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A patient is taking a chemotherapy drug that may stop the progression of their cancer, but they develop painful blisters and swelling on their hands and feet, which affects their daily life, another challenge on an already arduous journey navigating a cancer diagnosis. This condition, palmar-plantar erythrodysesthesia (PPE), causes inflammation and damage to the palms and soles of the feet as a side effect of certain anticancer treatments, limiting these drugs’ effectiveness.
Drug developers and researchers have struggled to identify new drugs’ potential for PPE because of a lack of reliable animal and laboratory models. Being able to identify this potential side effect earlier in the process could prevent researchers from expending effort developing treatments that’d cause it. In partnership with outside collaborators, the Nanotechnology Characterization Laboratory (NCL) at the Frederick National Laboratory for Cancer Research (FNL) worked backwards from drugs known to cause the toxicity to develop an assay that could identify it. Their study is published in Nanomedicine.
Alcyomics Ltd. approached NCL with a laboratory model they were interested in using to screen for adverse effects to the skin caused by exposure to certain substances. The model, a skin explant, involves using a small skin sample, taken during a surgical procedure, to study how the skin reacts to drugs, treatments, or other substances. With the test, skin can be monitored in a controlled environment, without needing to test for side effects in a person or animal right away—especially helpful when there’s no useful animal model available.
Marina Dobrovolskaia, Ph.D., NCL’s co-director, director of operations, and head of its immunology section, suggested trying to use the assay for PPE, and the group of researchers worked together to evaluate the model.
Working to Establish a Test for Drug-Induced PPE
Part of NCL’s work is developing and standardizing methodology, constantly updating its Assay Cascade by adding new methods, which is what interested Dobrovolskaia in this particular project as a way to contribute to this body of research. “I’m a scientist in my heart,” she said.
The team selected a pair of drug products known to cause PPE and tested them in cell cultures of skin samples and peripheral blood mononuclear cells (PBMCs), a type of immune cell, from the same healthy donors. The approach allowed them to test for skin damage in addition to the inflammation that leads to the damage and see whether they could replicate what’s been shown clinically—and they were successful.
To prove the lab test replicated clinical data, the group calculated what they call a “cumulative score.” This score is the sum of stimulation indices for skin damage (assessed by examining the cells) and inflammation (assessed by measuring inflammation markers in the PBMC cultures).
Stimulation indices are a common tool for understanding how the immune system—in this case, inflammation indicated by cytokine level—responds to stimuli like drugs, measured by dividing the level of the response in the test sample by that in the control sample.
The cumulative score correlated perfectly to what is seen clinically, meaning the team’s model is a sound way to test nanomedicines before they’re given to people. It would also enable testing for certain side effects while also reducing the use of research animals.
Now that the correlation is established for one drug, the skin explant assay can be used to understand whether new formulations have benefits compared to the legacy formulation. Dobrovolskaia suggests it could also be used to determine the potential for inflammatory skin damage to be caused by other drugs, but further validation is needed.
A History of Collaboration
Dobrovolskaia notes that NCL often partners with groups interested in advancing their nanomedicine projects, like Alcyomics was. The laboratory provides federally funded, outward-facing support for external organizations, and is the only laboratory in the world dedicated to advancing nanomedicine characterization, which helps researchers understand the chemical properties of nanomaterials with implications for treatment, to support eventual use in clinical settings.
In addition to the many collaborations with external organizations, NCL has a history of collaborations with other laboratories within FNL to increase its breadth of support to the extramural community. For example, Elijah Edmondson, D.V.M., Ph.D., a board-certified pathologist at the Molecular Histopathology Laboratory and a certified diplomate of the American Board of Toxicology, played a key role in validating the skin explant assay in Dobrovolskaia’s PPE study by providing one of three independent histopathological evaluations of the skin samples and establishing harmonized criteria for assessing skin damage.
NCL supports an average of 25 research groups per year, though many more apply. As the only nanotechnology characterization laboratory focused on nanomedicines, and with over 20 years of experience and a host of willing collaborators, the team is highly sought after. Dobrovolskaia calls the multidisciplinary team’s expertise an “invaluable, intangible asset.”
Even if a project is rejected, though, the answer is never just “no.” “We help them to design [further] studies and then they conduct these studies [before they] come back and reapply,” after which many do end up being accepted, Dobrovolskaia said.
In this way, she explains, “We are maximizing the use of our limited resources to support as many investigators as possible.”
NCL’s mission is to advance the science of nanoparticle characterization to enable the translation of nanomedicines from the bench to the clinic. By characterizing nanoparticles in the standardized NCL Assay Cascade, the lab helps researchers better understand new medical products involving nanotechnology.
Ultimately, the more researchers can learn about how nanomedicines are working or what can go wrong—like identifying an unpleasant side effect such as PPE—the sooner effective formulations can find their way to the clinic to help the patients who need them.
Karolina Wilk is a technical editor in Scientific Publications, Graphics & Media (SPGM), where she writes for NCI Frederick and Frederick National Laboratory’s news outlets and edits scientific manuscripts, corporate documentation, and other writing. SPGM is the facilities’ creative services department and hub for editing, illustration, graphic design, formatting, and multimedia training and support.