Rodrigues Matilde R, Pires Patrícia C, Melero Ana, Guillot Antonio José, Borrego-Sánchez Ana, Sesarman Alina, Banciu Manuela, Veiga Francisco, Paiva-Santos Ana Cláudia
Department of Pharmaceutical Technology, Faculty of Pharmacy of the University of Coimbra, University of Coimbra, Azinhaga de Santa Comba, 3000-548, Coimbra, Portugal.
Department of Pharmaceutical Technology, Faculty of Pharmacy of the University of Coimbra, University of Coimbra, Azinhaga de Santa Comba, 3000-548, Coimbra, Portugal; REQUIMTE/LAQV, Group of Pharmaceutical Technology, Faculty of Pharmacy of the University of Coimbra, University of Coimbra, 3000-548, Coimbra, Portugal; RISE-Health, Department of Medical Sciences, Faculty of Health Sciences, University of Beira Interior, Av. Infante D. Henrique, 6200-506, Covilhã, Portugal.
Eur J Pharmacol. 2025 Oct 5;1004:177992. doi: 10.1016/j.ejphar.2025.177992. Epub 2025 Jul 25.
the repurposing of non-steroidal anti-inflammatory drugs like ketoprofen (KET) has shown significant potential in melanoma treatment, with previously demonstrated anticancer properties. However, KET's low water solubility hinders its formulation at high concentrations.
to overcome this challenge, KET-loaded oil-in-water nanoemulsions were developed and optimized, for the topical treatment of melanoma.
formulations containing hydrophobic surfactants Capryol® 90, Lauroglycol™ 90, or Plurol® Diisostearique, hydrophilic surfactant Tween® 80, and cosurfactant/cosolvent Transcutol® were developed using spontaneous emulsification, and characterized in what concerned droplet size, polydispersity index (PDI), zeta potential, pH, stability, in vitro drug release, ex vivo drug permeation, and in vitro therapeutic efficacy and safety assessment.
optimized formulations achieved a high drug loading, small (139.1-170.5 nm) and reasonably homogeneous (PDI 0.240-0.292) droplet sizes, neutral zeta potential (-6.38 to - 9.40 mV), and a skin compatible pH (around 4). Additionally, a controlled and high cumulative in vitro drug release was achieved for selected compositions, with biphasic characteristics (initial burst release followed by a more sustained release), as well as effective ex vivo skin permeation and retention, and good real-time stability. Optimized nanoemulsions significantly reduced B16.F10 murine melanoma cell viability in in vitro cytotoxicity assays, having an enhanced effect when compared to the free drug.
therefore, novel KET-loaded nanoemulsions were successfully developed, combining drug repurposing and a relevant scalability potential. Future research should explore these nanoplatforms' potential in in vivo models, investigating the possible synergy when combined with UVA radiation.
像酮洛芬（KET）这样的非甾体抗炎药的重新利用在黑色素瘤治疗中已显示出巨大潜力，其抗癌特性先前已有证明。然而，KET的低水溶性阻碍了其高浓度制剂的制备。
为克服这一挑战，开发并优化了载有KET的水包油纳米乳剂，用于黑色素瘤的局部治疗。
使用自发乳化法开发了含有疏水性表面活性剂Capryol® 90、Lauroglycol™ 90或Plurol® Diisostearique、亲水性表面活性剂吐温® 80以及助表面活性剂/助溶剂Transcutol®的制剂，并对其粒径、多分散指数（PDI）、zeta电位、pH值、稳定性、体外药物释放、离体药物渗透以及体外治疗效果和安全性评估进行了表征。
优化后的制剂实现了高载药量、小粒径（139.1 - 170.5 nm）且粒径较为均匀（PDI为0.240 - 0.292）、中性zeta电位（-6.38至 - 9.40 mV）以及与皮肤相容的pH值（约为4）。此外，选定的组合物实现了可控且高的体外药物累积释放，具有双相特征（初始突释后接着是更持续的释放），以及有效的离体皮肤渗透和滞留，并且具有良好的实时稳定性。在体外细胞毒性试验中，优化后的纳米乳剂显著降低了B16.F10小鼠黑色素瘤细胞的活力，与游离药物相比具有增强的效果。
因此，成功开发了新型载有KET的纳米乳剂，将药物重新利用与相关的可扩展性潜力相结合。未来的研究应探索这些纳米平台在体内模型中的潜力，研究与紫外线A辐射联合时可能的协同作用。
