Engineered silica nanoparticles destroy prostate tumors in preclinical study

Prostate-targeted, engineered nanoparticles made of amorphous silica are effective in killing prostate tumors directly while enhancing anti-tumor immunity, according to a preclinical study led by investigators at Weill Cornell Medicine and the Cornell College of Engineering. The particles, derived from silicon dioxide, a common component of healthy foods or fossilized sedimentary structures from single-celled organisms, induced several complete remissions of aggressive tumors in mouse models, supporting the further investigation of their use in clinical trials.

Originally developed for medical imaging applications, these particles, known as ultrasmall fluorescent core-shell silica nanoparticles, or Cornell Prime dots (C' dots), have progressed into advanced-phase clinical trials for image-guided surgery and therapeutic applications. In recent years, the researchers have found that the C' dots on their own can exert therapeutic effects against cancerous cells, while sparing healthy cells. In the new study, published June 15 in Cancer Research, a journal of the American Association for Cancer Research, the researchers evaluated the particles' effects on mouse models of aggressive prostate cancer. They showed that the particles make the tumor cells highly susceptible to a powerful self-destruct process, and simultaneously convert the normally inactive, "cold" prostate tumor immune microenvironment into a "hot" one featuring strong antitumor immune activity—which can dramatically enhance the effects of other immunotherapies.

"We're very encouraged by these results; a treatment that directly induces tumor-cell death while transforming the immune microenvironment, as this does, would represent a new clinical paradigm," said study senior author Dr. Michelle Bradbury, the Endowed Professor of Imaging Research in Radiology and director of the Molecular Imaging Innovations Institute at Weill Cornell Medicine and a neuroradiologist at NewYork-Presbyterian/Weill Cornell Medical Center.

The study was part of a long-term collaboration between Dr. Bradbury's laboratory and the laboratory of co-corresponding author Dr. Ulrich Wiesner, the Spencer T. Olin Professor of Engineering in the Department of Materials Science and Engineering and a professor in the Department of Design Tech in the College of Architecture, Art, and Planning. It was funded in part by the Parker Institute for Cancer Immunotherapy at Weill Cornell Medicine.

As detailed in the study, the unusual effects of the C' dots include pushing prostate tumor cells toward a self-destruct mode called "ferroptosis," in which the overwhelming oxidation of molecules in the cells, especially the fat-related molecules that make up cell membranes, leads to the degradation of those membranes. Precisely how the particles trigger ferroptosis remains unclear, but the researchers have found evidence that the particles, originally designed as carriers for imaging agents, often pick up positively charged iron ions in the bloodstream, and transport those reactive cargoes inside tumor cells—where they ultimately can help catalyze runaway oxidation.

The C' dots had numerous immunological impacts, including the conversion of T cells, macrophages and other immune cells in the tumor vicinity from inert or actively immunosuppressive modes to robust antitumor activity. These results led to C' dots sensitizing tumors to clinically approved anticancer immunotherapies. The experiments also revealed extensive growth-inhibiting metabolic disruptions in different cell populations within the tumor microenvironment.

The silica particles were specifically targeted to prostate tumor cells by a molecule that homes in on a prostate cell surface protein called PSMA, but even in non-prostate tissues where the particles were briefly concentrated, such as the spleen, there was no sign of toxicity.

It seems unreal—how is it possible that rather than a single pathway we see all these effects happening simultaneously and only in tumors and not in healthy tissues? I have to wonder whether ultrasmall silica's very early and ubiquitous presence in the environment and foods like leafy greens or cereal grains has given it a connection to biology that we're only beginning to glimpse."

Dr. Ulrich Wiesner, the Spencer T. Olin Professor of Engineering, Department of Materials Science and Engineering, Cornell University

The most striking results came when the researchers conducted survival experiments in mice with aggressive prostate cancer. The C' dots on their own, and immunotherapies on their own, moderately extended survival compared to no treatment. But the combination of silica particles with an immunotherapy called immune checkpoint blockade synergistically resulted in complete or near-complete remissions and indefinite survival in four out of ten mice treated this way. Adding a third treatment called CSF-1R blockade, which targets tumor-associated macrophages, yielded five out of ten complete remissions.

"We think there's nothing else out there that has such a strong and durable tumor growth suppressing effect," Dr. Bradbury said.

"One of the most intriguing aspects of this work is the convergence of direct tumor cell killing with broad immune remodeling," said study co-author Dr. Jedd Wolchok, the Meyer Director of the Sandra and Edward Meyer Cancer Center, professor of medicine at Weill Cornell Medicine, director of the Parker Institute for Cancer Immunotherapy at Weill Cornell Medicine Meyer Cancer Center and an oncologist at NewYork-Presbyterian/Weill Cornell Medical Center. "By creating conditions that support a more effective antitumor immune response, these particles may help unlock the full potential of immunotherapy in prostate cancer, where durable responses have historically been difficult to achieve."

Dr. Bradbury  and her colleagues also recognized the contributions of the study's co-first authors, Drs. Nabil Siddiqui, Li Zhang, and Gabriel DeLeon, who led many of the biological, mechanistic, and translational studies, as well as the graduate students in Dr. Wiesner's laboratory, Nada Naguib and Rachel Lee, whose precision synthesis and characterization of particle batches made the work possible. "This study reflects years of collaborative effort across multiple laboratories and would not have been possible without the dedication, creativity and perseverance of this tremendous research team that helped drive the science forward," she said.

The researchers are continuing to explore these ultrasmall core-shell silica particles as a new class of anticancer therapeutics that can simultaneously modulate inflammatory, immune and metabolic pathways, with the ultimate goal of evaluating their safety and efficacy in clinical trials.