Design and preparation of pH-sensitive cytotoxic liposomal formulations containing antitumor colchicine analogues for target release

Abstract

Herein, we describe the synthesis of pH-sensitive lipophilic colchicine prodrugs for liposomal bilayer inclusion, as well as preparation and characterization of presumably stealth PEGylated liposomes with above-mentioned prodrugs. These formulations liberate strongly cytotoxic colchicinoid derivatives selectively under slightly acidic tumor-associated conditions, ensuring tumor-targeted delivery of the compounds. The design of the prodrugs is addressed to pH-triggered release of active compounds in the slight acidic media, that corresponds to tumor microenvironment, while keeping sufficient stability of the whole formulation at physiological pH. Correlations between the structure of the conjugates, their hydrolytic stability, colloidal stability, ability of the prodrug retention in the lipid bilayer are described. Several formulations were found promising for further development and in vivo investigations.

Keywords:

• Colchicinoids
• liposomes
• pH-triggered release
• drug design
• antitubulin agents
• antitumor agents

Author contributions

Ekaterina S. Shchegravina: Writing – original draft, Methodology, Investigation, Conceptualization, Data curation, Project Administration. Daria S. Tretiakova: Investigation, Conceptualization, Writing – review & editing. Alsu R. Sitdikova: Investigation. Sofia D. Usova: Investigation. Ivan A. Boldyrev: Resources, Writing – review & editing. Anna S. Alekseeva: Data curation. Elena V. Svirshchevskaya: Investigation. Elena L. Vodovozova: Resources. Alexey Yu. Fedorov: Writing – review & editing, Resources, Funding acquisition.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by the Russian Science Foundation under [Grant 19–13-00158].