School of Pharmaceutical Sciences, and Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiang'an South Road, Xiamen, Fujian 361102, China.
J Colloid Interface Sci. 2018 Oct 1;527:141-150. doi: 10.1016/j.jcis.2018.05.033. Epub 2018 May 15.
The abundance of B cell lymphoma gene 2 (Bcl-2) is closely correlated with the resistance of cancer cells to chemotherapeutic agents, and a peptide derived from orphan nuclear receptor Nur77 can convert Bcl-2 from a protector to a killer of cancer cells. However, successful application of the Bcl-2-converting peptide to treat drug-resistant cancer cells depends on an efficient delivery carrier. Mesoporous silica nanoparticles (MSNs) have been extensively studied as promising candidates for small molecule drug delivery. However, the effective encapsulation and intracellular delivery of peptides using small pore-sized MSNs still remain a great technical challenge. In this paper, an effective delivery platform for Bcl-2-converting peptide was fabricated by us to treat multidrug resistant-cancer cells via tuning the surface functionality of macroporous silica nanoparticles. The resulting large-sized pore silica nanoparticles, especially those modified with thiol group, exhibited the high Bcl-2-converting peptide-loading efficiency of over 40%. Moreover, the peptide induced MCF7/DOX cells into apoptotic status by penetrating cytomembrane into mitochondria and being bound with Bcl-2 to expose the BH3 domain with the aid of various surface functionalities-decorated MSNs. In particular, amine-modified surface of MSNs caused the greater influence on the cell apoptosis-inducing effects of peptide in comparison with other functionalities-modified ones. Taken together, our study, for the first time, demonstrates a special approach towards pore size and surface functionality-collectively modulated silica-based nanostructural material for effective delivery of bio-macromolecules (e.g., Bcl-2-converting peptide) to treat the multidrug resistant-cancer cells with elevated Bcl-2 levels.
B 细胞淋巴瘤基因 2（Bcl-2）的丰度与癌细胞对化疗药物的耐药性密切相关，孤儿核受体 Nur77 衍生的肽可以将 Bcl-2 从癌细胞的保护者转化为杀手。然而，将 Bcl-2 转化肽成功应用于治疗耐药性癌细胞取决于有效的递送载体。介孔硅纳米粒子（MSNs）已被广泛研究作为小分子药物递送的有前途的候选物。然而，使用小孔径 MSNs 有效包封和细胞内递肽仍然是一个巨大的技术挑战。在本文中，我们通过调节大孔硅纳米粒子的表面功能来构建有效的 Bcl-2 转化肽递药平台，以治疗多药耐药性癌细胞。所得的大孔硅纳米粒子，特别是那些经过巯基修饰的硅纳米粒子，表现出超过 40%的高 Bcl-2 转化肽载药效率。此外，肽在各种表面功能化修饰的 MSNs 的帮助下，通过穿透细胞质进入线粒体并与 Bcl-2 结合，暴露出 BH3 结构域，从而诱导 MCF7/DOX 细胞进入凋亡状态。特别是，与其他功能化修饰的 MSNs 相比，MSNs 的胺修饰表面对肽诱导细胞凋亡的影响更大。总之，我们的研究首次证明了一种特殊的方法，即通过孔尺寸和表面功能的联合调节，用于有效递送生物大分子（例如，Bcl-2 转化肽），以治疗 Bcl-2 水平升高的多药耐药性癌细胞。
