Tumor-pH–Triggered Doxorubicin Prodrug with On-Demand Shelf-Stable Precursor

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.