Kikka Maeda (Department of Materials Science, Graduate School of Pure an Applied Sciences, University of Tsukuba,) ; Babita Shashni (Organization for Research and Development of Innovative Science and Technology, Kansai University, Department of Materials Science, Graduate School of Pure an Applied Sciences, University of Tsukuba) ; Hirofumi Matsui (Division of Gastroenterology, Faculty of Medicine, University of Tsukuba,) ; Yukio Nagasaki (Department of Materials Science, Graduate School of Pure an Applied Sciences, University of Tsukuba)
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Citation
Description:
(abstract)4-Phenylbutyric acid (PBA) is a small molecule with promising therapeutic potential for treating various diseases, including cancer and neurodegenerative disorders, due to its dual ability to reduce endoplasmic reticulum stress and inhibit histone deacetylases. However, its clinical application is hindered by rapid clearance from the body, necessitating frequent dosing that increases the risk of adverse effects. To address these limitations, we developed a nanoparticle-based prodrug (NanoPBA) utilizing the amphiphilic block copolymer poly(ethylene glycol)-b-poly(vinyl 4-phenylbutyrate) [PEG-b-P(VPBA)]. This system self-assembles into micelles, enabling controlled and sustained PBA delivery. The synthesis and characterization of NanoPBA revealed its high stability under physiological conditions and enzyme-responsive PBA release. NanoPBA demonstrated a controlled release profile in vitro, reducing burst release while maintaining therapeutic efficacy. Cytotoxicity assays using normal cell lines, including endothelial cells (BAEC), macrophages (RAW264.7), and rat gastric cells (RGM-1), showed minimal cytotoxic effects compared to the parent low-molecular-weight PBA. Furthermore, in vivo studies conducted in healthy C57/BL6J mice confirmed NanoPBA’s biocompatibility, with no significant adverse effects observed at therapeutic doses ranging from 200 to 500 mg-PBA/kg via oral administration. In conclusion, NanoPBA offers a controlled release profile, enhanced biocompatibility, and reduced toxicity, addressing the limitations associated with conventional PBA administration. These attributes make NanoPBA a promising candidate for improving the therapeutic efficacy and safety of PBA in clinical applications, particularly in diseases where maintaining consistent drug levels is crucial for treatment outcomes.
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Keyword: 4-Phenylbutyric acid, Endoplasmic reticulum stress modulation, Amphiphilic block copolymer micelle, Chemical chaperone, Prodrug of short chain fatty acid, Sustained drug release
Date published: 2025-12-31
Publisher: Taylor & Francis
Journal:
- Science and Technology of Advanced Materials (ISSN: 14686996) vol. 26 2482512
Funding:
Manuscript type: Author's version (Accepted manuscript)
MDR DOI: https://doi.org/10.48505/nims.5383
First published URL: https://doi.org/10.1080/14686996.2025.2482512
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Updated at: 2025-07-16 16:17:05 +0900
Published on MDR: 2025-04-02 18:09:44 +0900
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