<b>Methods:</b> Two novel disulfide-based SN-38 prodrugs (SN-38-CSS and SN-38-LSS) were designed and synthesized; SN-38-CSS incorporates a constrained cis-piperazine-fused six-membered cyclic disulfide linker, while SN-38-LSS contains a linear disulfide tether, to differentially exploit the upregulated thioredoxin (Trx/TrxR) system in hypoxic tumor microenvironments. The gene discussed is TXN; the disease is neoplasm.