Growth of Mantle Cell Lymphoma Slowed by Nanoparticle Transported siRNA

Cancer researchers have used targeted lipid-based nanoparticles to deliver particles of siRNA (short inhibiting RNA) to silence the gene for production of cyclin D1 in mantle cell lymphoma (MCL).

MCL is an aggressive B-cell lymphoma that over expresses cyclin D1 with relatively poor prognosis, and down-regulation of cyclin D1 using RNA interference (RNAi) has been suggested as a potential therapeutic approach to this malignancy. Short inhibiting RNAs are members of the family of microRNAs, which are a class of about 20 nucleotides-long RNA fragments that block gene expression by attaching to molecules of messenger RNA (mRNA) in a fashion that prevents them from transmitting the protein synthesizing instructions they had received from the DNA. With their capacity to fine-tune protein expression via sequence-specific interactions, miRNAs help regulate cell maintenance and differentiation.

Investigators at Tel Aviv University (Israel) prepared lipid-based nanoparticles (LNPs) coated with anti-CD38 monoclonal antibodies that were specifically taken up by human MCL cells in the bone marrow of xenografted mice.

Results published in the December 23, 2015, online edition of the journal Proceedings of the National Academy of Sciences of the United States of America (PNAS) revealed that when loaded with siRNAs against cyclin D1, CD38-targeted LNPs induced gene silencing in MCL cells and prolonged survival of tumor-bearing mice with no observed adverse effects.

"MCL has a genetic hallmark," said senior author Dr. Dan Peer, professor of cell research and immunology at Tel Aviv University. "In 85% of cases, the characteristic that defines this aggressive and prototypic B-cell lymphoma is the heightened activity of the gene CCND1, which leads to the extreme overexpression—a 3,000 to 15,000-fold increase—of cyclin D1, a protein that controls the proliferation of cells. Downregulation of cyclin D1 using siRNAs is a potential therapeutic approach to this malignancy."

"In MCL, cyclin D1 is the exclusive cause of the over-production of B lymphocytes, the cells responsible for generating antibodies," said Dr. Peer. "This makes the protein a perfect target for RNA therapy by siRNAs. Normal, healthy cells do not express the gene, so therapies that destroy the gene will only attack cancer cells. The RNA interference we have developed targets the faulty cyclin D1 within the cancerous cells. And when the cells are inhibited from proliferating, they sense they are being targeted and begin to die off."

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