Nanotechnology

RNA nanoparticle therapy stops the spread of incurable bone marrow cancer

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June 17, 2023

(Nanowerk News) Multiple myeloma is an incurable bone marrow cancer that kills more than 100,000 people every year. Known for its rapid spread and lethality, this disease is one of the most challenging to overcome. As these cancer cells move through different parts of the body, they mutate, surpassing the possibilities of treatment. People diagnosed with severe chemotherapy-resistant multiple myeloma usually survive for only three to six months. Innovative therapies are urgently needed to prevent the spread of this disease and give those who suffer from it a fighting chance.

Michael Mitchell, J. Peter and Geri Skirkanich Assistant Professors of Innovation in Bioengineering (BE), and Christian Figueroa-Espada, doctoral student in BE at the University of Pennsylvania School of Engineering and Applied Science, created an RNA nanoparticle therapy that makes it impossible for multiple myeloma to move and mutate. Those treatments, described in their research published in PNAS (“In vivo bone marrow microenvironmental siRNA delivery using lipid-polymer nanoparticles for the therapy of multiple myeloma”), turns off the cancer-attracting function in blood vessels, inactivates the pathways that some myeloma cells travel. Myeloma cells produce monoclonal proteins of various types. Myeloma cells produce monoclonal proteins of various types. (Image: Scientific Animation)

By turning off these “GPS chemicals” that induce migration of cancer cells, the team’s therapy stops the spread of multiple myeloma, helping to eliminate it completely.

Endothelial cells, which line blood vessels, produce the proteins we need to survive. This protein, CyPA, is responsible for folding and transporting other proteins. It also activates the T-cell response when we are sick.

However, when multiple myeloma is present, endothelial cells overexpress CyPA and secrete it into the blood vessels where it becomes malignant. Here, CyPA is a chemo-attractant, meaning it attracts large numbers of myeloma cells from the bone marrow into the blood vessels where they move rapidly to other bones in the body.

“To stop the spread, we aim to shut down these CyPA functions using RNA therapy, targeting the cancer microenvironment, not the cancer cells themselves,” Mitchell said. “But getting nucleic acids into the marrow is challenging due to complex biological barriers.”

To get RNA into hard-to-reach bone marrow, the team needed to redesign traditional delivery vehicles for lipid nanoparticles.

“We designed a new hybrid nanoparticle that can deliver small interfering RNA (siRNA) to endothelial cells,” said Figueroa-Espada. “SiRNA stops the cell from producing CyPA. When tested in vitro, the therapy prevented the spread of cancer cells. When tested in mice, either alone or in combination with chemotherapy, our therapy was able to reduce tumor size, extend survival rates, and decrease cancer resistance to chemotherapy.”

“This work could help improve current treatments for multiple myeloma as well as other cancers that spread via blood vessels,” Mitchell added. “By using our platform for targeted nanoparticle development, we hope to investigate cancer and other diseases in which CyPA is overexpressed.”

By creating barriers in the cancer’s passage through the body, the Penn Engineering team removed long-standing barriers in the treatment of multiple myeloma, providing real hope for people diagnosed with this disease.

In future work, the team plans to investigate silencing additional functions in the cancer microenvironment to better address drug resistance, cancer initiation, and metastasis. They are currently working with Ruben Carrasco, Professor of Pathology at the Dana-Farber Cancer Institute and co-author of this study, to identify potential targets for this type of therapy. Once RNA nanoparticle therapy has been shown to be safe in larger animals, this proof-of-concept study can move on to clinical trials.



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