title: Albumin-binding caspase-cleavable prodrug that is selectively activated in radiation exposed local tumor.
abstract: Existence of the genomically and epigenomically diverse subclones in a tumor severely limits the therapeutic efficacy of targeted agents. To overcome such a limitation, we prepared a novel targeted prodrug, EMC-DEVD-S-DOX, which comprises two important features: radiation-induced apoptosis targeting and albumin-binding properties. In particular, the prodrug binds circulating albumin after intravenous administration and then activated by caspase-3, which is upregulated from apoptotic cells that responded to radiotherapy. The prodrug was designed to bind circulating albumin to extend half-life and facilitate tumor accumulation in order to increase the possibility of contacting caspase-3, which is only transiently upregulated during apoptosis. Our results showed that EMC-DEVD-S-DOX had a prolonged half-life with enhanced tumor accumulation, which clearly benefited the therapeutic effect of the prodrug. Also, agreeing with the in vitro studies that showed ignorable cytotoxic effect in the absence of caspase-3, the prodrug was effective only when combined with radiotherapy without any noticeable systemic toxicity in vivo. Due to the highly selective action of EMC-DEVD-S-DOX independent to the complex genomic profiles of tumor, the prodrug would overcome the limitation of current targeted therapy and potentiate radiotherapy in the clinical oncology.
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 08826, South Korea.
authors.forename: Seung Woo
authors.initials: SW
authors.lastname: Chung
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 08826, South Korea.
authors.forename: Jeong Uk
authors.initials: JU
authors.lastname: Choi
authors.affiliation: Department of Otolaryngology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, 05505, South Korea; Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, 02792, South Korea.
authors.forename: Beom Seok
authors.initials: BS
authors.lastname: Lee
authors.affiliation: Franklin & Marshall College, Lancaster, PA, 17604-3003, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Byun
authors.affiliation: Pharosgen Co., Seoul, 06034, South Korea.
authors.forename: Ok-Cheol
authors.initials: OC
authors.lastname: Jeon
authors.affiliation: Department of Biochemistry and Molecular Biology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, 05505, South Korea.
authors.forename: Seong Who
authors.initials: SW
authors.lastname: Kim
authors.affiliation: Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, 02792, South Korea.
authors.forename: In-San
authors.initials: IS
authors.lastname: Kim
authors.affiliation: Department of Otolaryngology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, 05505, South Korea. Electronic address: sykim2@amc.seoul.kr.
authors.forename: Sang Yoon
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 08826, South Korea; Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergent Science and Technology, Seoul National University, Seoul, 08826, South Korea. Electronic address: yrbyun@snu.ac.kr.
authors.forename: Youngro
authors.initials: Y
authors.lastname: Byun
mesh_terms: D000418:Albumins / Q000378:metabolism*; D000818:Animals; D002208:Caproates; D053148:Caspase 3 / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008297:Male; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D010455:Peptides / Q000737:chemistry; D011355:Prodrugs / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D015854:Up-Regulation
chemical_list: D000418:Albumins; D002208:Caproates; D010455:Peptides; D011355:Prodrugs; C037652:hexanoic acid; D004317:Doxorubicin; D053148:Caspase 3
keywords: Albumin; Apoptosis; Caspase; Drug delivery; Prodrug; Radiotherapy