Alginate formulations with high loads of zebularine and retinoic acid promote tissue growth and innervation and induce extensive epigenetic repatterning
The study presents the development of a small-molecule epigenetic regenerative therapy that combines a demethylating agent, zebularine, with retinoic acid, acting as a transcriptional activator, and an alginate carrier. Subcutaneously injected formulations based on 2% sodium alginate containing high loads of zebularine (240 mg/ml) and retinoic acid (0.8 mg/ml) promoted regenerative responses in a mouse model of ear pinna punch wound involving the restoration of tissue architecture, the growth of nerve and vessel networks, and extensive alterations in gene methylation and expression profiles with no adverse effects in the animals. Among the remarkable changes in global gene methylation are those in neurodevelopmental genes. In vitro studies showed rapid discharge of zebularine but not retinoic acid from the alginate formulations. Live ultrasound imaging demonstrated gradual absorption of the subcutaneously injected alginate formulations, which may explain the in vivo activity of retinoic acid following subcutaneous administration. Cell culture tests exhibited no significant cytotoxicity of the alginate formulations. The simplicity of composition, preparation, and administration of alginate-based drug formulations is a distinctive advantage. The effective induction of regenerative response, together with a high safety profile of subcutaneously administered pro-regenerative alginate formulations, opens the way to testing further regenerative therapies for hard-to-reach lesions.
Authors
- Paulina Słonimska (ORCID: https://orcid.org/0000-0001-5928-806X)
- Piotr Sass (ORCID: https://orcid.org/0000-0002-1199-8203)
- Anna Kostecka (ORCID: https://orcid.org/0000-0001-5705-0795)
- Jakub Baczyński-Keller (ORCID: https://orcid.org/0000-0002-0435-9972)
- Rafał Płatek (ORCID: https://orcid.org/0000-0001-8850-8674)
- Paweł Sachadyn (ORCID: https://orcid.org/0000-0002-5087-844X)
- Arkadiusz Piotrowski (ORCID: https://orcid.org/0000-0002-0823-0607)
- Milena Deptuła (ORCID: https://orcid.org/0000-0003-4875-770X)
- Maria Dzierżyńska (ORCID: https://orcid.org/0000-0003-0861-2514)
- Justyna Sawicka (ORCID: https://orcid.org/0000-0002-1506-3202)
- Magdalena Koczkowska (ORCID: https://orcid.org/0000-0001-9451-8027)
- David K. Crossman (ORCID: https://orcid.org/0000-0002-0981-169X)
- Paweł Sosnowski (ORCID: https://orcid.org/0000-0003-1506-0279)
- Sylwia Rodziewicz‐Motowidło (ORCID: https://orcid.org/0000-0002-4471-5951)
- Ryszard T. Smoleński (ORCID: https://orcid.org/0000-0002-0190-9414)
- Michał Pikuła (ORCID: https://orcid.org/0000-0001-7751-9781)
- Piotr Mariusz Skowron (ORCID: https://orcid.org/0000-0003-1345-3271)
- Oliwia Król (ORCID: https://orcid.org/0000-0001-5599-0417)
- Michael R. Crowley
Institutions
- Gdańsk University of Technology (PL)
- University of Alabama at Birmingham (US)
- University of Gdańsk (PL)
- Gdansk University of Physical Education and Sport (PL)
- Mossakowski Medical Research Institute, Polish Academy of Sciences (PL)
- Gdańsk Medical University (PL)
Publication Details
- Journal
- Scientific Reports
- Published
- 2025-10-29
- DOI
- https://doi.org/10.1038/s41598-025-22528-8
- Primary Topic
- Wound Healing and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Politechnika Gdańska
- Gdański Uniwersytet Medyczny
- Narodowe Centrum Badań i Rozwoju