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Multimodal Nanosensor Can Both Detect And Locate Cancerous Tumors

By Deborah Borfitz

August 17, 2021 | Researchers at Massachusetts Institute of Technology have developed a urine-based molecular assay that can both reveal the presence of cancerous proteins and pinpoint a tumor’s location. The double-duty diagnostic nanosensor could one day be of clinical value in evaluating treatment response and long-term monitoring of tumor recurrence, according to Liangliang Hao, a post-doctoral trainee in the lab of bioengineer Sangeeta N. Bhatia, M.D., Ph.D.

The multimodal approach is described in a study recently published in Nature Materials (DOI: 10.1038/s41563-021-01042-y) where the nanosensor was engineered to target tumors through acidosis and respond to proteases in the microenvironment to release urinary reporters in mouse models of colorectal cancer. Additionally, the protease-responsive nanoparticles can be deployed as a positron emission tomography-computed (PET-CT) imaging agent to show localization of the disease.

Synthetic biomarkers detect tumors by harnessing the cancer cells to produce a signal that did not previously exist in the body, explains Hao, the study’s lead author. They are designed to “stand out from the noise of background signals made by the body’s cells and… to be activated by cancer-associated enzymes called proteases in the tumor microenvironment” that help them escape their original locations.

The protease-responsive imaging sensors for malignancy (PRISM) platform used in the study is based on a series of Bhatia’s previous inventions that have been licensed to Glympse Bio, a company she cofounded in 2015, says Hao. These nanosensors are made to release peptides into the urine when they encounter disease-associated proteases and were reported to be safe in phase 1 clinical trials.

To amplify signals in the latest study, researchers added acidosis targeting to the nanoparticle, says study coauthor Heather Fleming, research operations director of the Bhatia lab. Traditionally, the radioactive PET tracer fluorodeoxyglucose labels areas of the body where cells are active, which includes the intestines, brain, and heart as well as cancerous tumors. Signals from the heart are particularly bright and can mask biochemical changes in metabolic processes that are indicative of lung cancer.

Using PRISM, the researchers loaded their acidosis-targeting nanosensors with copper-64 as a radioactive tracer and found that the imaging agent localized to areas in the tumor environment based on pH levels rather than relying on affinity targeting, she continues. They were capitalizing on the fact that acidosis is a common feature of tumors, which in the paper appear as discernable dots on a cross-section of a diseased mouse lung.

A patent application has been filed by Bhatia and Hao on the targeting and specificity components of the PRISM molecule, which awaits commercialization.

PRISM is a modular system that can be tailored to the specificity of the disease, notes Hao. The platform for the Nature Materials study leverages a peptide that is responsive to matrix metallopeptidase 9 (MMP9), which is dysregulated in many types of cancers and has previously been validated to be more sensitive than circulating protein or DNA biomarkers in certain mouse models.  

Flexible By Design

Imaging-based testing is the current clinical standard for detecting and locating tumors in the body, but false-positive results can be problematic—for example, when using CT scans as a general screening tool for lung cancer, says Hao. This testing approach can lead to invasive follow-up procedures such as biopsies, which is one reason to focus on alternative procedures, such as measuring cancer-associated molecules that collect in bodily fluids.

The twin goals of the research team are to detect cancer in its earliest, most treatable stages before metastasis has occurred and to provide a surveillance tool for monitoring at-risk populations and localizing malignant lesions for surgical intervention, she adds. In their study, diagnostic particles were tested in mouse models of colon cancer that had metastasized to the liver and the lungs and, after chemotherapy treatment, both the urine signal and imaging agent were used to track treatment response.

As envisioned by Hao, patients could come in for the urine test and only those with positive results would go through the more intensive imaging type of analysis.

Multiple Initiatives

Researchers in the Bhatia lab have been working with the synthetic biomarker platform for many years now, says Hao. Not all cancers shed enough DNA or proteins for liquid biopsies to extract an accurate diagnosis, so they are hopeful that probing the tumor microenvironment can fill in the gaps. “While it’s possible that synthetic biomarkers could be useful in a screening paradigm, it’s more likely that they will initially be utilized in a focused setting such as patient stratification, drug response monitoring, or post-resection surveillance.”

Glympse Bio last summer secured $46.7 million in a Series B fundraising round to advance its non-alcoholic steatohepatitis (NASH) biosensor program along with strategic collaborator Gilead Sciences since 2019. Shortly thereafter, the company announced that its injectable mixture of synthetic sensors, which quantify protease activity and predict treatment response in NASH, was demonstrated as safe and well tolerated in a first-in-human study.

Data from the phase 1 study was presented at the American Association for the Study of Liver Disease 2020 Annual Meeting last November. In addition to nanosensor applications in NASH oncology, studies are underway for sensors for a variety of fibrotic and infectious diseases.

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