amiji ORCID: orcid.org/0000-0001-6170-881X1,4 &
- …
- Benjamin S. Bleier3
Lab Animal (2024)Cite this article
-
Metrics details
Subjects
- Drug delivery
- Drug development
- Neurological disorders
Abstract
The blood–brain barrier (BBB) poses a substantial obstacle to the successful delivery of therapeutics to the central nervous system (CNS). The transnasal route has been extensively explored, but success rates have been modest due to challenges related to the precise anatomical placement of drugs, the small volumes that the olfactory cleft can accommodate and short drug residence times due to mucociliary clearance. Here, to address these issues, we have developed a surgical technique known as the minimally invasive nasal depot (MIND), which allows the accurate placement of depot drugs into the submucosal space of the olfactory epithelium of rats. This technique exploits the unique anatomy of the olfactory apparatus to enable transnasal delivery of drugs into the CNS, bypassing the BBB. In our rat model, a bony window is created in the animal snout to expose the submucosal space. Using the MIND technique, we have successfully delivered oligonucleotides to the CNS in Sprague-Dawley and Long-Evans rats, leading to an upregulation of brain-derived neurotrophic factor in the substantia nigra and hippocampus. In this Protocol, we describe the procedural steps for MIND. This procedure takes about 45 min and can be performed by researchers with basic surgical skills. We additionally describe modifications to perform MIND in mice, which are anatomically smaller. The MIND procedure represents a unique platform that can be used to overcome the limitations posed by the BBB. This technique can potentially expand the therapeutic toolkit in the treatment of neurological diseases.
This is a preview of subscription content, access via your institution
Access options
Change institution
Buy or subscribe
Data availability
The authors declare that the main data discussed in this protocol are available in the supporting primary research paper (https://doi.org/10.1016/j.jconrel.2021.01.027). The raw datasets are too large to be publicly shared but are available for research purposes from the corresponding authors upon reasonable request.
References
Dong, X. Current strategies for brain drug delivery. Theranostics 8, 1481–1493 (2018).
Pardridge, W. M. The blood–brain barrier: bottleneck in brain drug development. NeuroRx 2, 3–14 (2005).
Agrawal, M. et al. Nose-to-brain drug delivery: an update on clinical challenges and progress towards approval of anti-Alzheimer drugs. J. Control. Release 281, 139–177 (2018).
Lee, D. & Minko, T. Nanotherapeutics for nose-to-brain drug delivery: an approach to bypass the blood brain barrier. Pharmaceutics https://doi.org/10.3390/pharmaceutics13122049 (2021).
Miyake, M. M. & Bleier, B. S. Bypassing the blood–brain barrier using established skull base reconstruction techniques. World J. Otorhinolaryngol. Head Neck Surg. 1, 11–16 (2015).
Padmakumar, S. et al. Minimally invasive nasal depot (MIND) technique for direct BDNF AntagoNAT delivery to the brain. J. Control. Release 331, 176–186 (2021).
Padmakumar, S. et al. Osmotic core–shell polymeric implant for sustained BDNF AntagoNAT delivery in CNS using minimally invasive nasal depot (MIND) approach. Biomaterials 276, 120989 (2021).
AA, D. S., Kulkarni, P., Ferris, C. F., Amiji, M. M. & Bleier, B. S. Mild repetitive TBI reduces brain-derived neurotrophic factor (BDNF) in the substantia nigra and hippocampus: a preclinical model for testing BDNF-targeted therapeutics. Exp. Neurol. 374, 114696 (2024).
Di Francesco, V. et al. Minimally invasive nasal infusion (MINI) approach for CNS delivery of protein therapeutics: a case study with ovalbumin. J. Control. Release 372, 674–681 (2024).
Pawar, G. N., Parayath, N. N., Nocera, A. L., Bleier, B. S. & Amiji, M. M. Direct CNS delivery of proteins using thermosensitive liposome-in-gel carrier by heterotopic mucosal engrafting. PLoS ONE 13, e0208122 (2018).
Pawar, G. et al. Endonasal CNS delivery system for blood–brain barrier impermeant therapeutic oligonucleotides using heterotopic mucosal engrafting. Front. Pharmacol. 12, 660841 (2021).
Palasz, E. et al. BDNF as a promising therapeutic agent in Parkinson’s disease. Int. J. Mol. Sci. 21, 1170 (2020).
Madadi, A. K. & Sohn, M. J. Advances in intrathecal nanoparticle delivery: targeting the blood-cerebrospinal fluid barrier for enhanced CNS drug delivery. Pharmaceuticals 17, 1070 (2024).
Arms, L. M. et al. Current status and advances to improving drug delivery in diffuse intrinsic pontine glioma. J. Control. Release 370, 835–865 (2024).
Gadhave, D. G. et al. Mucoadhesive chitosan-poly (lactic-co-glycolic acid) nanoparticles for intranasal delivery of quetiapine—development & characterization in physiologically relevant 3D tissue models. Int. J. Biol. Macromol. 267, 131491 (2024).
Gao, X. et al. Mucus adhesion vs. mucus penetration? Screening nanomaterials for nasal inhalation by MD simulation. J. Control. Release 353, 366–379 (2023).
Lofts, A. et al. In situ-gelling hydrophobized starch nanoparticle-based nanoparticle network hydrogels for the effective delivery of intranasal olanzapine to treat brain disorders. Int. J. Biol. Macromol. 277, 134385 (2024).
Sercombe, L. et al. Advances and challenges of liposome assisted drug delivery. Front. Pharmacol. 6, 286 (2015).
Acknowledgements
This work was supported by an NINDS grant (1R01NS108968-01) and the NMRC Research Training Fellowship, Singapore (MOH-RTF21nov-0008).
Author information
Authors and Affiliations
Department of Pharmaceutical Sciences, School of Pharmacy, Bouve College of Health Sciences, Northeastern University, Boston, MA, USA
Andy J. Chua,Valentina Di Francesco,Anisha D’Souza&Mansoor Amiji
Department of Otorhinolaryngology – Head and Neck Surgery, Sengkang General Hospital, Singapore, Singapore
Andy J. Chua
Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, Boston, MA, USA
Valentina Di Francesco,Anisha D’Souza&Benjamin S. Bleier
Department of Chemical Engineering, College of Engineering, Northeastern University, Boston, MA, USA
Mansoor Amiji
Authors
- Andy J. Chua
View author publications
You can also search for this author in PubMedGoogle Scholar
- Valentina Di Francesco
View author publications
You can also search for this author in PubMedGoogle Scholar
- Anisha D’Souza
View author publications
You can also search for this author in PubMedGoogle Scholar
- Mansoor Amiji
View author publications
You can also search for this author in PubMedGoogle Scholar
- Benjamin S. Bleier
View author publications
You can also search for this author in PubMedGoogle Scholar
Contributions
A.J.C., V.D.F., A.D., M.A. and B.S.B. conceptualized the study, supported data collection and analysis, prepared the original draft, and reviewed and edited the manuscript.
Corresponding author
Correspondence to Andy J. Chua.
Ethics declarations
Competing interests
A.J.C. received consulting fees from Acclarent Inc, MicrogenDx, and Elsevier Inc. B.S.B. holds a patent assigned to Massachusetts Eye and Ear covering transmucosal delivery methods to the CNS. All other authors declare no competing interests.
Peer review
Peer review information
Lab Animal thanks Joana Bicker, Katharina Schindowski and Dezhuang Ye for their contribution to the peer review of this work.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Chua, A.J., Di Francesco, V., D’Souza, A. et al. Murine model of minimally invasive nasal depot (MIND) technique for central nervous system delivery of blood–brain barrier-impermeant therapeutics. Lab Anim (2024). https://doi.org/10.1038/s41684-024-01460-w
Received:
Accepted:
Published:
DOI: https://doi.org/10.1038/s41684-024-01460-w
