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Automated Preparation of [68Ga]Ga-3BP-3940 on a Synthesis Module for PET Imaging of the Tumor Microenvironment
Published on: April 25, 2025
Albumin-binding caspase-cleavable prodrug that is selectively activated in radiation exposed local tumor
Seung Woo Chung1, Jeong Uk Choi1, Beom Seok Lee2
1Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 08826, South Korea.
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.
Insights
This study introduces EMC-DEVD-S-DOX, a novel prodrug that targets tumors by binding albumin and activating in response to radiotherapy-induced apoptosis. This approach enhances therapeutic efficacy against diverse cancer subclones with minimal systemic toxicity.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Tumor heterogeneity from genomic and epigenomic diversity limits targeted therapy effectiveness.
- Developing novel therapeutic strategies is crucial to overcome treatment resistance in cancer.
Purpose of the Study:
- To develop a novel targeted prodrug, EMC-DEVD-S-DOX, with radiation-induced apoptosis targeting and albumin-binding properties.
- To evaluate the efficacy and safety of EMC-DEVD-S-DOX in overcoming tumor heterogeneity and enhancing radiotherapy.
Main Methods:
- Design of EMC-DEVD-S-DOX with albumin-binding and caspase-3 cleavable moieties.
- Intravenous administration of the prodrug and assessment of its pharmacokinetics, tumor accumulation, and therapeutic effect in combination with radiotherapy.
- In vitro studies to evaluate cytotoxicity in the presence and absence of caspase-3.
Main Results:
- EMC-DEVD-S-DOX exhibited a prolonged half-life and enhanced tumor accumulation.
- The prodrug demonstrated significant therapeutic benefits when combined with radiotherapy.
- EMC-DEVD-S-DOX showed minimal systemic toxicity in vivo and negligible cytotoxicity without caspase-3 in vitro.
Conclusions:
- EMC-DEVD-S-DOX effectively targets tumors via albumin binding and radiation-induced apoptosis.
- This prodrug overcomes limitations of current targeted therapies by being independent of complex tumor genomic profiles.
- EMC-DEVD-S-DOX shows promise for potentiating radiotherapy in clinical oncology.
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