Next-generation imaging agents

Current medical imaging technology detects structural changes, such as those caused by tumors that have grown enough to induce rearrangements in surrounding organs. Such changes generally occur late in disease progression, necessitating more aggressive treatments and reducing the chances of success. Earlier diagnosis requires detecting molecular changes that occur earlier; the new field of molecular imaging is focused on this problem.

While
molecular imaging has traditionally been the realm of nuclear medicine, CNME researchers are interested in creating tools to enable detection of disease via modalities that do not require ionizing radiation and that afford greater spatial resolution, such as ultrasound, fluorescence, and magnetic resonance imaging (MRI). By applying the advantages of nano- and microscale structures, engineers within the Center are designing imaging agents with vastly enhanced signal or whose signal can be switched on by the biochemistry of disease.

Ultrasound

Though ultrasound is safe and widely used, few molecular ultrasound contrast agents have yet been introduced, as traditional receptor-based targeting rarely yields sufficiently selective accumulation to distinguish target cells. Recent work by a team including Robert Mattrey has overcome this challenge by engineering a means of modulating their response to ultrasound, creating one of the first agents whose signal is turned on by a biological interaction, in this case with thrombin, allowing detection of blood clots. Just as ingeniously, his group has shown that incorporation of catalase into the shell of a nanoparticle allows production of sufficiently large oxygen bubbles for detection of hydrogen peroxide at low concentrations.


Thrombin-activated ultrasound agent. Addition of thrombin (b) relieves crosslinking on microbubble surfaces, increasing their vibration upon insonation (the ultrasound signal) relative to the control (a).

Fluorescence

Another important advance towards clinically relevant activatable imaging agents is the development by Roger Tsien’s group of activatable cell-penetrating peptides (ACPPs), whose fluorescence is turned on by either a specific enzyme or reactive oxygen species. The key to the significance of ACPPs is their incorporation of polycationic sequences, whose unveiling upon activation causes intracellular accumulation; prior activatable fluorescent agents were not designed to remain in sites of activation. Further, he has collaborated with surgeons to demonstrate their potential to guide tumor resection, finding a clinical use even for agents whose signal does not pass through many layers of tissue.

Other work by CNME investigators to enhance the clinical relevance of fluorescence aims towards agents whose signal can be distinguished from tissue autofluorescence. One creative example is the work of David Hall and Mattrey, who recognized that ultrasound-induced deformations of microbubbles could be used to modulate the signal of attached fluorescent dyes, creating a fluorescent imaging agent detectable at significant depths by effectively eliminating the background signal. Targeting such agents to disease-specific receptors could yield clinically relevant diagnostics. Another important advance is the development of luminescent porous silicon nanoparticles by Michael Sailor’s research group, which emit near infrared, wavelengths of light that pass through tissues more effectively than shorter wavelengths. Their relatively rapid biodegradation compared to other optically active nanomaterials such as gold and quantum dots makes them less likely to pose a toxicity risk.

MRI

The advantages of nanoscale formulations have also been employed by Adah Almutairi’s lab to advance the potential of molecular MRI in multiple directions. By shielding gadolinium, the key component in clinically used MRI contrast agents, from water in a nanocapsule of bioresponsive polymer, they have created a system with an unprecedented difference between “on” and “off” states. This system could be used to detect a broad range of conditions by incorporating polymers that dissociate in response to various disease indicators (e.g. hydrogen peroxide to detect inflammation or acidic pH to detect tumors). The Almutairi group has also devised a highly original means of incorporating metals into nanoscale particles (which enhances the MRI signal from gadolinium) that is both highly stable and versatile, and could lead to multimodal or theranostic agents.

Other CNME research related to imaging involves the application of MRI to nanomedicine research itself; both Mattrey and Michael Sailor’s groups have collaborated with investigators at other institutions to use MRI to assess creative strategies to target nanoparticles to tumors or other disease sites. Notably, the Sailor lab designed a novel MRI contrast agent, an iron oxide nanoworm, to interact more effectively with target receptors than the more widely used iron oxide nanoparticles.





Transmission electron micrsoscopy of iron oxide nanoworms.