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Extracellular Vesicle–Mediated In Vitro Transcribed mRNA Delivery for Treatment of HER2+ Breast Cancer Xenografts in Mice by Prodrug CB1954 without General Toxicity
Open accessPublished version of a preprint
Abstract
Prodrugs are harmless until activated by a bacterial or viral gene product; they constitute the basis of gene-delivered prodrug therapies called GDEPT, which can kill tumors without major side effects. Previously, we utilized the prodrug CNOB (C16H7CIN2O4; not clinically tested) and enzyme HChrR6 in GDEPT to generate the drug MCHB (C16H9CIN2O2) in tumors. Extracellular vesicles (EVs) were used for directed gene delivery and HChrR6 mRNA as gene. Here, the clinical transfer of this approach is enhanced by: (i) use of CB1954 (tretazicar) for which safe human dose is established; HChrR6 can activate this prodrug. (ii) EVs delivered in vitro transcribed (IVT) HChrR6 mRNA, eliminating the potentially harmful plasmid transfection of EV producer cells we utilized previously; this has not been done before. IVT mRNA loading of EVs required several steps. Naked mRNA being unstable, we ensured its prodrug activating functionality at each step. This was not possible using tretazicar itself; we relied instead on HChrR6′s ability to convert CNOB into MCHB, whose fluorescence is easily visualizable. HChrR6 mRNA-translated product's ability to generate fluorescence from CNOB vicariously indicated its competence for tretazicar activation. (iii) Systemic IVT mRNA–loaded EVs displaying an anti-HER2 single-chain variable fragment (“IVT EXO-DEPTs”) and tretazicar caused growth arrest of human HER2+ breast cancer xenografts in athymic mice. As this occurred without injury to other tissues, absence of off-target mRNA delivery is strongly indicated. Many cancer sites are not amenable for direct gene injection, but current GDEPTs require this. In circumventing this need, a major advance in GDEPT applicability has been accomplished.
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“CB1954, as a prodrug, was employed, which showed better suppression of HER2 breast cancer cells after conversion into an active drug [134].”
From Exosome for mRNA delivery: Strategies and therapeutic applications (2024) · cites this paper as [134]
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“Forterre et al. developed in vitro transcribed (IVT) HChrR6 mRNA-exosomes and revealed selective uptake by HER2 cancer cells without toxicity to other cells and very insignificant compromise to bone marrow.”
From Exosome for mRNA delivery: Strategies and therapeutic applications (2024) · cites this paper as [134]
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Metadata
- Authors
- Forterre, A. V., Wang, J.-H., Delcayre, A., Kim, K., Green, C., Pegram, M. D., Jeffrey, S. S., & Matin, A. C.
- Affiliations
- Stanford Medicine (US)
- 2ExoThera LLC, Menlo Park, California.
- SRI International (US)
- Corresponding author
- Matin, A.C.
- Venue
- Molecular Cancer Therapeutics
- Published
- 2020-03-01
- Volume
- 19
- Issue
- 3
- Pages
- 858-867
- ISSN
- 1535-7163 (ISSN-L)
- 1538-8514
- PMC
- PMC7056535
- OpenAlex
- W2999926188
- Cited by
- 62
- References
- 56
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 13 · 2023: 13 · 2022: 10 · 2021: 8 · 2020: 6
- FWCI
- 3.00
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Cancer Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- HHS | NIH | National Center for Advancing Translational Sciences (UH3TR000902)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Keywords
- gene-directed enzyme prodrug therapy, extracellular vesicles, in vitro transcribed mRNA, CB1954, HER2-positive breast cancer, mRNA delivery, off-target toxicity
- MeSH terms
- Extracellular Vesicles, Animals, Bacterial Proteins, Breast Neoplasms, Female, Humans, Mice, Inbred BALB C, Mice, Nude, Prodrugs, RNA, Messenger, Tumor Cells, Cultured, Genetic Therapy, Apoptosis, Gene Transfer Techniques, Erb-b2 Receptor Tyrosine Kinases, Receptor, ErbB-2, Xenograft Model Antitumor Assays, Cell Proliferation, Mice
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