Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Damanhour University, Damanhour, 22514, Beheira, Egypt.
J Biomed Nanotechnol. 2022 Jan 1;18(1):97-111. doi: 10.1166/jbn.2022.3217.
Itraconazole (ITC), an antifungal drug with anticancer activity, shows potential for oral treatment of skin cancer. There is clinical need for topical ITC for treating low-risk skin carcinogenesis. Our objective was to develop ITC nanoformulations with enhanced anticancer efficacy. Lipid nanocapsules (LNC), either unmodified (ITC/LNC) or modified with the amphiphiles miltefosine (ITC/MF-LNC) or the lipopeptide biosurfactant surfactin (ITC/SF-LNC) as bioactive additives were developed. LNC formulations showed high ITC entrapment efficiency (>98%), small diameter (42-45 nm) and sustained ITC release. Cytotoxicity studies using malignant SCC 9 cells and normal human fibroblasts (NHF) demonstrated significant enhancement of ITC anticancer activity and selectivity for cancer cells by the LNC formulations and a synergistic ITC-amphiphile interaction improving the combination performance. Treatment of intradermal tumor-bearing mice with the ITC nanoformulation gels compared with ITC and 5-FU gels achieved significant tumor growth inhibition that was remarkably enhanced by ITC/MF-LNC and ITC/SF-LNC as well as recovery of skin architecture. Molecularly, tumoral expression of Ki-67 and cytokeratin proliferative proteins was significantly suppressed by LNC formulations, the suppressive effect on cytokeratins was superior to that of 5-FU. These findings provide new evidence for effective topical treatment of low-risk skin carcinogenesis utilizing multiple approaches that involve drug repurposing, nanotechnology, and bioactive amphiphiles as formulation enhancing additives.
伊曲康唑（ITC）是一种具有抗癌活性的抗真菌药物，显示出在口服治疗皮肤癌方面的潜力。临床上需要局部使用 ITC 来治疗低风险皮肤癌前病变。我们的目标是开发具有增强抗癌疗效的 ITC 纳米制剂。开发了未修饰的脂质纳米胶囊（ITC/LNC）或用两亲物米替福新（ITC/MF-LNC）或脂肽生物表面活性剂表面活性剂（ITC/SF-LNC）修饰的脂质纳米胶囊（ITC/LNC）作为生物活性添加剂。LNC 制剂显示出高 ITC 包封效率（>98%）、小直径（42-45nm）和持续的 ITC 释放。使用恶性 SCC 9 细胞和正常人类成纤维细胞（NHF）的细胞毒性研究表明，LNC 制剂显著增强了 ITC 的抗癌活性和对癌细胞的选择性，并且 ITC-两亲物相互作用具有协同性，提高了联合性能。与 ITC 和 5-FU 凝胶相比，用 ITC 纳米制剂凝胶治疗真皮内荷瘤小鼠实现了显著的肿瘤生长抑制，ITC/MF-LNC 和 ITC/SF-LNC 的作用更为显著，并且恢复了皮肤结构。分子水平上，LNC 制剂显著抑制了肿瘤 Ki-67 和细胞角蛋白增殖蛋白的表达，对细胞角蛋白的抑制作用优于 5-FU。这些发现为利用药物再利用、纳米技术和生物活性两亲物作为制剂增强添加剂的多种方法为低风险皮肤癌前病变提供了有效的局部治疗提供了新的证据。
