New analytical method improves safety assessment of metal-based nanomedicines

New analytical method improves safety assessment of metal-based nanomedicines

Nanomedicines, particularly those based on nanoparticles, are revolutionizing healthcare in terms of both diagnostics and therapeutics. These particles, which often contain metals such as iron or gold, can serve as contrast agents in medical imaging, act as nutritional supplements, and even act as drug delivery vehicles. Thanks to their unique properties and careful engineering, nanomedicines can reach and accumulate in places within the body that conventional drugs cannot, making them promising for the detection and treatment of cancer. However, the same characteristics that make nanomedicines more valuable also present challenges in ensuring their safety and quality.

Current pharmaceutical guidelines, including those of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH), have a significant blind spot: they assess only the total amount of elements present in a drug, without distinguishing between their different forms or different sized particles. This distinction is crucial because these different forms can have different effects on the body, including different toxicity profiles.

With this in mind, a research team led by Assistant Professor Yu-Ki Tanaka from the Graduate School of Pharmaceutical Sciences at Chiba University, Japan, has developed a new analytical method to address the existing regulatory gap. Their study, which was made available online in the journalTalantaApril 8, 2025 introduces a technique for separately quantifying ions, nanoparticles and aggregated particles in nanomedicines. The study by Yasumitsu Ogra and Sana Hasegawa, also by Yasumitsu Ogra and Sana Hasegawa, shows how this method can improve quality control for these advanced pharmaceutical products. “By incorporating a novel evaluation method that addresses a previously overlooked issue in current evaluation guidelines, we can ensure that nanomedicines such as Resovist® and Ferinject® are used safelyDr. Tanaka explains.

The researchers combined two existing technologies-asymmetric flow misfractionation (AF4) and inductively coupled plasma mass spectrometry (ICP-MS). They used the AF4 method in a novel way, leveraging its initial “focus step.” During this step, particles in the AF4 channel are held by two countercurrents. Using a special permeable membrane, the cross-flows filter out the smallest dissolved particles (ions) and enable quantification based on the differences in ICP-MS signals between samples with and without ion removal - namely with and without a focus step. Once the ions are separated, the system then uses AF4's standard separation process to sort the retained nanoparticles by size. Finally, the ICP-MS device connected to the output can determine the approximate number of nanoparticles of each size. This combination allowed the team to distinguish between free metal ions, small hydroxide colloids, and nanoparticles of various sizes, all containing the same metal element.

They tested their approach on Resovist®, a nanomedicine used as a contrast agent in liver magnetic resonance imaging scans. The analysis showed that only 0.022% of the iron in Resovist® was present in ionic form. At approximately 6.3 micrograms per milliliter, this negligible amount is well below scale. Additionally, the team confirmed that the active nanoparticles were smaller than 30 nanometers in diameter, with some aggregates around 50 nanometers. Importantly, no large aggregates were detected, which could reduce the effectiveness of the contrast agent. These results confirm both the safety and stability of Resovist® as a nanomedicine.

The proposed technique is particularly relevant to emerging cancer treatments that use gold nanoparticles as drug delivery systems or metallic particles for photothermal therapy. These advanced treatments rely on the “enhanced permeability and retention effect (EPR),” which causes nanoparticles to drain from blood vessels around tumors and accumulate in cancer tissue. “Since many novel nanomedicines consist of metal-based nanoparticles as active ingredients and reliable methods to evaluate their safety and quality control will promote their development and clinical use“Remarks Dr. Tanaka.

Furthermore, this novel analytical approach extends beyond pharmaceuticals. It can also evaluate the safety of metal nanoparticles in food additives, cosmetics and environmental samples to ensure public health in multiple sectors. The researchers demonstrated their versatility by successfully analyzing both negatively charged ions (silicon) and positively charged ions (iron), indicating the potential for a variety of nanomaterials.

Overall, this research provides the path to safer and more effective nanomedicines and nanoparticle-based technologies through a more comprehensive assessment of the composition, quality and stability of nanoparticles.

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