Home Medizin Neues „GPS-Nanopartikel“ verleiht dem Protein, das an der Tumorausbreitung beteiligt ist, einen genetischen Schlag

Neues „GPS-Nanopartikel“ verleiht dem Protein, das an der Tumorausbreitung beteiligt ist, einen genetischen Schlag

von NFI Redaktion

Researchers at Penn State have developed a new „GPS nanoparticle“ that can be intravenously injected into cancer cells, penetrate them, and deliver a genetic blow to the protein involved in tumor growth and spread. They tested their approach on human cell lines and mice to effectively knock out a cancer-causing gene, suggesting that this technique could offer a more precise and effective treatment for notoriously hard-to-treat basal breast cancer types.

Their work was published today (March 11) in ACS Nano. They also filed a provisional patent application for the technology described in this study.

„We have developed a GPS nanoparticle that finds its way to where it’s needed. Once there -; and only there -; it can deliver gene-editing proteins to prevent the spread of cancer cells. It was a challenging task, but we have shown that the system works for basal breast cancer.“

Dipanjan Pan, corresponding author, Dorothy Foehr Huck & J. Lloyd Huck Chair Professor of Nanomedicine and Professor of Nuclear Engineering and Materials Science & Engineering at Penn State

Similar to triple-negative breast cancer, basal breast cancers may be less common than other types of breast cancer but can be much harder to treat, particularly because they lack the three therapeutic targets found in other types of breast cancer. They also tend to be aggressive, fast-growing tumors that shed cells that can spread to other parts of the body. These cells can form additional tumors, a process known as metastasis.

„Metastasis is a major challenge, especially in cancers like triple-negative and basal breast cancer,“ Pan said. „The cancer can be difficult to detect and may not be visible on a routine mammogram. It primarily affects younger or African American populations who may not be receiving preventive treatment. The outcome can be very, very bad, so there is a clear unmet clinical need for more effective treatments if the cancer is not detected early.“

The team created a Trojan horse nanoparticle, disguising it with specially designed fat molecules that resemble natural lipids and filled it with CRISPR-Cas9 molecules. These molecules can target a cell’s genetic material, identify a specific gene, and turn it off or render it ineffective. In this case, the system targeted the human Forkhead Box c1 (FOXC1), which is involved in triggering metastasis.

Pan described the designer lipids as „zwitterionic,“ meaning they have a nearly neutral charge on the surface of the nanoparticle. This prevents the body’s immune system from attacking the nanoparticle because it is disguised as a harmless, normal molecule -; and can help release the payload only when the lipids recognize the low pH environment of the cancer cell. To ensure that the lipids are activated only at this low pH, the researchers designed them to shift their charge to positive once they enter the more acidic microenvironment of the tumor, triggering the release of the payload.

But the body is a huge place. How could the researchers ensure that the CRISPR-Cas9 payload reaches the right target? To ensure that the nanoparticle binds to the right cells, they attached an Epithelial Cell Adhesion Molecule (EpCAM), known to bind to basal-like breast cancer cells.

„No one has ever attempted to target a basal breast-like cancer cell with a context-responsive delivery system that can genetically turn off the gene of interest,“ Pan said. „We are the first to show that it can be done.“

Others have developed viral delivery systems where a virus particle is hijacked to transport the treatment to the cells, and non-viral delivery systems involving nanoparticles. The difference, Pan said, for his team’s approach is that the surface lipid is designed to react only in the target environment, reducing the potential for off-target delivery and harm to healthy cells. He also added that the likelihood of an immune response is lower since the body does not see the lipids as a threat, which they confirmed in their experiments.

The team initially tested the approach on human triple-negative breast cancer cells and confirmed that the nanoparticle would deliver the CRISPR/Cas9 system in the correct environment. They confirmed that the nanoparticle found its way to a tumor in a mouse model, deployed the system, and successfully knocked out FOXC1.

Next, Pan said, the researchers plan to further test the nanoparticle platform with the aim of eventually applying it clinically in humans.

„We are also exploring how else we could apply the platform technology,“ Pan said. „We can customize the molecules on the surface and the payload it carries to promote healing in other areas. This platform holds a lot of potential.“

The lead author Parikshit Moitra was a research assistant professor of nuclear engineering in Pan’s lab at Penn State University at the time of the study and is now an assistant professor at the Indian Institute of Science Education and Research in Berhampur; David Skrodzki, Matthew Molinaro, Nivetha Gunaseelan, all doctoral students at Penn State; Dinabandhu Sar, University of Illinois, Urbana-Champaign; Teresa Aditya, postdoctoral fellow in nuclear engineering at Penn State; Dipendra Dahal and Priyanka Ray, both postdoctoral fellows in Pan’s lab at his former institution, the University of Maryland, Baltimore.

Source:

Journal Reference:

Moitra, P., et al. (2024) Context-responsive nanoparticles from synthetic zwitterionic ionizable phospholipids in targeted CRISPR/Cas9 therapy for basal breast cancer. ACS Nano. doi.org/10.1021/acsnano.4c01400.

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