Department of Chemical Engineering and Materials Science, University of Minnesota, Minneapolis, MN, 55455, USA.
Department of Chemical and Biomolecular Engineering, Yonsei University, Seoul, 03722, Republic of Korea.
Adv Healthc Mater. 2021 Jul;10(13):e2001368. doi: 10.1002/adhm.202001368. Epub 2021 May 29.
Advanced stage ovarian cancer is challenging to treat due to widespread seeding of tumor spheroids throughout the mesothelial lining of the peritoneal cavity. In this work, a therapeutic strategy using graphene nanoribbons (GNR) functionalized with 4-arm polyethylene glycol (PEG) and chlorin e6 (Ce6), a sonosensitizer, to target metastatic ovarian cancer spheroids is reported. GNR-PEG-Ce6 adsorbs onto the spheroids and disrupts their adhesion to extracellular matrix proteins or LP-9 mesothelial cells. Furthermore, for spheroids that do adhere, GNR-PEG-Ce6 delays spheroid disaggregation and spreading as well as mesothelial clearance, key metastatic processes following adhesion. Owing to the sonodynamic effects of Ce6 and its localized delivery via the biomaterial, GNR-PEG-Ce6 can kill ovarian cancer spheroids adhered to LP-9 cell monolayers when combined with mild ultrasound irradiation. The interaction with GNR-PEG-Ce6 also loosens cell-cell adhesions within the spheroids, rendering them more susceptible to treatment with the chemotherapeutic agents cisplatin and paclitaxel, which typically have difficulty in penetrating ovarian cancer spheroids. Thus, this material can facilitate effective chemotherapeutic and sonodynamic combination therapies. Finally, the adhesion inhibiting and sonodynamic effects of GNR-PEG-Ce6 are also validated with tumor spheroids derived from the ascites fluid of ovarian cancer patients, providing evidence of the translational potential of this biomaterial approach.
晚期卵巢癌由于肿瘤球体广泛播散到腹腔的间皮衬里而难以治疗。在这项工作中，报道了一种使用功能化有 4 臂聚乙二醇（PEG）和氯乙酮（Ce6）的石墨烯纳米带（GNR）的治疗策略，Ce6 是一种声敏剂，用于靶向转移性卵巢癌球体。GNR-PEG-Ce6 吸附在球体上，并破坏它们与细胞外基质蛋白或 LP-9 间皮细胞的黏附。此外，对于已经黏附的球体，GNR-PEG-Ce6 会延迟球体的解聚和扩散以及间皮细胞的清除，这是黏附后关键的转移过程。由于 Ce6 的声动力学效应及其通过生物材料的局部递送，GNR-PEG-Ce6 在与温和超声辐射联合使用时，可以杀死黏附在 LP-9 细胞单层上的卵巢癌细胞球体。与 GNR-PEG-Ce6 的相互作用还会使球体内部的细胞-细胞黏附松动，使它们更容易受到顺铂和紫杉醇等化疗药物的治疗，这些药物通常难以穿透卵巢癌细胞球体。因此，这种材料可以促进有效的化疗和声动力学联合治疗。最后，还验证了 GNR-PEG-Ce6 的黏附抑制和声动力学效应与源自卵巢癌患者腹水的肿瘤球体，为这种生物材料方法的转化潜力提供了证据。
