Tech Spotlight: Targeted Delivery of Doxazolidine - Novel Cancer Therapy Prodrugs

Doxazolidine (Doxaz) is a formaldehyde conjugate of the anthracycline antibiotic doxorubicin (Dox) developed by Dr. Tad Koch of the University of Colorado. Doxaz is functionally distinct from Dox and induces cancer cell death in sensitive and multidrug resistant cells by crosslinking DNA. Due to its increased toxicity and instability, Doxaz is an ideal candidate for prodrug delivery. Dr. Koch has designed a series of prodrugs for the targeted delivery of Doxaz to cancers. Pentyl PABC Doxaz (PPD) is one such prodrug and is activated to Doxaz by the cytosolic and microsomal protein carboxylesterase 2 (CES2) expressed by liver, non-small cell lung, colon, pancreatic, renal, and thyroid cancer cells.

Preclinical work with PPD has supported an improved safety and efficacy profile: PPD-induced inhibition of tumor growth followed dose escalation and exceeded inhibition of tumor growth by doxorubicin near its maximum tolerated dose. Heart sections treated with PPD showed significantly less evidence of cardiotoxicity than heart sections treated with doxorubicin. Unlike Dox, PPD is potentially orally bioavailable. Dr. Koch is currently workong on next-generation leads based on PPD.

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