Extra-domain B of fibronectin as an alternative target for drug delivery and a cancer diagnostic and prognostic biomarker for malignant glioma

• Published in: Theranostics 2021-01, Vol.11 (2), p.941-957
• Main Authors: Saw, Phei Er, Xu, Xiaoding, Kang, Bo Ram, Lee, Jungsul, Lee, Yeo Song, Kim, Chungyeul, Kim, Hyungsin, Kang, Shin-Hyuk, Na, Yoo Jin, Moon, Hong Joo, Kim, Joo Han, Park, Youn-Kwan, Yoon, Wonki, Kim, Jong Hyun, Kwon, Taek-Hyun, Choi, Chulhee, Jon, Sangyong, Chong, Kyuha
• Format: Article
• Language: English
• Subjects: Biomarkers; Brain cancer; Cell culture; Datasets; Dehydrogenases; Deoxyribonucleic acid; DNA; Drug delivery systems; Extracellular matrix; Gene expression; Glioma; Medical prognosis; Mutation; Peptides; Polymerase chain reaction; Research Paper; Survival analysis; Tumors
• ISSN: 1838-7640; 1838-7640
• DOI: 10.7150/thno.44948

Extra-domain B of fibronectin (EDB-FN) is an alternatively spliced form of fibronectin with high expression in the extracellular matrix of neovascularized tissues and malignant cancer cells. In this study, we evaluated the practicality of using EDB-FN as a biomarker and therapeutic target for malignant gliomas (MGs), representative intractable diseases involving brain tumors. The microarray- and sequence-based patient transcriptomic database 'Oncopression' and tissue microarray of MG patient tissue samples were analyzed. EDB-FN data were extracted and evaluated from 23,344 patient samples of 17 types of cancer to assess its effectiveness and selectivity as a molecular target. To strengthen the results of the patient data analysis, the utility of EDB-FN as a molecular marker and target for MG was verified using active EDB-FN-targeting ultrasmall lipidic micellar nanoparticles (~12 nm), which had a high drug-loading capacity and were efficiently internalized by MG cells and . Brain tumors had a 1.42-fold cancer-to-normal ratio ( < 0.0001), the second highest among 17 cancers after head and neck cancer. Patient tissue microarray analysis showed that the EDB-FN high-expression group had a 5.5-fold higher risk of progression than the EDB-FN low-expression group ( < 0.03). By labeling docetaxel-containing ultrasmall micelles with a bipodal aptide targeting EDB-FN (termed APT -DSPE-DTX), we generated micelles that could specifically bind to MG cells, leading to superior antitumor efficacy of EDB-FN-targeting nanoparticles compared to nontargeting controls. Taken together, these results show that EDB-FN can be an effective drug delivery target and biomarker for MG.