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.
|Journal||Advanced Healthcare Materials|
|Publication status||Published - 2021 Jul 7|
Bibliographical noteFunding Information:
The authors would like to thank Laura Bendzick for assistance with patient ascites spheroid sample preparation, Han Seung Lee for help with SEM training and imaging, and Kateryna Artyushkova for assistance with XPS data interpretation. Parts of this work were carried out in the Characterization Facility, University of Minnesota, which receives partial support from the National Science Foundation through the MRSEC program. Research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health, United States, award number UL1TR000114. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This work was supported by the Dr. Ralph and Marian Falk Medical Research Trust Bank of America, N.A., the NIH (U54 CA210190), the Kwanjeong Educational Foundation (H.R.L.), a Doctoral Dissertation Fellowship from the Graduate School of the University of Minnesota (H.R.L.), the Research Experiences for Undergraduates (REU) Program of the National Science Foundation under award number DMR‐1852044, and through the University of Minnesota MRSEC under award number DMR‐1420013.
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All Science Journal Classification (ASJC) codes
- Biomedical Engineering
- Pharmaceutical Science