Department of Pharmaceutics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China.
Hospital of Integrated Traditional Chinese and Western Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing 210009, China; Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210023, China.
Int J Pharm. 2020 Jun 30;584:119432. doi: 10.1016/j.ijpharm.2020.119432. Epub 2020 May 19.
Niclosamide (NLM) has prominent antitumor activities on various kinds of cancer. In this study, we developed a novel niclosamide nanocrystals (NLM-NCs) stabilized by phosphate buffered saline (PBS) and poloxamer188 (P188). The formed NLM-NCs displayed 12,039 times solubility improvement (2.769 mg/mL) than that of free NLM and desired storage stability. Transmission electron microscope (TEM) observation illustrated NLM-NCs were needle-like shape. Differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD) analysis indicated that NLM-NCs were not anhydrate or any monohydrate but probable a polymorphic mixture. In vitro release evaluation manifested more than 95% NLM released in 48 h from NLM-NCs. In comparison to free NLM, NLM-NCs showed stronger cytotoxic effect on MDA-MB-231 cells and promoted cellular uptake. Wound healing assays indicated that NLM-NCs could inhibit cell migration and also decrease the expression of CD44 which is a marker of breast cancer stem cells. Overall, NLM-NCs were of raised solubility, feasible storage stability and desired killing effect for MDA-MB-231 cell, which revealed the impacts of NLM crystal form on its nanocrystals and provided a novel idea for the design of NLM antineoplastic formulation.
硝氯酚（NLM）对多种癌症具有显著的抗肿瘤活性。在这项研究中，我们开发了一种由磷酸盐缓冲盐水（PBS）和泊洛沙姆 188（P188）稳定的新型硝氯酚纳米晶体（NLM-NCs）。形成的 NLM-NCs 的溶解度比游离 NLM 提高了 12039 倍（2.769 mg/mL），并具有良好的储存稳定性。透射电子显微镜（TEM）观察表明 NLM-NCs 呈针状形状。差示扫描量热法（DSC）和 X 射线粉末衍射（XRPD）分析表明，NLM-NCs 既不是无水物也不是任何一水合物，而是可能的多晶混合物。体外释放评估表明，NLM-NCs 在 48 小时内释放超过 95%的 NLM。与游离 NLM 相比，NLM-NCs 对 MDA-MB-231 细胞表现出更强的细胞毒性作用，并促进细胞摄取。划痕愈合试验表明，NLM-NCs 可抑制细胞迁移，并降低乳腺癌干细胞标志物 CD44 的表达。总的来说，NLM-NCs 具有提高的溶解度、可行的储存稳定性和对 MDA-MB-231 细胞的理想杀伤作用，这揭示了 NLM 晶体形态对其纳米晶体的影响，并为 NLM 抗肿瘤制剂的设计提供了新的思路。
