Tumor-Shrinking Triple-Helices

A braided structure and some adhesive hydrogel make therapeutic microRNAs both stable and sticky.

MicroRNAs (miRs) are small, noncoding ribonucleic acids that control the translation of target messenger RNAs (mRNAs). Given their roles in development, differentiation, and other cellular processes, misregulation of miRs can contribute to diseases such as cancer. Indeed, “they are recognized as important modulators of cancer progression,” says Natalie Artzi of Harvard Medical School.

In addition to occasionally promoting cancer pathology, miRs also hold the potential to treat it—either by restoring levels of suppressed miRs, or by repressing overactive ones using antisense miRs (antagomiRs). While miRs are promising therapeutic molecules, says Daniel Siegwart of the University of Texas Southwestern Medical Center in Dallas, their use “is currently hindered by at least two issues: nucleic acid instability in vivo, and the development of effective delivery systems to transport miRs into tumor cells.”

Artzi and her team have now addressed both of these issues in one fell swoop. They first assembled two therapeutic miRs—one antagomiR and one that replaced a deficient miR—together with a third miR, a complement of the replacement strand, into triple-helix structures, which increased molecular stability without affecting function. They then complexed these helices with dendrimers—large synthetic branching polymer particles—and mixed these complexes with dextran aldehyde to form an adhesive hydrogel. The gel could then be applied directly to the surface of tumors to deliver the therapeutic miRs into cells with high efficiency.

In mice with induced breast tumors, the triple-helix–hydrogel approach led to dramatic tumor shrinkage and

extended life span: the animals survived approximately one month longer than those treated with standard-of-care chemotherapy drugs. Because the RNA-hydrogel mixture must be applied directly to the tumor, the approach will not be suitable for all cancers. But one potential application, says Siegwart, is that “the hydrogel could be applied by a surgeon after performing bulk tumor removal...[and] might kill remaining tumor cells that would otherwise cause tumor recurrence.”

miR DELIVERY SYSTEM VEHICLE DOSE TUMOR TARGETING APPLICABLE

TUMOR TYPES

Nanoparticles Examples: gold Usually Combining miRs with Multisite or

particles, liposomes, multiple aptamers or antibodies blood cancers

peptide nucleic injections can guide nanoparticles

acids, or polymers to target cells, but leads

to some off-target

dispersion.

RNA–triple- Dendrimer- One Adhesive hydrogel sticks Solid Tumors

helix-hydrogel dextran hydrogel miRs to tumor site with

minimal dispersion to other

tissues.

Source:

Nature Materials,doi:10.1038/NMAT4497, 2015

#cancer #drugdelivery #microRNA #miRNA #ModusOperandi #genetics