1. Novel injectable polypeptide nanoparticle encapsulated siRNA targeting TGF-β1 and COX-2 for localized fat reduction I: Preclinical in vitro and animal models.
- Author
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Nestor MS, Hetzel J, Awad N, Bhupalam V, Lu P, and Molyneaux M
- Subjects
- Animals, Swine, Mice, Obesity metabolism, Obesity therapy, Adipogenesis drug effects, Disease Models, Animal, Gene Silencing drug effects, Subcutaneous Fat drug effects, Subcutaneous Fat metabolism, RNA, Small Interfering administration & dosage, RNA, Small Interfering pharmacology, Transforming Growth Factor beta1 metabolism, Transforming Growth Factor beta1 genetics, Nanoparticles administration & dosage, Cyclooxygenase 2 metabolism, Cyclooxygenase 2 genetics, Swine, Miniature, Peptides administration & dosage, Adipocytes drug effects
- Abstract
Background: Obesity and localized fat accumulation continue to drive the demand for minimally invasive body contouring technologies including injectable compounds for local fat reduction. siRNA offers a potential for an injectable to specifically target and silence genes involved in adipogenesis with minimal inflammatory side effects., Aims: This study evaluates the efficacy of STP705, an injectable containing siRNA encapsulated within histidine-lysine polypeptide (HKP) nanoparticles targeting transforming growth factor β1 (TGF-β1) and cyclooxygenase-2 (COX-2), crucial mediators in adipocyte differentiation and fat retention, using in vitro, porcine, and murine models., Methods: In vitro experiments on mouse preadipocytes and in vivo trials using Diet Induced Obese (DIO) mice and Yucatan minipigs were conducted to assess the gene silencing efficiency, tissue localization, pharmacodynamics, and safety profile of STP705., Results: STP705 effectively reduced the expression of TGF-β1 and COX-2, with a notable decrease in adipocyte volume and lipid content without adverse systemic effects. In DIO mice, the HKP-siRNA complex demonstrated precise localization to injected adipose tissue, maintaining significant gene silencing, and detectable levels of siRNA for up to 14 days post-administration. Similar results in minipigs showed a significant reduction in subcutaneous adipose tissue thickness., Conclusion: The results of these studies support the use of targeted siRNA therapy specifically targeting TGF-β1 and COX-2, for localized fat reduction, offering a potential minimally invasive alternative to current fat reduction methods., (© 2024 The Author(s). Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.)
- Published
- 2024
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