pH-sensitive and biodegradable charge-transfer nanocomplex for second near-infrared photoacoustic tumor imaging

The emerging technique of photoacoustic imaging, especially in the near infra-red (NIR) window, permits high resolution, deep-penetration, clinically reliable sensing. However, few contrast agents are available that can specifically respond to intricate biological environments, and which are biodegradable and biocompatible. Herein, we introduce a new class of pH-sensitive organic photoacoustic contrast agent that operates in the second NIR window (NIR-II, 960-1,700 nm), which is derived from the self-assembled charge-transfer nanocomplex (CTN) by 3,3',5,5'-tetramethylbenzidine (TMB) and its dication structure (TMB++). The unique NIR-II-responsive CTN can specifically respond to pH change in the physiological range and allows noninvasive and sensitive visualization of the tumor acidic microenvironment (e.g. at pH 5) in mice with higher signal-to-noise ratio. The CTN is biodegradable under physiological conditions (e.g. pH 7.4), which alleviates the biosafety concern of nanoparticle accumulation in vivo. These results clearly show the potential of the TMB/TMB++-based CTN as a promising pH-activated and biodegradable molecular probe for specific tumor photoacoustic imaging in the NIR-II region.