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

Sewoom Baek, Seung Eun Yu, Yu Heng Deng, Yong Jae Lee, Dong Gue Lee, Surim Kim, Seonjin Yoon, Hye Seon Kim, Jeongeun Park, Chan Hee Lee, Jung Bok Lee, Hyun Joon Kong, Seok Gu Kang, Young Min Shin, Hak Joon Sung

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)


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.

Original languageEnglish
Article number2102226
JournalAdvanced Healthcare Materials
Issue number8
Publication statusPublished - 2022 Apr 20

Bibliographical note

Funding Information:
S.B., S.E.Y., Y.M.S., and H.‐J.S. contributed equally to this work. The work was supported by i) the Bio & Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MSIT) (2019R1A2C22010802 to H.‐J.S.), ii) the Korea Medical Device Development Fund Grant funded by the Ministry of Science and ICT, the Ministry of Trade, Industry and Energy, the Ministry of Health & Welfare, the Ministry of Food and Drug Safety (KMDF_PR_20200901_0152 to H.‐J.S.), iii) the National Research Foundation (NRF) funded by the Ministry of Science and ICT (NRF‐2020M2D9A2092372 to H.‐J.S.).

Publisher Copyright:
© 2022 The Authors. Advanced Healthcare Materials published by Wiley-VCH GmbH.

All Science Journal Classification (ASJC) codes

  • Biomaterials
  • Biomedical Engineering
  • Pharmaceutical Science


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