Increased Nanoparticle Delivery to Brain Tumors by Autocatalytic Priming for Improved Treatment and Imaging
Open accessAbstract
The blood-brain barrier (BBB) is partially disrupted in brain tumors. Despite the gaps in the BBB, there is an inadequate amount of pharmacological agents delivered into the brain. Thus, the low delivery efficiency renders many of these agents ineffective in treating brain cancer. In this report, we proposed an "autocatalytic" approach for increasing the transport of nanoparticles into the brain. In this strategy, a small number of nanoparticles enter into the brain via transcytosis or through the BBB gaps. After penetrating the BBB, the nanoparticles release BBB modulators, which enables more nanoparticles to be transported, creating a positive feedback loop for increased delivery. Specifically, we demonstrated that these autocatalytic brain tumor-targeting poly(amine-co-ester) terpolymer nanoparticles (ABTT NPs) can readily cross the BBB and preferentially accumulate in brain tumors at a concentration of 4.3- and 94.0-fold greater than that in the liver and in brain regions without tumors, respectively. We further demonstrated that ABTT NPs were capable of mediating brain cancer gene therapy and chemotherapy. Our results suggest ABTT NPs can prime the brain to increase the systemic delivery of therapeutics for treating brain malignancies.
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CTX-mHph2-III-62% nanoparticles co-encapsulating minoxidil, lexiscan, and NECA can release blood-brain barrier modulators in the local tumor site, adjusting paracellular permeability to ensure more nanoparticles in the same area.
“Through co-encapsulation, such nanoparticles could release BBB modulators in the local tumor site, which adjust the permeability of BBB in the paracellular pathway to ensure more nanoparticles in the same area.”
From The blood–brain barrier: Structure, regulation and drug delivery (2023) · cites this paper as [151]
The Results and Discussion section (page not provided) reports that nanoparticles carrying a BBB modulator increased delivery to mouse brain tumors, and describes changes to tight-junction molecules consistent with altered paracellular permeability. It evaluates minoxidil, Lexiscan, and NECA as alternatives, however, not as three agents co-encapsulated in the same nanoparticles. The Conclusion and Outlook also says the mechanism of Lexiscan’s BBB modulation from the brain side has not been elucidated, so the specific paracellular mechanism is not established for these nanoparticles. (LLM, conf=0.86)
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“150 Zhou et al. developed brain tumor-targeting ligand-modi fi ed nanoparticles named CTX-mHph2-III-62%, inside which co-encapsulation of three modulators, minoxidil, lexiscan, and NECA.”
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- Authors
- Han, L., Kong, D. K., Zheng, M.-Q., Murikinati, S., Ma, C., Yuan, P., Li, L., Tian, D., Cai, Q., Ye, C., Holden, D., Park, J.-H., Gao, X., Thomas, J.-L., Grutzendler, J., Carson, R. E., Huang, Y., Piepmeier, J. M., & Zhou, J.
- Affiliations
- Yale University (US)
- Department of Neurosurgery, #Department of Biomedical Engineering, ‡PET Center, Department of Diagnostic Radiology, §Department of Neurology, and ⊥Department of Pathology, Yale University, New Haven, Connecticut 06511, United States
- Corresponding author
- Zhou, Jiangbing
- ORCID
- Venue
- ACS Nano
- Publisher
- American Chemical Society (ACS)
- Published
- 2016-03-16
- Volume
- 10
- Issue
- 4
- Pages
- 4209-4218
- ISSN
- 1936-0851 (ISSN-L)
- 1936-086X
- PMC
- PMC5257033
- OpenAlex
- W2294107204
- Cited by
- 122
- References
- 54
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 11 · 2023: 6 · 2022: 15 · 2021: 15 · 2020: 25 · 2019: 12 · 2018: 16 · 2017: 7 · 2016: 5
- FWCI
- 5.45
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- ACS Nano (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Center for Advancing Translational Sciences (UL1 TR000142)
- National Institute of Neurological Disorders and Stroke (NS095817)
- China Scholarship Council
- Matthew Larson Foundation for Pediatric Brain Tumors
- State of Connecticut
- Topics
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- brain tumors, blood-brain barrier, nanoparticle delivery, transcytosis, tumor-targeting nanoparticles, tumor imaging
- MeSH terms
- Animals, Antineoplastic Agents, Biological Transport, Blood-Brain Barrier, Brain Neoplasms, Decanoic Acids, Ethanolamines, Female, Humans, Mice, Inbred C57BL, Permeability, Polymers, Purines, Pyrazoles, Scorpion Venoms, Genetic Therapy, Drug Delivery Systems, Paclitaxel, Matrix Metalloproteinase 2, Cell Line, Tumor, Mice, Nanoparticles, Transcytosis, Tumor Microenvironment, Optical Imaging, Heterografts
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