Nano-Machine Contrast Agent


Nano-medicine Innovation Center and Tokyo University jointly developed a “nano-machine contrast agent” that detects malignancy of a cancer.


Kazunori Kataoka, the chief of Nano-medicine Innovation Center (a research professor of Policy Vision Research Center at Tokyo University) et. al. developed an MRI nano-machine contrast agent that enhances visibility of a “low oxygen region in a tumor” that relates to malignancy and treatment resistance in a microscopic environment of a cancer.  The low oxygen region in the cancer has gained attention as a treatment resistant region where a drug cannot be sufficiently delivered and a radiation therapy is not effective and the cancer metastasizes.   





The research team revealed that the developed nano-machine contrast agent has a function that detects a microscopic environment of a cancer tissue and amplifies a strength of an MRI signal and that images characteristics of the tumor unlike the conventional contrast agents.  In addition, the research group has succeeded in detecting microscopic colon cancers whose diameter was as small as 1.5 mm and that had been metastasized to the livers with high sensitivity.   



The nano-machine contrast agent is expected to be practically used as a "pathologically imaging diagnosis technique" that is less invasive than the biopsy that has been widely used in clinical settings and that can be applied to any organ and any tissue in the body.  In addition, the nano-machine contrast agent can be applied to prediction for a pre-treatment effect and determination for a post-treatment effect.  In future, the nano-machine contrast agent is expected to more securely diagnose cancers rather than overlooking them so as to more strategically and securely treat them than before.    


The MRI device is a non-invasive diagnosing device that images the interior of the body without exposing it with radiations.  As many as around 6000 MRI devices have been widely used and installed in Japan.  The MRI device is desired to have high resolution, improve the capability for detecting a cancer tissue, and advance diagnostic information (changes of microscopic environment) so as to diagnose malignant tumors (cancers) that are the first cause of death in Japan.  To accomplish these desires, manufacturers are competing for the technologies.  Along with advancing MRI devices, contrast agents that are safer and have more advanced functions than before have been strongly demanded in recent years.     


In this background, the research team developed a nano-machine contrast agent in which a Mn-contrast agent that has an MRI contrast effect is introduced into "calcium phosphate nanoparticles" that are biologically safe and that dissolves in a low pH environment where cancer tissues reside.  The nano-machine contrast agent is composed of an inner shell portion containing a contrast agent and an outer shell made from a high polymer material that has an excellent biocompatibility, where the inner shell portion is surrounded by the outer shell.



Although the nano-machine contrast agent is stable in the blood flow (pH 7.4), the medium releases the Mn-contrast agent depending on the pH level in the tumor (ranging from pH 6.5 to pH 6.7).  In addition, when the Mn-contrast agent released from the nanoparticles binds to protein in the cancer tissue, the MRI signal is amplified seven-fold.  Thus, the research team thought that the nano-machine contrast agent would change the MRI signal as the pH level in the tumor slightly changes (ranging from pH 6.6 to 6.7). 


The research team injected the nano-machine contrast agent into a mouse where cancer cells had been subcutaneously transplanted.  Thereafter, the research team found that the entire tumor had been contrasted by the nano-machine contrast agent 30 minutes after the injection and the MRI signal at the center of the tumor became stronger as time passed.  The change of the strength of the MRI signal was much greater than that of the strength of the signal by a contrast agent (Magnevist, Gd-DTPA) that has been widely used in clinical settings and showed that the nano-machine contrast agent is effective for imaging a solid cancer.    


A portion where the MRI signal remarkably became strong at the center of the tumor matched the "low oxygen region (hypoxia)" of the cancer according to the result of immunostaining of a slice of the tissue.  In addition, the portion where the MRI signal remarkably became strong matched a portion where lactic acid built up in the cancer.  Thus, the finding reveled that "the low oxygen region could be imaged with high sensitivity and high accuracy."


The research team measured a liver metastasis model of a bowel cancer whose diameter was as small as 1.5 mm using the nano-machine contrast agent on the MRI and found that the nano-machine contrast agent was superior in resolution to Primovist, which is a conventional MRI contrast agent used for liver cancers.


The low oxygen region is known to have resistance for chemotherapy and radiation therapy.  Thus, examining whether or not the cancer has the low oxygen region is important to decide a treatment plan and verify a treatment effect.  The current medicine does not generally examine whether or not the cancer has the low oxygen region.  Instead, the current medicine provides only a low resolution technique that causes an examinee to be exposed with radiation.  This study would be expected to provide a means for three-dimensionally analyzing the low oxygen region where malignant cancer cells would reside with no-radiation exposure and high resolution and establish new medicine for advanced diagnoses that ascertain cancers' characteristics and for treating patients and developing new drugs while verifying effects of the treatment. 



As an important thing, the finding in this study was obtained by a low magnetic field 1-Tesla MRI devices that have been most commonly installed in clinical settings and that are relatively inexpensive rather than high-magnetic field MRI devices that have not been widely installed and that are expensive.  The nano-machine contrast agent allows the MRI signal to become strong on the low-magnetic field MRI device.  The nano-machine contrast agent would be expected to be used anytime, anywhere, and anybody as an innovative MRI contrast agent that allows a lesion to be detected with high sensitivity and diagnosis information to be advanced.