Aldoxorubicin (INNO-206)

Aldoxorubicin (formerly INNO-206) is a prodrug of the anthracycline antibiotic doxorubicin, specifically designed to bind to endogenous serum albumin for targeted delivery to malignant tissues. It is not a biological target itself but a therapeutic agent that utilizes albumin as a carrier to exploit the enhanced permeability and retention (EPR) effect characteristic of solid tumors (Kratz, 2008). The molecule features an acid-sensitive hydrazone linker that remains stable in the neutral pH of the bloodstream but undergoes hydrolysis in the acidic microenvironment of a tumor, releasing the active doxorubicin payload directly at the site of disease (Chawla et al., 2015). Once released, doxorubicin exerts its cytotoxic effects by intercalating into DNA and inhibiting the enzyme Topoisomerase II, which prevents DNA replication and induces apoptosis (Pommier et al., 2010). This delivery mechanism is intended to increase the maximum tolerated dose of doxorubicin while significantly reducing systemic toxicities, most notably the dose-limiting cardiotoxicity associated with conventional anthracycline therapy. Aldoxorubicin has been primarily investigated for the treatment of difficult-to-treat cancers such as soft tissue sarcoma, glioblastoma, and small cell lung cancer.

Other names

INNO-206DOXO-EMCH6-maleimidocaproyl hydrazine derivative of doxorubicinSerum albumin-binding doxorubicinSerum albumin-linked doxorubicin

Aldoxorubicin is an acid-sensitive prodrug that binds covalently to the cysteine-34 residue of endogenous serum albumin. It is transported to tumor sites via the enhanced permeability and retention (EPR) effect, where the acidic microenvironment (pH 4.5–5.5) triggers the cleavage of its hydrazone linker. This release of active doxorubicin allows the drug to intercalate into DNA and inhibit Topoisomerase II, leading to double-strand breaks and cell death (Kratz, 2008; Pommier et al., 2010).