This invention introduces a small-molecule doxorubicin prodrug that remains inert in blood and rapidly activates in the mildly acidic tumor microenvironment. Featuring a shelf-stable maleimide pre-prodrug that converts on demand to the ultra-acid-labile DMA form, it enables targeted chemotherapy with improved selectivity, scalable synthesis, and reduced cardiotoxicity.
Background: Doxorubicin is a cornerstone chemotherapeutic but is limited by severe cardiotoxicity and systemic side effects. Current pH-sensitive formulations—such as liposomes, hydrazone-linked conjugates, and polymeric carriers—either release drug prematurely or require complex manufacturing. The narrow pH difference between tumor tissue (pH 6.5–7.0) and blood (pH 7.4) demands a precise, tunable linker that can remain stable in circulation yet cleave predictably under tumor conditions, offering a simpler and more reliable route to selective chemotherapy.
Technology Overview: This innovation links doxorubicin through a 2,3-dialkyl-substituted maleamic acid (DMA) linker modified with 3-(2-aminoethoxy)propanoic acid to create an ultra-acid-labile prodrug. It remains stable at physiological pH (7.4) but rapidly cleaves at pH 6.5–7.0 to release active doxorubicin. A shelf-stable maleimide “pre-prodrug” (Dox-DMI) form can be stored long-term and converted to the DMA form immediately before use, ensuring stability during manufacturing and storage. The major regioisomer demonstrates ~9.4× higher release at tumor pH than blood pH, ~9 hours of serum stability at 37 °C, and significantly reduced off-target toxicity in vitro and in vivo. The synthetic route is PEG-free and compatible with GMP production.
Advantages: • Tumor-selective activation with ~9.4× faster release at pH 6.5 vs 7.4 • Maleimide “pre-prodrug” offers on-demand conversion and long shelf stability • Small-molecule design—no liposomes, enzymes, or polymers required • Enhanced serum stability (~9 h @ 37 °C) and reduced cardiotoxicity • PEG-free composition avoids anti-PEG immune responses • Simplified, scalable synthesis suitable for GMP manufacturing
Applications: • Systemic chemotherapy for solid tumors with reduced cardiotoxicity • pH-selective chemoembolization and localized drug delivery • Acid-triggered implants or beads for intracavitary tumor treatment • Platform linker chemistry adaptable to other acidosis-activated prodrugs
Intellectual Property Summary: • US Provisional Application 63/756,472 – Filed February 10, 2025
Stage of Development: In vivo validation – Demonstrated tumor-selective activation, pH-dependent cytotoxicity, and improved stability over existing doxorubicin formulations. TRL ~5.
Licensing Status: This technology is available for licensing.
Licensing Potential: Ideal for pharmaceutical developers and oncology drug manufacturers seeking an acidosis-activated, small-molecule delivery platform with simplified production and improved therapeutic index.
Additional Information: In vivo efficacy data, linker synthesis procedures, and comparative cytotoxicity profiles available upon request.
Inventors: Ming An, Vladyslav Nazarenko, Lan Yao