PLX038A, a long-acting SN-38, penetrates the blood-tumor-brain-barrier, accumulates and releases SN-38 in brain tumors to increase survival of tumor bearing mice Article Swipe
Jinkyu Jung
,
Eric L. Schneider
,
Wei Zhang
,
Hua Song
,
Meili Zhang
,
William Chou
,
Niranjan Meher
,
Henry F. VanBrocklin
,
Mary Helen Barcellos‐Hoff
,
Tomoko Ozawa
,
Mark R. Gilbert
,
Daniel V. Santi
·
YOU?
·
· 2024
· Open Access
·
· DOI: https://doi.org/10.1038/s41598-024-64186-2
YOU?
·
· 2024
· Open Access
·
· DOI: https://doi.org/10.1038/s41598-024-64186-2
Central nervous system tumors have resisted effective chemotherapy because most therapeutics do not penetrate the blood-tumor-brain-barrier. Nanomedicines between ~ 10 and 100 nm accumulate in many solid tumors by the enhanced permeability and retention effect, but it is controversial whether the effect can be exploited for treatment of brain tumors. PLX038A is a long-acting prodrug of the topoisomerase 1 inhibitor SN-38. It is composed of a 15 nm 4-arm 40 kDa PEG tethered to four SN-38 moieties by linkers that slowly cleave to release the SN-38. The prodrug was remarkably effective at suppressing growth of intracranial breast cancer and glioblastoma (GBM), significantly increasing the life span of mice harboring them. We addressed the important issue of whether the prodrug releases SN-38 systemically and then penetrates the brain to exert anti-tumor effects, or whether it directly penetrates the blood-tumor-brain-barrier and releases the SN-38 cargo within the tumor. We argue that the amount of SN-38 formed systemically is insufficient to inhibit the tumors, and show by PET imaging that a close surrogate of the 40 kDa PEG carrier in PLX038A accumulates and is retained in the GBM. We conclude that the prodrug penetrates the blood-tumor-brain-barrier, accumulates in the tumor microenvironment and releases its SN-38 cargo from within. Based on our results, we pose the provocative question as to whether the 40 kDa nanomolecule PEG carrier might serve as a “Trojan horse” to carry other drugs past the blood-tumor-brain-barrier and release them into brain tumors.
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Metadata
- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.1038/s41598-024-64186-2
- https://www.nature.com/articles/s41598-024-64186-2.pdf
- OA Status
- gold
- Cited By
- 2
- References
- 30
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4399800157
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
-
https://openalex.org/W4399800157Canonical identifier for this work in OpenAlex
- DOI
-
https://doi.org/10.1038/s41598-024-64186-2Digital Object Identifier
- Title
-
PLX038A, a long-acting SN-38, penetrates the blood-tumor-brain-barrier, accumulates and releases SN-38 in brain tumors to increase survival of tumor bearing miceWork title
- Type
-
articleOpenAlex work type
- Language
-
enPrimary language
- Publication year
-
2024Year of publication
- Publication date
-
2024-06-19Full publication date if available
- Authors
-
Jinkyu Jung, Eric L. Schneider, Wei Zhang, Hua Song, Meili Zhang, William Chou, Niranjan Meher, Henry F. VanBrocklin, Mary Helen Barcellos‐Hoff, Tomoko Ozawa, Mark R. Gilbert, Daniel V. SantiList of authors in order
- Landing page
-
https://doi.org/10.1038/s41598-024-64186-2Publisher landing page
- PDF URL
-
https://www.nature.com/articles/s41598-024-64186-2.pdfDirect link to full text PDF
- Open access
-
YesWhether a free full text is available
- OA status
-
goldOpen access status per OpenAlex
- OA URL
-
https://www.nature.com/articles/s41598-024-64186-2.pdfDirect OA link when available
- Concepts
-
Prodrug, Blood–brain barrier, Brain tumor, Cancer research, Chemotherapy, Tumor microenvironment, Medicine, Central nervous system, Pharmacology, Chemistry, Pathology, Tumor cells, Internal medicineTop concepts (fields/topics) attached by OpenAlex
- Cited by
-
2Total citation count in OpenAlex
- Citations by year (recent)
-
2025: 2Per-year citation counts (last 5 years)
- References (count)
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30Number of works referenced by this work
- Related works (count)
-
10Other works algorithmically related by OpenAlex
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