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Folate-Bound MicroRNAs Slow Tumor Progression in Models

By BiotechDaily International staff writers
Posted on 15 Aug 2017
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Image: Folate as a yellow-orange crystalline powder (Photo courtesy of Wikimedia Commons).
Image: Folate as a yellow-orange crystalline powder (Photo courtesy of Wikimedia Commons).
A growth-inhibiting microRNA conjugated to molecules of folate reduced tumor size when delivered to mice with lung and breast cancer tumors that overexpressed the folate receptor.

MicroRNAs (miRNAs) are a family of noncoding 19- to 25-nucleotide RNAs that regulate gene expression by targeting messenger RNAs (mRNAs) in a sequence specific manner, inducing translational repression or mRNA degradation, depending on the degree of complementarity between miRNAs and their targets. Many miRNAs are conserved in sequence between distantly related organisms, suggesting that these molecules participate in essential processes. In fact, miRNAs have been shown to be involved in the regulation of gene expression during development, cell proliferation, apoptosis, glucose metabolism, stress resistance, and cancer. Since changes in microRNA expression can promote or maintain disease states, microRNA-based therapeutics are being evaluated extensively.

Despite the attractions of using miRNAs as therapeutic agents, the rapid degradation of miRNA in vivo necessitates the use of protection strategies such as liposomes or backbone modification; however, this can hinder miRNA stability, activity, and uptake efficiency and may in themselves have toxic porperties.

To avoid these problems, investigators at Purdue University developed a novel transport method that relied on direct attachment of microRNAs to folate (FolamiR), which mediated delivery of the conjugated microRNA into cells that overexpressed the folate receptor.

Results published in the August 2, 2017, online edition of the journal Science Translational Medicine showed that the tumor-suppressive FolamiR, FolamiR-34a, was quickly taken up both by triple-negative breast cancer cells in vitro and in vivo and by tumors in a mouse lung cancer model and slowed their progression. FolamiR-34a, which acted as a ligand of the folate receptor, increased miR-34a copy number and reduced tumor size.

The folate receptor-targeted method delivered microRNAs directly to tumors in vivo without the use of toxic vehicles, representing an advance in the development of nontoxic, cancer-targeted therapeutics.

"RNAs are inherently unstable; they are subject to being degraded in the bloodstream. It has been hypothesized that if we want to use RNA as a therapy, we have to protect it," said senior author Dr. Andrea Kasinski, professor biology at Purdue University. "Protective vehicles are usually some sort of nanoparticle, often a lipid-encapsulated particle. Although the RNA is protected, the protection typically comes at a price. These particles tend to be a little larger, so penetrating the dense architecture of the tumor can be difficult. Many of these lipids are also toxic."

"Folate is generally pro-growth. That is why cancer cells overexpress the receptor - they want more folate," said Dr. Kasinski. "We are just hijacking that idea and saying, "Okay, you can have all the folate you want, but we are going to conjugate it to a warhead that will hopefully knock out the cancer cell." I think everything we do scientifically, especially in a cancer lab, moves us closer to an effective cancer therapy. But there is still more we need to do. Maybe there are other microRNAs that will be better."

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