Rational Design, Synthesis, and Systematic Evaluation of Redox-Responsive SN-38 Prodrugs for Selective Activation in...

Area of Science:

• Medicinal Chemistry
• Drug Delivery
• Oncology

Background:

• SN-38, a potent topoisomerase I inhibitor, faces clinical limitations due to severe systemic toxicity.
• Prodrug strategies offer a way to improve SN-38's therapeutic index by enabling selective tumor activation.
• Hypoxic tumor microenvironments present a target for novel drug activation mechanisms.

Purpose of the Study:

• To design, synthesize, and evaluate novel disulfide-based SN-38 prodrugs for redox-responsive activation in hypoxic tumors.
• To engineer prodrugs that exploit the upregulated thioredoxin (Trx/TrxR) system in hypoxic tumor microenvironments.
• To improve the therapeutic index of SN-38 by reducing systemic toxicity and enhancing tumor-specific drug release.

Main Methods:

• Synthesis of two novel disulfide-based SN-38 prodrugs: SN-38-CSS (cyclic disulfide) and SN-38-LSS (linear disulfide).
• Evaluation of prodrug stability under physiological conditions (pH 7.4, human plasma) and their degradation kinetics in the presence of various reductants (TCEP, DTT, GSH, L-Cys).
• In vitro cytotoxicity assays of prodrugs and SN-38 under normoxic and hypoxic conditions across multiple cell lines.

Main Results:

• Both SN-38-CSS and SN-38-LSS showed high stability in physiological conditions and plasma, preventing premature drug release.
• Prodrugs exhibited selective and rapid degradation with dithiol reductants (TCEP, DTT) mimicking the Trx system, but remained stable against monothiols.
• Under normoxic conditions, prodrugs showed reduced toxicity compared to SN-38, while hypoxic conditions significantly restored their cytotoxic activity.
• SN-38-CSS demonstrated comparable cytotoxicity to SN-38 in MCF-7 and NCI-N87 cells under hypoxia, indicating efficient activation.

Conclusions:

• SN-38-CSS is a promising dual-responsive prodrug candidate, activated by both redox potential and hypoxia.
• The use of cyclic disulfide linkers is a strategic approach for achieving selective drug release in the tumor microenvironment.
• This prodrug strategy holds potential for improving the safety and efficacy of SN-38-based cancer therapies.