A tumor microenvironment dual responsive contrast agent for contrary contrast-magnetic resonance imaging and specific chemotherapy of tumors

Development of magnetic resonance imaging (MRI) contrast agents (CAs) is still one of the research hotspots due to the inherent limitations of T1- or T2-weighted CAs and T1/T2 dual-mode CAs. To dramatically enhance the MRI contrast between tumors and normal tissues, we propose a new concept of contrary contrast-MRI (CC-MRI), whose specific definition is that CC-MRI CAs present a positive or negative signal at normal tissues, but show contrary signals at diseased tissues. To realize CC-MRI of tumors, we designed and developed a tumor microenvironment (TME) dual responsive CA (i.e., SA-FeGdNP-DOX@mPEG), which is almost not responsive under normal physiological conditions, but highly responsive to the acidic and reductive TME. Our SA-FeGdNP-DOX@mPEG shows a negative MRI signal under normal physiological conditions due to the high r2 value (336.9 mM-1 s-1) and high r2/r1 ratio (18.4), but switches to a positive MRI signal in the TME because of the high r1 value (20.32 mM-1 s-1) and low r2/r1 ratio (7.2). Our TME dual responsive SA-FeGdNP-DOX@mPEG significantly enhanced the contrast of MR images between tumors and livers, and the ΔSNR difference reached 501%. In addition, our SA-FeGdNP-DOX2@mPEG2 with tumor targetability and controlled DOX release responding to the TME was also used for tumor-specific chemotherapy with reduced side effects.