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 T-1- or T-2-weighted CAs and T-1/T-2 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 r(2) value (336.9 mM(-1) s(-1)) and high r(2)/r(1) ratio (18.4), but switches to a positive MRI signal in the TME because of the high r(1) value (20.32 mM(-1) s(-1)) and low r(2)/r(1) ratio (7.2). Our TME dual responsive SA-FeGdNP-DOX@mPEG significantly enhanced the contrast of MR images between tumors and livers, and the Delta SNR 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.