Open AccessSelf‐Triggered Apoptosis Enzyme Prodrug Therapy (STAEPT): Enhancing Targeted Therapies via Recurrent Bystander Killing Effect by Exploiting Caspase‐Cleavable Linker
Author(s) -
Chung Seung Woo,
Choi Jeong Uk,
Cho Young Seok,
Kim Ha Rin,
Won Tae Hyung,
Dimitrion Peter,
Jeon OkCheol,
Kim Seong Who,
Kim InSan,
Kim Sang Yoon,
Byun Youngro
Publication year - 2018
Publication title -
advanced science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.388
H-Index - 100
ISSN - 2198-3844
DOI - 10.1002/advs.201800368
Subject(s) - prodrug , bystander effect , cytotoxicity , immunotoxin , downregulation and upregulation , apoptosis , cytotoxic t cell , cancer research , caspase , chemistry , targeted therapy , programmed cell death , linker , pharmacology , biology , medicine , immunology , in vitro , biochemistry , cancer , computer science , operating system , gene
Tumor heterogeneity is associated with the therapeutic failures of targeted therapies. To overcome such heterogeneity, a novel targeted therapy is proposed that could kill tumor populations with diverse phenotypes by delivering nonselective cytotoxins to target‐positive cells as well as to the surrounding tumor cells via a recurrent bystander killing effect. A representative prodrug is prepared that targets integrin αvβ3 and releases cytotoxins upon entering cells or by caspase‐3. This allows the prodrug to kill integrin αvβ3‐positive cells and upregulate caspase‐3, which in turn, activates the prodrug to release a cytotoxin that could subsequently diffuse into and kill the neighboring tumor cells. Apoptotic cells further upregulate and release caspase‐3, which activate more prodrugs leading to another round of adjacent cell death and caspase‐3 release. Thus, the bystander killing effect could occur repeatedly, leading to augmented and widespread anticancer activity. This strategy provides an avenue that could advance the current targeted therapy.