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Self‐Triggered Apoptosis Enzyme Prodrug Therapy (STAEPT): Enhancing Targeted Therapies via Recurrent Bystander Killing Effect by Exploiting Caspase‐Cleavable Linker
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.
Self‐Triggered Apoptosis Enzyme Prodrug Therapy (STAEPT): Enhancing Targeted Therapies via Recurrent Bystander Killing Effect by Exploiting Caspase‐Cleavable Linker
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.
Self‐Triggered Apoptosis Enzyme Prodrug Therapy (STAEPT): Enhancing Targeted Therapies via Recurrent Bystander Killing Effect by Exploiting Caspase‐Cleavable Linker
Chung, Seung Woo (Autor:in) / Choi, Jeong Uk (Autor:in) / Cho, Young Seok (Autor:in) / Kim, Ha Rin (Autor:in) / Won, Tae Hyung (Autor:in) / Dimitrion, Peter (Autor:in) / Jeon, Ok‐Cheol (Autor:in) / Kim, Seong Who (Autor:in) / Kim, In‐San (Autor:in) / Kim, Sang Yoon (Autor:in)
Advanced Science ; 5
01.07.2018
12 pages
Aufsatz (Zeitschrift)
Elektronische Ressource
Englisch
| Wiley | 2024
| Wiley | 2024