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

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.

Stimuli-responsive ferroptosis for cancer therapy

“…Utilizing this mechanism can circumvent the major hurdles faced by conventional apoptosis-based cancer therapy, such as adaptive drug resistance, a high recurrence rate, and inefficient drug targeting to treat refractory cancers. For example, the lack of drug-targeting receptors (typically overexpressed in other cancer types) in triple-negative breast cancer, 90 and epigenetic multi-drug resistance accompanied by significant recurrence rates of glioblastoma, 91 colorectal cancer, 92 and hepatocellular carcinoma 51 make them highly resistant to apoptosis-based therapy but still susceptible to ferroptosis. 93 Careful activation and modulation of ferroptosis can provide a strategy for patient-customized on-demand cancer therapy.…”

Tumor-on-a-chip model for advancement of anti-cancer nano drug delivery system

“…TOCs are promising for reproducing these conditions in vitro. For example, Baek et al evaluated the effect of the anti-hypoxic microparticles in a 3D patient-derived glioblastoma spheroid-loaded microchannel network chip (GBM-chip) [ 62 ]. They first concluded a new mechanistic insight into the effects of hypoxia on epigenetic alterations and consequent progressive drug resistance by the GBM-chip.…”

“…Every step can be influenced by varied aspects development, toxicity evaluation, and so on. As cancer has become one of the most serious causes of death this century, the use of TOCs to model anticancer drug responses has attracted the attention of many researchers [52][53][54][55][56][57][58][59][60][61][62][63][64]. TOCs are OOCs in which healthy tissue cells are replaced with tumor cells.…”

Perspectives of metal-organic framework nanosystem to overcome tumor drug resistance

“…MDR in tumors is complex and multifactorial, including biological barrier formed by the tumor microenvironment (TME) [ 48 - 53 ] and overexpression of drug efflux transporter resulting in the inability to accumulate drugs intracellularly [ 40 , 54 - 57 ] , the drug inactivation due to the specific environment of gene control and metabolism, the resistance to apoptosis and deoxyribonucleic acid (DNA) damage repair [ 58 - 63 ] , and immune evasion [ 64 - 71 ] , as shown in Figure 1 .…”

“…Drugs entering the cells are often depleted by GSH and cannot increase ROS content to generate oxidative stress, which leads to the failure of dynamic therapy. Resistance based on GSH and ROS mechanisms has led to the inefficiency or even failure of most chemotherapeutic and kinetic treatments that rely on stimulating oxidative stress [ 3 , 56 , 57 , 76 ] .…”