Crisóstomo Luiziana Cavalcante Costa Fernandes, Carvalho Genuína Stephanie Guimarães, Leal Luzia Kalyne Almeida Moreira, de Araújo Tamara Gonçalves, Nogueira Karina Alexandre Barros, da Silva Durcilene Alves, de Oliveira Silva Ribeiro Fábio, Petrilli Raquel, Eloy Josimar O
Faculty of Pharmacy, Dentistry and Nursing, Department of Pharmacy, Fortaleza Universidade Federal do Ceará, Fortaleza, CE, Brazil.
Center of Technology, Department of Chemical Engineering, Federal University of Ceará, Fortaleza, Brazil.
AAPS PharmSciTech. 2022 Aug 2;23(6):212. doi: 10.1208/s12249-022-02356-z.
Squamous cell carcinoma (SCC) represents 20% of cases of non-melanoma skin cancer, and the most common treatment is the removal of the tumor, which can leave large scars. 5-Fluorouracil (5FU) is a drug used in the treatment of SCC, but it is highly hydrophilic, resulting in poor skin penetration in topical treatment. Some strategies can be used to increase the cutaneous penetration of the drug, such as the combination of liposomes containing penetration enhancers, for instance, surfactants, associated with the use of microneedling. Thus, the present work addresses the development of liposomes with penetration enhancers, such as sorbtitan monolaurate, span 20, for topical application of 5-FU and associated or not with the use of microneedling for skin delivery. Liposomes were developed using the lipid film hydration, resulting in particle size, polydispersity index, zeta potential, and 5-FU encapsulation efficiency of 88.08 nm, 0.169, -12.3 mV, and 50.20%, respectively. The presence of span 20 in liposomes potentiated the in vitro release of 5-FU. MTT assay was employed for cytotoxicity evaluation and the IC values were 0.62, 30.52, and 24.65 μM for liposomes with and without span 20 and 5-FU solution, respectively after 72-h treatment. Flow cytometry and confocal microscopy analysis evidenced high cell uptake for the formulations. In skin penetration studies, a higher concentration of 5-FU was observed in the epidermis + dermis, corresponding to 1997.71, 1842.20, and 2585.49 ng/cm in the passive penetration and 3214.07, 2342.84, and 5018.05 ng/cm after pretreatment with microneedles, for solution, liposome without and with span 20, respectively. Therefore, herein, we developed a nanoformulation for 5-FU delivery, with suitable physicochemical characteristics, potent skin cancer cytotoxicity, and cellular uptake. Span 20-based liposomes increased the skin penetration of 5-FU in association of microneedling. Altogether, the results shown herein evidenced the potential of the liposome containing span 20 for topical delivery of 5-FU.
鳞状细胞癌（SCC）占非黑色素瘤皮肤癌病例的20%，最常见的治疗方法是切除肿瘤，但这可能会留下大的疤痕。5-氟尿嘧啶（5FU）是一种用于治疗SCC的药物，但它具有高度亲水性，导致局部治疗时皮肤渗透性差。可以采用一些策略来增加药物的皮肤渗透性，例如含有渗透促进剂（如表面活性剂）的脂质体与微针联合使用。因此，本研究致力于开发含有渗透促进剂（如山嵛酸单月桂酸酯、司盘20）的脂质体，用于5-FU的局部应用，并研究其是否与微针联合使用以实现皮肤给药。通过脂质膜水化法制备脂质体，所得脂质体的粒径、多分散指数、zeta电位和5-FU包封率分别为88.08 nm、0.169、-12.3 mV和50.20%。脂质体中司盘20的存在增强了5-FU的体外释放。采用MTT法进行细胞毒性评估，处理72小时后，含司盘20和不含司盘20的脂质体以及5-FU溶液的IC值分别为0.62、30.52和24.65 μM。流式细胞术和共聚焦显微镜分析表明制剂具有较高的细胞摄取率。在皮肤渗透研究中，在表皮+真皮中观察到较高浓度的5-FU，对于溶液、不含司盘20的脂质体和含司盘20的脂质体，被动渗透时分别为1997.71、1842.20和2585.49 ng/cm²，微针预处理后分别为3214.07、2342.84和5018.05 ng/cm²。因此，我们在此开发了一种用于5-FU递送的纳米制剂，其具有合适的理化特性、强大的皮肤癌细胞毒性和细胞摄取能力。基于司盘20的脂质体在与微针联合使用时增加了5-FU的皮肤渗透性。总之，本文所示结果证明了含司盘20的脂质体用于5-FU局部递送的潜力。
