Potent drug delivery enhancement of betulinic acid and NVX-207 into equine skin in vitro – a comparison between a novel oxygen flow-assisted transdermal application device and microemulsion gels.
Abstract: Gray horses are predisposed to equine malignant melanoma (EMM) with advancing age. Depending on the tumor's location and size, they can cause severe problems (e.g., defaecation, urination, feeding). A feasible therapy for EMM has not yet been established and surgical excision can be difficult depending on the location of the melanoma. Thus, an effective and safe therapy is needed. Naturally occurring betulinic acid (BA), a pentacyclic triterpene and its synthetic derivate, NVX-207 (3-acetyl-betulinic acid-2-amino-3-hydroxy-2-hydroxymethyl-propanoate) are known for their cytotoxic properties against melanomas and other tumors and have already shown good safety and tolerability in vivo. In this study, BA and NVX-207 were tested for their permeation potential into equine skin in vitro in Franz-type diffusion cell (FDC) experiments after incubation of 5 min, 30 min and 24 h, aiming to use these formulations for prospective in vivo studies as a treatment for early melanoma stages. Potent permeation was defined as reaching or exceeding the half maximal inhibitory concentrations (IC) of BA or NVX-207 for equine melanoma cells in equine skin samples. The active ingredients were either dissolved in a microemulsion (ME) or in a microemulsion gel (MEG). All of the formulations were transdermally applied but the oil-in-water microemulsion was administered with a novel oxygen flow-assisted (OFA) applicator (DERMADROP TDA). Results: All tested formulations exceeded the IC values for equine melanoma cells for BA and NVX-207 in equine skin samples, independently of the incubation time NVX-207 applied with the OFA applicator showed a significant time-dependent accumulation and depot-effect in the skin after 30 min and 24 h (P < 0.05). Conclusions: All tested substances showed promising results. Additionally, OFA administration showed a significant accumulation of NVX-207 after 30 min and 24 h of incubation. Further in vivo trials with OFA application are recommended.
© 2024. The Author(s).
Publication Date: 2024-05-16 PubMed ID: 38755639PubMed Central: PMC11097577DOI: 10.1186/s12917-024-04064-1Google Scholar: Lookup
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- Journal Article
- Comparative Study
Summary
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The research focuses on examining the delivery of betulinic acid (BA) and its synthetic derivative, NVX-207, into horse skin as a potential treatment for equine malignant melanoma (EMM), a common tumor in grey horses not yet treatable. The two substances were shown to effectively penetrate equine skin when applied with a novelty tool termed oxygen flow-assisted (OFA) applicator, with NVX-207 showing a time-dependent accumulation effect in skin after 30 minutes and 24 hours of incubation.
Background
- Malignant melanoma is a common tumor found in grey horses and as they age, the risk of developing EMM increases.
- EMM can cause severe problems depending on its location and size, affecting horse functions such as feeding, defecation, and urination. Unlike human melanoma, a complete cure for EMM is not available yet.
- BA and NVX-207 are natural substances with cytotoxic properties against melanoma and other tumors and have already shown good safety and tolerability when used on animals.
Procedure and Experimentation
- The researchers tested BA and NVX-207’s ability to permeate equine skin in vitro, using Franz-type diffusion cell experiments. They tested permeation at intervals of 5 minutes, 30 minutes, and 24 hours.
- BA and NVX-207 were either dissolved in a microemulsion (ME) or a microemulsion gel (MEG) for the experiments. Furthermore, the oil-in-water microemulsion was administered transdermally using a novel oxygen flow-assisted (OFA) applicator.
Results
- All the formulations exceeded the inhibitory concentrations (IC) of BA and NVX-207 for equine melanoma cells in equine skin samples, regardless of the incubation period.
- NVX-207, when applied with the OFA applicator, showed a significant accumulation in the skin after 30 minutes and 24 hours, indicating a depot-effect (long-lasting effect).
Conclusions and Future Recommendations
- All substances tested showed promising results in treating EMM, with the novel OFA tool showing a significant accumulation of NVX-207 in the skin after 30 minutes and 24 hours’ incubation.
- The research recommends further in vivo trials (that is, on live organisms) with OFA application to explore these findings in a real-life setting.
Cite This Article
APA
Zscherpe P, Kalbitz J, Weber LA, Paschke R, Mäder K, von Rechenberg B, Cavalleri JV, Meißner J, Klein K.
(2024).
Potent drug delivery enhancement of betulinic acid and NVX-207 into equine skin in vitro – a comparison between a novel oxygen flow-assisted transdermal application device and microemulsion gels.
BMC Vet Res, 20(1), 202.
https://doi.org/10.1186/s12917-024-04064-1 Publication
Researcher Affiliations
- Musculoskeletal Research Unit, Vetsuisse Faculty, University of Zurich, Winterthurerstrasse 260, Zurich, 8057, Switzerland.
- Biosolutions Halle GmbH, Weinbergweg 22, Halle (Saale), 06120, Germany.
- Clinic for Horses, University of Veterinary Medicine Hannover, Foundation, Bünteweg 9, Hannover, 30559, Germany.
- BioCenter, Martin Luther University Halle-Wittenberg, Weinbergweg 22, Halle (Saale), 06120, Germany.
- Institute of Pharmacy, Faculty of Biosciences, Martin-Luther-University Halle-Wittenberg, Wolfgang-Langenbeck-Strasse 4, Halle (Saale), 06120, Germany.
- Musculoskeletal Research Unit, Vetsuisse Faculty, University of Zurich, Winterthurerstrasse 260, Zurich, 8057, Switzerland.
- Center for Applied Biotechnology and Molecular Medicine, Vetsuisse Faculty, University of Zurich, Winterthurerstrasse 260, Zurich, 8057, Switzerland.
- Equine Internal Medicine, Clinical Centre for Equine Health and Research, Clinical Department for Small Animals and Horses, University of Veterinary Medicine Vienna (Vetmeduni), Veterinärplatz 1, Vienna, 1210, Austria. jessika.cavalleri@vetmeduni.ac.at.
- Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine Hannover, Foundation, Bünteweg 17, Hannover, 30559, Germany.
- Musculoskeletal Research Unit, Vetsuisse Faculty, University of Zurich, Winterthurerstrasse 260, Zurich, 8057, Switzerland.
MeSH Terms
- Animals
- Horses
- Betulinic Acid
- Pentacyclic Triterpenes
- Triterpenes / administration & dosage
- Administration, Cutaneous
- Emulsions
- Skin / metabolism
- Skin / drug effects
- Drug Delivery Systems / veterinary
- Gels
- Melanoma / drug therapy
- Melanoma / veterinary
- Oxygen / metabolism
- Skin Absorption
- Horse Diseases / drug therapy
- Propanolamines
Conflict of Interest Statement
The authors declare no conflict of interest.
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