Department of Biochemistry, Soonchunhyang University College of Medicine, Cheonan 31151, Korea.
Department of Biochemistry, BK21FOUR Project2, College of Medicine, Soonchunhyang University, Cheonan 31151, Korea.
Int J Mol Sci. 2021 Feb 17;22(4):1976. doi: 10.3390/ijms22041976.
Anticancer drugs, such as fluorouracil (5-FU), oxaliplatin, and doxorubicin (Dox) are commonly used to treat colorectal cancer (CRC); however, owing to their low response rate and adverse effects, the development of efficient drug delivery systems (DDSs) is required. The cellular prion protein PrP, which is a cell surface glycoprotein, has been demonstrated to be overexpressed in CRC, however, there has been no research on the development of PrP-targeting DDSs for targeted drug delivery to CRC. In this study, PrP aptamer (Apt)-conjugated gold nanoparticles (AuNPs) were synthesized for targeted delivery of Dox to CRC. Thiol-terminated PrP-Apt was conjugated to AuNPs, followed by hybridization of its complementary DNA for drug loading. Finally, Dox was loaded onto the AuNPs to synthesize PrP-Apt-functionalized doxorubicin-oligomer-AuNPs (PrP-Apt DOA). The PrP-Apt DOA were spherical nanoparticles with an average diameter of 20 nm. Treatment of CRC cells with PrP-Apt DOA induced reactive oxygen species generation by decreasing catalase and superoxide dismutase activities. In addition, treatment with PrP-Apt DOA inhibited mitochondrial functions by decreasing the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha, complex 4 activity, and oxygen consumption rates. Compared to free Dox, PrP-Apt DOA decreased proliferation and increased apoptosis of CRC cells to a greater degree. In this study, we demonstrated that PrP-Apt DOA targeting could effectively deliver Dox to CRC cells. PrP-Apt DOA can be used as a treatment for CRC, and have the potential to replace existing anticancer drugs, such as 5-FU, oxaliplatin, and Dox.
抗癌药物，如氟尿嘧啶（5-FU）、奥沙利铂和阿霉素（Dox），常用于治疗结直肠癌（CRC）；然而，由于其反应率低和副作用，需要开发有效的药物传递系统（DDS）。细胞朊蛋白 PrP 是一种细胞表面糖蛋白，已被证明在 CRC 中过度表达，但是，尚未有研究开发针对 PrP 的 DDS 用于 CRC 的靶向药物传递。在本研究中，合成了 PrP 适体（Apt）-偶联的金纳米颗粒（AuNPs）用于将 Dox 靶向递送至 CRC。硫醇末端的 PrP-Apt 与 AuNPs 缀合，然后进行其互补 DNA 的杂交以进行药物加载。最后，将 Dox 加载到 AuNPs 上以合成 PrP-Apt 功能化阿霉素寡聚物-AuNPs（PrP-Apt DOA）。PrP-Apt DOA 是具有平均直径为 20nm 的球形纳米颗粒。用 PrP-Apt DOA 处理 CRC 细胞会通过降低过氧化氢酶和超氧化物歧化酶的活性来诱导活性氧的产生。此外，用 PrP-Apt DOA 处理会通过降低过氧化物酶体增殖物激活受体γ共激活因子 1-α、复合物 4 活性和耗氧量来抑制线粒体功能。与游离 Dox 相比，PrP-Apt DOA 更能降低 CRC 细胞的增殖并增加其凋亡。在本研究中，我们证明了 PrP-Apt DOA 靶向可以有效地将 Dox 递送至 CRC 细胞。PrP-Apt DOA 可用作 CRC 的治疗方法，并且有潜力替代现有的抗癌药物，如 5-FU、奥沙利铂和 Dox。
