Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka State, India.
Department of Research and Development, Glanbia Nutritionals, Twin Falls, ID 83301, USA.
Int J Pharm. 2020 Oct 15;588:119735. doi: 10.1016/j.ijpharm.2020.119735. Epub 2020 Aug 4.
Multimodal therapeutic approach has been gaining lot of attention for effective therapy of cancer. In the present work, a novel and unique pH responsive nanoplatform have been developed for multimodal therapy of glioblastoma using protein, biopolymer and MOFs. Lactoferrin (Lf) has been used as protein matrix for loading titanocene which was then enclosed in ZIF-8 framework along with 5-FU (ZIF-8@Lf-TC). The ZIF-8 was further coated with Lenalidomide-HA conjugate linked via hydrazone linkage (LND-HA@ZIF-8@Lf-TC). The developed nanocomposite was extensively characterized using spectroscopic, x-ray and electron microscopic techniques. The nanocomposites were evaluated for pH responsive drug release, stability, bio-interaction, and haemocompatibility which confirmed pH responsive nature of nanocomposite, stability and absence of any significant interaction with biomolecules. In obtained results for in vitro cell line studies performed in U87MG and RAW264.7 cells demonstrated enhanced cell cytotoxicity against cancer cells which was further supported by results of cellular ROS generation and surface ROS generation by nanocomposites. The Zinc and Lf mediated disruption of intracellular IL-6 and TNFα levels was observed with synthesized nanocomposites. They demonstrated pH responsive release of 5-FU and LND along with sustained release of both drugs in simulated medium. The LND-HA@ZIF-8@Lf-TC demonstrated superior cell growth supressing ability compared to ZIF-8@Lf-TC and ZIF-8. The nanocomposites were stable in biomimicking environment as well as did not show any significant interaction with RBC, plasma or CSF. The overall results suggest that LND-HA@ZIF-8@Lf-TC can be explored as promising platform for dual drug delivery mediated multimodal therapy of cancer.
多模态治疗方法在癌症的有效治疗中受到了广泛关注。在本工作中，开发了一种新颖独特的 pH 响应纳米平台，用于使用蛋白质、生物聚合物和 MOFs 对神经胶质瘤进行多模态治疗。乳铁蛋白 (Lf) 已被用作负载钛卡烯的蛋白质基质，然后将其与 5-FU（ZIF-8@Lf-TC）一起封闭在 ZIF-8 框架中。ZIF-8 进一步用通过腙键连接的来那度胺-HA 缀合物（LND-HA@ZIF-8@Lf-TC）进行包覆。使用光谱、X 射线和电子显微镜技术对所开发的纳米复合材料进行了广泛的表征。对纳米复合材料进行了 pH 响应药物释放、稳定性、生物相互作用和血液相容性的评估，证实了纳米复合材料的 pH 响应性质、稳定性以及与生物分子没有任何显著相互作用。在 U87MG 和 RAW264.7 细胞中进行的体外细胞系研究的结果表明，纳米复合材料对癌细胞的细胞毒性增强，这一结果得到了纳米复合材料细胞内 ROS 生成和表面 ROS 生成结果的支持。锌和 Lf 介导的细胞内 IL-6 和 TNFα 水平的破坏与合成的纳米复合材料有关。它们表现出 pH 响应性释放 5-FU 和 LND 以及在模拟介质中两种药物的持续释放。与 ZIF-8@Lf-TC 和 ZIF-8 相比，LND-HA@ZIF-8@Lf-TC 表现出优越的细胞生长抑制能力。纳米复合材料在仿生环境中稳定，并且与 RBC、血浆或 CSF 没有任何显著相互作用。总的来说，这些结果表明，LND-HA@ZIF-8@Lf-TC 可以作为有前途的平台，用于癌症的双重药物输送介导的多模态治疗。
