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Quenching Epigenetic Drug Resistance Using Antihypoxic Microparticles in Glioblastoma Patient-Derived Chips

Authors
Baek, SewoomYu, Seung EunDeng, Yu-HengLee, Yong-JaeLee, Dong GueKim, SurimYoon, SeonjinKim, Hye-SeonPark, JeongeunLee, Chan HeeLee, Jung BokKong, Hyun JoonKang, Seok-GuShin, Young MinSung, Hak-Joon
Issue Date
Apr-2022
Publisher
WILEY
Keywords
3D glioblastoma chip; drug resistance; epigenetic alterations; hypoxia rescue; oxygen-releasing microparticles
Citation
ADVANCED HEALTHCARE MATERIALS, v.11, no.8, pp.1 - 16
Journal Title
ADVANCED HEALTHCARE MATERIALS
Volume
11
Number
8
Start Page
1
End Page
16
URI
https://scholarworks.sookmyung.ac.kr/handle/2020.sw.sookmyung/151307
DOI
10.1002/adhm.202102226
ISSN
2192-2640
Abstract
Glioblastoma (GBM) is one of the most intractable tumor types due to the progressive drug resistance upon tumor mass expansion. Incremental hypoxia inside the growing tumor mass drives epigenetic drug resistance by activating nongenetic repair of antiapoptotic DNA, which could be impaired by drug treatment. Hence, rescuing intertumor hypoxia by oxygen-generating microparticles may promote susceptibility to antitumor drugs. Moreover, a tumor-on-a-chip model enables user-specified alternation of clinic-derived samples. This study utilizes patient-derived glioblastoma tissue to generate cell spheroids with size variations in a 3D microchannel network chip (GBM chip). As the spheroid size increases, epigenetic drug resistance is promoted with inward hypoxia severance, as supported by the spheroid size-proportional expression of hypoxia-inducible factor-1a in the chip. Loading antihypoxia microparticles onto the spheroid surface significantly reduces drug resistance by silencing the expression of critical epigenetic factor, resulting in significantly decreased cell invasiveness. The results are confirmed in vitro using cell line and patient samples in the chip as well as chip implantation into a hypoxic hindlimb ischemia model in mice, which is an unprecedented approach in the field.
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