CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience , National Center for Nanoscience and Technology , Beijing 100190 , P.R. China.
Center of Materials Science and Optoelectronics Engineering , University of Chinese Academy of Sciences , Beijing 100049 , P.R. China.
ACS Nano. 2019 Nov 26;13(11):13445-13455. doi: 10.1021/acsnano.9b07032. Epub 2019 Nov 4.
Platinum (Pt)-based chemotherapy is a broadly used therapeutic regimen against various cancers. However, the insufficient cellular uptake, deactivation by thiol-containing species and nonspecific distribution of cisplatin (CDDP) result in its low chemosensitivity as well as systemic side effects, which can largely constrain the employment of CDDP in clinical treatment. To circumvent these problems, in this study, polymeric nanoparticles were utilized to codeliver a water-soluble CDDP derivative, poly(γ,l-glutamic acid)-CDDP conjugate, and a naturally occurring compound derived from broccoli, sulforaphane, which can achieve efficient glutathione (GSH) depletion, to improve the accumulation of CDDP in cancer cells. Results show that compared with combinational treatment of CDDP and SFN, the nanoparticles were more effectively internalized and could significantly reduce GSH content in breast cancer cells, leading to a notable increase in DNA-bound Pt and DNA damage-induced apoptosis. Moreover, in an orthotopic breast cancer model, the nanoparticles achieved a significantly higher tumor accumulation and exhibited a more powerful antitumor activity. Finally, this nanoenhanced chemotherapy was further confirmed in a liver cancer model with high-expression of GSH. Taken together, this sulforaphane-based nanostrategy holds great promise to enhance the sensitivity and therapeutic efficacy of Pt-based chemotherapy.
铂类化疗是一种广泛应用于治疗各种癌症的治疗方案。然而，顺铂（CDDP）的细胞摄取不足、被含巯基的物质失活以及非特异性分布，导致其化疗敏感性低和全身副作用大，这在很大程度上限制了 CDDP 在临床治疗中的应用。为了克服这些问题，本研究利用聚合物纳米粒子共递送一种水溶性 CDDP 衍生物，聚（γ，L-谷氨酸）-CDDP 缀合物，以及一种来源于西兰花的天然化合物，即萝卜硫素，以实现高效的谷胱甘肽（GSH）耗竭，从而提高 CDDP 在癌细胞中的积累。结果表明，与 CDDP 和 SFN 的联合治疗相比，纳米粒子的内化效率更高，能够显著降低乳腺癌细胞中的 GSH 含量，导致 DNA 结合的 Pt 显著增加和 DNA 损伤诱导的细胞凋亡。此外，在原位乳腺癌模型中，纳米粒子实现了更高的肿瘤积累，并表现出更强的抗肿瘤活性。最后，在高表达 GSH 的肝癌模型中进一步证实了这种基于萝卜硫素的纳米策略能够提高铂类化疗的敏感性和治疗效果。综上所述，这种基于萝卜硫素的纳米策略具有提高铂类化疗敏感性和治疗效果的巨大潜力。
