A "smart" PARACEST MRI contrast agent was synthesized to detect caspase-3, which is an important biomarker in apoptosis. The well-known caspase-3 substrate, DEVD (Asp-Glu-Val-Asp), was elongated using the amino group on one sidearm of lanthanide ligand anchored on the polymer support. The amide of DEVD-(Tm-DOTA) showed a PARACEST effect with MR saturation at -51 ppm. DEVD-(Tm-DOTA) amide was successfully cleaved by caspase-3, exposing the free amine group, which showed PARACEST with saturation at +8 ppm. The enzymatic activity of caspase-3 can be detected by the change in PARACEST effect caused by this biotransformation.

This review focuses on MR contrast agents that are responsive to a change in physiological environment. The "response" mechanisms are dependent on 6 physicochemical phenomena, including the accessibility of water to the agent, rotational tumbling time, proton exchange rate, electron spin state, MR frequency, or local field inhomogenieties caused by the agent. These phenomena can be affected by the physiological environment, including changes in concentrations or activities of proteins, enzymes, nucleic acids, metabolites, oxygen and metal ions, and changes in pH and temperature. A total of 52 examples are presented, which demonstrate the variety and creativity of different approaches used to create responsive MRI contrast agents.

PARAmagnetic Chemical Exchange Saturation Transfer (PARACEST) is a novel contrast mechanism for MRI. A PARACEST MRI methodology with high temporal resolution is highly desired for in vivo MRI applications of molecular imaging. To address this need, a strategy has been developed that includes a long selective saturation period before each repetition of a Rapid Acquisition with Relaxation Enhancement (RARE) pulse sequence. This strategy is suitable for the application of PARACEST contrast agents to environments with long T1 relaxation times. An alternative strategy uses short selective saturation periods before the acquisition of each k-space trajectory to maintain steady state conditions, which can be implemented with a Fast Low Angle Shot (FLASH) pulse sequence. These short saturation periods lengthen the total scan time as compared to the first approach but compensate for the loss in PARACEST contrast related to T1 relaxation. Both approaches have been demonstrated in vitro and in vivo with significantly improved temporal resolutions as compared to a conventional gradient-echo PARACEST method without sacrificing CNR efficiency. These demonstrations also adopted a strategy for measuring the PARACEST effect that only requires selective saturation at a single MR frequency, which further improves temporal resolution for PARACEST detection.

The therapeutic promise of microRNA in cancer has yet to be realized. In this study, we identified and therapeutically exploited a new role for miR-10b at the metastatic site, which links its overexpression to tumor cell viability and proliferation. In the protocol developed, we combined a miR-10b-inhibitory nanodrug with low-dose anthracycline to achieve complete durable regressions of metastatic disease in a murine model of metastatic breast cancer. Mechanistic investigations suggested a potent anti-proliferative, pro-apoptotic effect of the nanodrug in the metastatic cells, potentiated by a cell-cycle arrest produced by administration of the low-dose anthracycline. miR-10b was overexpressed specifically in cells with high metastatic potential, suggesting a role for this miRNA as a metastasis-specific therapeutic target. Taken together, our results implied the existence of pathways that regulate the viability and proliferation of tumor cells only after they have acquired the ability to grow at distant metastatic sites. As illustrated by miR-10b targeting, such metastasis-dependent apoptotic pathways would offer attractive targets for further therapeutic exploration.