de Moura Ludmilla David, Ribeiro Lígia N M, de Carvalho Fabíola V, Rodrigues da Silva Gustavo H, Lima Fernandes Priscila C, Brunetto Sérgio Q, Ramos Celso D, Velloso Lício A, de Araújo Daniele R, de Paula Eneida
Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas-UNICAMP, Campinas 13083-862, SP, Brazil.
Institute of Biotechnology, Federal University of Uberlândia-UFU, Uberlândia 38405-319, MG, Brazil.
Pharmaceutics. 2021 Sep 24;13(10):1552. doi: 10.3390/pharmaceutics13101552.
Melanoma is the most aggressive skin carcinoma and nanotechnology can bring new options for its pharmacological treatment. Nanostructured lipid carriers (NLC) are ideal drug-delivery carriers for hydrophobic drugs, such as the antineoplastic docetaxel (DTX), and hybrid (NLC-in-hydrogel) systems are suitable for topical application. This work describes a formulation of NLC in xanthan-chitosan hydrogel containing lidocaine (LDC) with anticancer and analgesia effects. The optimized nanoparticles encapsulated 96% DTX and rheological analysis revealed inherent viscoelastic properties of the hydrogel. In vitro assays over murine fibroblasts (NIH/3T3) and melanoma cells (B16-F10), human keratinocytes (HaCaT) and melanoma cells (SK-MEL-103) showed reduction of docetaxel cytotoxicity after encapsulation in NLC and HGel-NLC. Addition of LDC to the hybrid system (HGel-NLC-LDC) increased cell death in tumor and normal cells. In vivo tests on C57BL/6J mice with B16-F10-induced melanoma indicated that LDC, NLC, HGel-NLC-LDC and NLC + HGel-LDC significantly inhibited tumor growth while microPET/SPECT/CT data suggest better prognosis with the hybrid treatment. No adverse effects were observed in cell survival, weight/feed-consumption or serum biochemical markers (ALT, AST, creatinine, urea) of animals treated with NLC or the hybrid system. These results confirm the adjuvant antitumor effect of lidocaine and endorse HGel-NLC-LDC as a promising formulation for the topical treatment of melanoma.
黑色素瘤是最具侵袭性的皮肤癌，而纳米技术可为其药物治疗带来新选择。纳米结构脂质载体（NLC）是疏水性药物（如抗肿瘤药物多西他赛（DTX））的理想药物递送载体，而混合（水凝胶包封NLC）系统适用于局部应用。本文描述了一种含利多卡因（LDC）的黄原胶-壳聚糖水凝胶中NLC的配方，该配方具有抗癌和镇痛作用。优化后的纳米颗粒包封了96%的DTX，流变学分析揭示了水凝胶固有的粘弹性特性。对小鼠成纤维细胞（NIH/3T3）和黑色素瘤细胞（B16-F10）、人角质形成细胞（HaCaT）和黑色素瘤细胞（SK-MEL-103）进行的体外试验表明，多西他赛包封于NLC和水凝胶包封NLC（HGel-NLC）后细胞毒性降低。向混合系统（HGel-NLC-LDC）中添加LDC会增加肿瘤细胞和正常细胞的死亡。对B16-F10诱导的黑色素瘤C57BL/6J小鼠进行的体内试验表明，LDC、NLC、HGel-NLC-LDC和NLC+HGel-LDC均显著抑制肿瘤生长，而微型PET/SPECT/CT数据表明混合治疗的预后更好。在用NLC或混合系统治疗的动物的细胞存活率、体重/饲料消耗量或血清生化标志物（ALT、AST、肌酐、尿素）方面未观察到不良反应。这些结果证实了利多卡因的辅助抗肿瘤作用，并认可HGel-NLC-LDC作为一种有前景的黑色素瘤局部治疗配方。
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