School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiang'an South Road, Xiamen, Fujian, 361102, China.
School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiang'an South Road, Xiamen, Fujian, 361102, China.
Mater Sci Eng C Mater Biol Appl. 2020 Mar;108:110386. doi: 10.1016/j.msec.2019.110386. Epub 2019 Nov 5.
Therapeutic peptide, NuBCP-9 (N9) as a Bcl-2 functional converter, has been demonstrated to have the remarkable anticancer efficiency in Bcl-2-abundant cancer. However, it faced technical challenges in clinical use, such as the low bioavailability, the easily-destroyed bio-stability, and the insusceptibility to cellular interior. With the potential of mesoporous silica nanoparticles (MSNs) as the promising delivery vehicle of therapeutic macromolecules, we developed a kind of MSNs with the surface coating of folic acid (FA) for cancer cell targeting and with the macropore loading of N9 peptide for cancer therapy. Our results showed that the functional MSNs had the relatively greater biosafety than the naked MSNs in zebrafish models, leading to less than 30% embryo of death at 200 μg/ml, which could further specifically target the folate receptor (FR)-overexpressed cervical cancer HeLa cells instead of FR-negative normal embryonic kidney HEK 293T cells in a FA-competitive manner. N9 peptide with the delivery of functional MSNs could be internalized by HeLa cells, and co-localized with mitochondria in a Bcl-2-dependent manner. Moreover, N9 peptide delivered by FA-modified MSNs displayed the excellent anticancer efficiency with great selectivity, inducing approximately 52% HeLa cells into apoptosis. In summary, our results illustrated the potential of functional MSNs with large pore size as an efficient nanocarrier for the intracellular delivery of peptide drugs with targeting proteins to realize cancer therapy.
治疗性肽 NuBCP-9（N9）作为一种 Bcl-2 功能转化物，已被证明在 Bcl-2 丰富的癌症中具有显著的抗癌效率。然而，它在临床应用上面临一些技术挑战，如生物利用度低、生物稳定性易被破坏以及对细胞内部的不敏感性。鉴于介孔硅纳米粒子（MSNs）作为治疗性大分子的有前途的递送载体的潜力，我们开发了一种表面涂覆有叶酸（FA）的 MSNs，用于癌细胞靶向，并通过大孔装载 N9 肽进行癌症治疗。我们的结果表明，与裸 MSNs 相比，功能化 MSNs 在斑马鱼模型中具有相对更大的生物安全性，导致在 200μg/ml 时不到 30%的胚胎死亡，这可以通过 FA 竞争方式特异性靶向叶酸受体（FR）过表达的宫颈癌 HeLa 细胞，而不是 FR 阴性的正常胚胎肾 HEK 293T 细胞。载有 N9 肽的功能化 MSNs 可以被 HeLa 细胞内化，并与线粒体在 Bcl-2 依赖性方式下共定位。此外，FA 修饰的 MSNs 递送的 N9 肽表现出出色的抗癌效率和高选择性，诱导约 52%的 HeLa 细胞进入凋亡。总之，我们的结果表明，具有大孔径的功能化 MSNs 作为一种有效的纳米载体，可用于将靶向蛋白的肽类药物递送到细胞内，从而实现癌症治疗。
