PUBLICATION
Safety of bovine milk derived extracellular vesicles used for delivery of RNA therapeutics in zebrafish and mice
- Authors
- Matsuda, A., Moirangthem, A., Angom, R.S., Ishiguro, K., Driscoll, J., Yan, I.K., Mukhopadhyay, D., Patel, T.
- ID
- ZDB-PUB-191227-3
- Date
- 2019
- Source
- Journal of applied toxicology : JAT 40(5): 706-718 (Journal)
- Registered Authors
- Angom, Ramcharan Singh, Mukhopadhyay, Debabrata
- Keywords
- extracellular vesicles, immune cell, mouse, safety, toxicology, zebrafish
- MeSH Terms
-
- Animals
- Cattle
- Embryo, Nonmammalian/drug effects
- Embryonic Development
- Extracellular Vesicles/genetics
- Extracellular Vesicles/immunology
- Extracellular Vesicles/metabolism*
- Female
- Gene Transfer Techniques*
- Male
- Mice, Inbred C57BL
- Milk/immunology
- Milk/metabolism
- Milk/toxicity*
- RNA, Small Interfering/genetics
- RNA, Small Interfering/immunology
- RNA, Small Interfering/metabolism
- RNA, Small Interfering/toxicity*
- RNAi Therapeutics*
- Risk Assessment
- Spleen/drug effects
- Spleen/immunology
- Spleen/metabolism
- Toxicity Tests, Acute
- Zebrafish/embryology
- PubMed
- 31877238 Full text @ J. Appl. Toxicol.
Citation
Matsuda, A., Moirangthem, A., Angom, R.S., Ishiguro, K., Driscoll, J., Yan, I.K., Mukhopadhyay, D., Patel, T. (2019) Safety of bovine milk derived extracellular vesicles used for delivery of RNA therapeutics in zebrafish and mice. Journal of applied toxicology : JAT. 40(5):706-718.
Abstract
Extracellular vesicles are endogenous biological nanoparticles that have potential for use as therapeutic nanoparticles or as delivery vehicles for therapeutic agents. Milk nanovesicles (MNV) are extracellular vesicles isolated from bovine milk that have been explored for use as delivery vehicles for RNA therapeutics such as small interfering RNA (siRNA). We performed in vivo toxicological studies of MNV or therapeutic MNV (tMNV) loaded with siRNA as a prelude to their clinical use. Development toxicity was assessed in zebrafish embryos. Acute toxicity was assessed in both mice and zebrafish whereas safety, biochemical, histological and immune effects after multiple dosing were assessed in mice. Zebrafish embryo hatching was accelerated with MNV and tMNV. While acute toxicity or effects on mortality were not observed in zebrafish, developmental effects were observed at high concentrations of MNV. There was a lack of discernable toxicity, mortality and systemic inflammatory or immunological responses in mice following administration of either MNVs or tMNVs. The tolerability and lack of discernable developmental or systemic in vivo toxicity support their use as biological nano-therapeutics. Adoption of a standardized protocol for systematic analysis of in vivo safety and toxicity will facilitate preclinical assessment of EV based formulations for therapeutic use.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping