Breakthroughs in nano-sized contrast agents and drug carriers using self-folding molecules

Gadolinium-containing self-folding polymers forming nanoscale complexes could be the key to improved magnetic resonance imaging and next-generation drug delivery, as demonstrated by Tokyo Tech scientists. Thanks to their small size, low toxicity and good accumulation and tumor penetration, these complexes represent a leap forward in the field of contrast agents for cancer diagnosis, as well as for neutron capture radiotherapy.

Magnetic resonance imaging (MRI) is a crucial diagnostic tool for cancer, enabling the capture of detailed images of soft tissues. To view tumors more clearly on MRI scans, doctors usually inject patients with contrast agents. These compounds affect how nearby hydrogen ions respond to radiofrequency pulses used in MRI. Ideally, contrast agents should selectively accumulate in tumors and increase their contrast on MRI.

However, despite numerous research efforts, conventional gadolinium (Gd)-based contrast agents are reaching their performance limits. Simply put, achieving an optimal dose in the distribution of Gd chelates in tumors, healthy tissues, and blood has proven difficult without resorting to excessive doses of Gd.

In this context, a collaborative study led by a research team from Tokyo Institute of Technology (Tokyo Tech), National Institutes of Quantum Science and Technology (QST), and Nanomedicine Innovation Center (iCONM), led by Associate Professor Yutaka Miura of Tokyo Tech, successfully developed a novel nano-contrast agent (NCA) with exceptional performance through innovative molecular design. Their findings were published in the Advanced science on November 29.

The proposed NCA is based on the use of Gd as a contrast agent in what the researchers called a “self-folding macromolecular drug carrier (SMDC).” They incorporated clinically approved Gd-containing chelates into a polymer chain composed of poly(ethylene glycol) methyl ether acrylate (PEGA) and benzyl acrylate (BZA). Since the polymer contained both hydrophilic and hydrophobic segments, it quickly folded into a small capsule shape when immersed in water, with the hydrophobic segments at the core and the hydrophilic segments at the shell. external.

Using this approach, researchers could produce SMDC-Gds molecules with a diameter of less than 10 nanometers. Through experiments on mice with colon cancer, they verified that these NCAs not only accumulated better in tumors, but were also rapidly cleared from the bloodstream, leading to improved performance of MRI without toxic effects.

“The high tumor accumulation and rapid blood clearance profile of SMDC-Gds allows for increased tumor/major organ accumulation rates as well as minimizing unnecessary Gds deposition,” explains Professor Miura.

The team also demonstrated a new effect that places SMDC-Gds ahead of existing Gd-chelates. Ideally, the movement of Gd ions should be minimal so that their influence on nearby hydrogen ions is constant and prolonged. In the proposed molecular design, the core/shell structure creates a “crowded” molecular environment that suppresses not only rotation, but also segmental and internal movements of Gd ions.

The resulting effect is stronger contrast in MRI images, which will allow the use of alternative elements with safer profiles not only for patients but also for the environment in the future.

It should be emphasized that the applications of SMDC-Gds extend beyond MRI. These compounds can be used in neutron capture therapy (NCT), a promising targeted radiotherapy technique in which Gds capture neutrons and release high-energy radiation, killing nearby cancer cells.

Experiments in mice revealed that NCT following repeated injection of SMDC-Gd resulted in significantly suppressed tumor growth. The team believes the reason is the selective accumulation and deep penetration of SMDC-Gds into tumor tissues.

Collectively, the researchers’ collaborative efforts to achieve these results highlight the potential of SMDCs not only for better MRI diagnostics, but also as effective tools to treat cancer and other diseases.

“This study presents further possibilities for exploiting drug delivery using various therapeutic cargoes, and we are currently investigating the development of such SMDC systems,” concludes Professor Miura.