Innovative Linker Strategies for Tumor‐Targeted Drug Conjugates

• Published in: Chemistry : a European journal 2019-11, Vol.25 (65), p.14740-14757
• Main Authors: Dal Corso, Alberto, Pignataro, Luca, Belvisi, Laura, Gennari, Cesare
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - metabolism; Antineoplastic Agents - therapeutic use; antitumor agents; bioorthogonal reactions; Chemical bonds; Chemistry; Cleavage; Conjugation; Cytotoxic agents; Cytotoxicity; Drug Carriers - chemistry; drug delivery; Drug Liberation; Enzymes - metabolism; Humans; Hydrolysis; Infrared Rays; Macromolecules; Neoplasms - drug therapy; Neoplasms - pathology; Organic chemistry; photocages; prodrugs; Side effects; Tumor Microenvironment; Tumors
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201903127

The covalent conjugation of potent cytotoxic agents to either macromolecular carriers or small molecules represents a well‐known approach to increase the therapeutic index of these drugs, thus improving treatment efficacy and minimizing side effects. In general, cytotoxic activity is displayed only upon cleavage of a specific chemical bond (linker) that connects the drug to the carrier. The perfect balance between the linker stability and its selective cleavage represents the key for success in these therapeutic approaches and the chemical toolbox to reach this goal is continuously expanding. In this Review article, we highlight recent advances on the different modalities to promote the selective release of cytotoxic agents, either by exploiting specific hallmarks of the tumor microenvironment (e.g. pH, enzyme expression) or by the application of external triggers (e.g. light and bioorthogonal reactions). Tie and Cut: Many tumor targeting strategies exploit the covalent connection of anticancer therapeutics to different carriers. We survey new linker technologies to promote controlled drug release triggered by the tumor microenvironment or by external stimuli (see scheme).