ABSTRACT
This single-center, open label, dose escalation cohort study evaluated the safety and efficacy of various doses of intralesional injections of TGF-β1/COX-2 combined with histidine-lysine polypeptide (siRNA/HKP) nanoparticle silencing therapeutic in patients with cutaneous in situ squamous cell carcinoma. Twenty-five patients (mean age: 67, SD: 10 years; 52% men) with cutaneous in situ squamous cell carcinoma participated. TGF-β1/COX-2 siRNA/HKP nanoparticle therapeutic was injected weekly for up to 6 weeks based on the following dosing cohorts: 10 μg/treatment, 20 μg/treatment, 30 μg/treatment, 60 μg/treatment, and 120 μg/treatment. The primary endpoint was the proportion of subjects with complete histological clearance. Also evaluated were the incidence/severity of treatment emergent adverse events and serious adverse events and incidence/severity of Local Skin Response. Twenty-five subjects received the TGF-β1/COX-2 siRNA/HKP nanoparticle therapeutic; 19 (76%) achieved histological clearance. In the 30 μg/treatment group and 60 μg/treatment group, percent cleared was 80% and 100%, respectively. Five subjects had 7 adverse events. There were no severe or serious adverse events; none led to treatment discontinuation, study interruption, or were related to the investigational product. Local skin response was none to minimal in most subjects, with improvement observed in the 10 μg/treatment, 20 μg/treatment, 30 μg/treatment, and 60 μg/treatment cohorts. Intralesional TGF-β1/COX-2 siRNA/HKP nanoparticle therapeutic injections appear to be noninvasive, safe, and efficacious in treating cutaneous in situ squamous cell carcinoma. The recommended doses for future study of the investigational product are 30 μg/treatment and 60 μg/treatment. J Drugs Dermatol. 2022;21(5):472-477. doi:10.36849/JDD.6384.
Subject(s)
Carcinoma, Squamous Cell , Skin Neoplasms , Adult , Aged , Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/genetics , Cohort Studies , Cyclooxygenase 2 , Female , Humans , Male , RNA, Small Interfering/adverse effects , RNA, Small Interfering/genetics , Skin Neoplasms/drug therapy , Skin Neoplasms/genetics , Transforming Growth Factor beta1/genetics , Transforming Growth Factor beta1/therapeutic useABSTRACT
Macrophages are mononuclear phagocytes established during embryogenesis and derived from the yolk sac or the fetal liver but also recruited from the blood and bone marrow under proliferative inflammatory conditions (such as tissue repair). Most importantly, they take on distinct phenotypes and functions crucial to healing upon localization in the wound. The objective of this review is to summarize recent findings in regard to the cellular mechanisms of macrophages and chronic wounds. Advances in the potential use of macrophage therapy have arisen based, in part, on the fact that early recruitment of macrophages is critical to wound healing. Higher quality evidence is needed to support the use of macrophage therapy for chronic wound types, as is a better understanding of the signaling related to macrophage polarization, activation of macrophages, and their effect of mechanisms of repair. An evaluation of the currently available research on mechanism of action may lead to a better understanding of the signaling processes of the many macrophage phenotypes, as well as their roles and outcomes in wound healing, which could then guide the development and eventual widespread use of macrophage therapies.
Subject(s)
Macrophages/physiology , Wound Healing/physiology , Wounds and Injuries/therapy , Animals , Cytokines/metabolism , Disease Models, Animal , Humans , Inflammation Mediators/therapeutic use , Intercellular Signaling Peptides and Proteins , Macrophage Activation , Macrophages/cytology , Macrophages/drug effects , Molecular Targeted Therapy , Neovascularization, Physiologic , Phenotype , Wounds and Injuries/pathologyABSTRACT
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 ß1 (TGF-ß1) 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-ß1 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-ß1 and COX-2, for localized fat reduction, offering a potential minimally invasive alternative to current fat reduction methods.