Reversing the undesirable pH-profile of doxorubicin via activation of a disubstituted maleamic acid prodrug at tumor acidity

US12285437B2 · kind B2 · utility

Assignee

• The Research Foundation for The State University of New York · US

Inventors

• Ming An · Vestal, US
• Lan Yao · Suzhou, CN
• Anqi Zhang · Canton, US

Key dates

• Filing date: Oct 30, 2020
• Grant date: Apr 29, 2025
• Expiry date: Feb 21, 2042

Classification

• Technology area (CPC A): Human Necessities
• CPC primary: A61P35/00
• WIPO field: Pharmaceuticals
• WIPO sector: Chemistry

Abstract

A pre-prodrug, comprising a drug, e.g., doxorubicin, which has off-target toxicity (e.g., cardiotoxicity) with respect to its antineoplastic activity, and an amine functionality of the drug incorporated into a disubstituted maleimide (DMI). The pre-prodrug may be linked to a targeting or de-targeting agent or a polar modulator, e.g., charged ligand, amino acid, peptide, etc., to increase therapeutic index. The pre-prodrug is hydrolyzed to the prodrug, having a disubstituted maleamic acid (DMA). A polar modulator such as glutamic acid prevents cellular uptake of the prodrug, but not the doxorubicin drug released from the prodrug after dissociation. The prodrug is pH sensitive, and below pH 7.0, tends to cleave to form free drug and cyclized maleic anhydride. Tumor environments tend to be more acidic, e.g., pH 6.8, than cardiac tissue, e.g., pH 7.4, and therefore the heart is spared while the drug is selectively released within a tumor.