Gd-labeled glycol chitosan as a pH-responsive magnetic resonance imaging agent for detecting acidic tumor microenvironments

摘要

Neoplastic lesions can create a hostile tumor microenvironment with low extracellular pH. It is commonly believed that these conditions can contribute to tumor progression and resistance to therapy. We report the development and characterization of a pH-responsive magnetic resonance imaging contrast agent, for imaging the acidic tumor microenvironment. The preparation included conjugation of 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid 1-(2,5-dioxo-1-pyrrolidinyl) ester (DOTA-NHS) to the surface of a water soluble glycol chitosan (GC) polymer, which contains pH titrable primary amines, followed by gadolinium complexation (GC-NH2-GdDOTA). GC-NH2-GdDOTA had a chelate to polymer ratio of approximately1:24 and a molar relaxivity of 9.1 mM⁻¹s⁻¹. GC-NH2-GdDOTA demonstrated pH-dependent cellular association in vitro compared to the control. It also generated a 2.4-fold enhancement in signal in tumor bearing mice 2 h post-injection. These findings suggest that glycol chitosan coupled with contrast agents can provide important diagnostic information about the tumor microenvironment.