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Tumor Shrinking Triple Helices

Posted in Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, RNA Biology, Cancer and Therapeutics, tagged , , , , , , , , , , , on April 30, 2016| Leave a Comment »

Tumor Shrinking Triple Helices

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Tumor-Shrinking Triple-Helices

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

By Ruth Williams | April 1, 2016

http://www.the-scientist.com/?articles.view/articleNo/45576/title/Tumor-Shrinking-Triple-Helices

 

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.” (Nature Materials, http://dx.doi.org:/10.1038/NMAT4497, 2015)

STICKING IT TO TUMORS: To deliver therapeutic microRNAs (miRs) to tumors, braids of three microRNAs (miRs)—an antisense strand that blocks a miR overactive in cancer, a strand that replaces a deficient miR, and a stabilizing strand (1)—are added to a dendrimer (2) and mixed with a hydrogel scaffold (3). When researchers introduced the sticky gel onto mouse mammary tumors (4), the malignancies shrank and the animals lived longer (5)© GEORGE RETSECK; J.CONDE ET AL., NATURE MATERIALS

 

miR DELIVERY SYSTEM VEHICLE DOSE TUMOR TARGETING APPLICABLE TUMOR TYPES
Nanoparticles Examples: gold particles, liposomes, peptide nucleic acids, or polymers Usually multiple injections Combining miRs with aptamers or antibodies can guide nanoparticles to target cells, but systemic delivery inevitably leads to some off-target dispersion. Multisite or blood cancers
RNA–triple-helix-hydrogel Dendrimer-dextran hydrogel One Adhesive hydrogel sticks miRs to tumor site with minimal dispersion to other tissues. Solid Tumors

 

Self-assembled RNA-triple-helix hydrogel scaffold for microRNA modulation in the tumour microenvironment

João Conde, Nuria Oliva, Mariana Atilano, Hyun Seok Song & Natalie Artzi
Nature Materials15,353–363(2016)                         http://dx.doi.org:/10.1038/nmat4497

The therapeutic potential of miRNA (miR) in cancer is limited by the lack of efficient delivery vehicles. Here, we show that a self-assembled dual-colour RNA-triple-helix structure comprising two miRNAs—a miR mimic (tumour suppressor miRNA) and an antagomiR (oncomiR inhibitor)—provides outstanding capability to synergistically abrogate tumours. Conjugation of RNA triple helices to dendrimers allows the formation of stable triplex nanoparticles, which form an RNA-triple-helix adhesive scaffold upon interaction with dextran aldehyde, the latter able to chemically interact and adhere to natural tissue amines in the tumour. We also show that the self-assembled RNA-triple-helix conjugates remain functional in vitro and in vivo, and that they lead to nearly 90% levels of tumour shrinkage two weeks post-gel implantation in a triple-negative breast cancer mouse model. Our findings suggest that the RNA-triple-helix hydrogels can be used as an efficient anticancer platform to locally modulate the expression of endogenous miRs in cancer.

 

Figure 1: Self-assembled RNA-triple-helix hydrogel nanoconjugates and scaffold for microRNA delivery.

Self-assembled RNA-triple-helix hydrogel nanoconjugates and scaffold for microRNA delivery.

a, Schematic showing the self-assembly process of three RNA strands to form a dual-colour RNA triple helix. The RNA triplex nanoparticles consist of stable two-pair FRET donor/quencher RNA oligonucleotides used for in vivo miRNA inhibit…

 

Figure 4: Proliferation, migration and survival of cancer cells as a function of RNA-triple-helix nanoparticles treatment.close

Proliferation, migration and survival of cancer cells as a function of RNA-triple-helix nanoparticles treatment.

a, miR-205 and miR-221 expression in breast cancer cells at 24, 48 and 72 h of incubation (n = 3, statistical analysis performed with a two-tailed Student’s t-test, ∗∗, P < 0.01). miRNA levels were normalized to the RNU6B reference gene

 

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