Oligonucleotide Nanostructure Targets Cancer Cells for RNA Therapy

The delivery of therapies specifically to cancer cells has always been hindered by limitations of the delivery molecules – all too often off-target effects can be detrimental to a patient’s overall health. Moreover, while chemotherapies have been highly useful as targeted treatments for cancer, unwanted side effects still plague therapeutic outcomes. However now, researchers at the University of Missouri (MU) have demonstrated that specialized nucleic acid-based nanostructures could be used to target cancer cells while bypassing normal cells.

Findings from the new study were published recently in Nature Communications through an article titled “Modular cell-internalizing aptamer nanostructure enables targeted delivery of large functional RNAs in cancer cell lines.”

“Most of the therapeutic drugs are not able to discriminate the cancer cells from healthy cells,” explains lead study investigator David Porciani, Ph.D., a postdoctoral fellow at the MU Bond Life Sciences Center. “They are killing both cell populations (healthy and malignant), and the treatment can have harsher side effects than the cancer itself in the short term. We are developing ‘smart’ molecules that can bind with receptors that are found on the surface of cancer cells, thus representing a cancer signature. The idea is to use these smart molecules as vehicles to deliver chemotherapeutic drugs or diagnostics.”

In the current study, the research team used a molecular process that mimics a highly-accelerated form of natural evolution – the scientists looked to nucleic acid ligands or aptamers. Because of their three-dimensional structures, aptamers can be engineered to bind to certain target molecules with high affinity and selectivity. When the target is a cancer-associated receptor, these aptamers can be used as molecular tools to recognize specifically diseased cells.

The team then mimicked a therapeutic payload and “loaded” the aptamers with large, fluorescent RNAs. Upon incubation with target cancer and nontarget cells, only malignant cells were illuminated by the nanostructure showing that the structures had correctly bonded with their intended targets.

“We demonstrated a modular nanostructure for cellular delivery of large, functional RNA payloads (50–80 kDa, 175–250 nt) by aptamers that recognize multiple human B cell cancer lines and transferrin receptor-expressing cells,” the authors wrote. “Fluorogenic RNA reporter payloads enable accelerated testing of platform designs and rapid evaluation of assembly and internalization. Modularity is demonstrated by swapping in different targeting and payload aptamers. Both modules internalize into leukemic B cell lines and remained colocalized within endosomes.”

“Next steps for our studies are to prove that these aptamers can be loaded with therapeutic molecules that specifically target and treat cancer cells leaving normal tissues untouched,” Dr. Porciani adds. “While aptamers have been proven in the past as tools to deliver small drugs, our method paves the way to deliver even larger and potentially more powerful RNA-based drugs possibly creating that ‘magic bullet’ that [Paul] Ehrlich described in the last century.”