Researchers from Boston Children’s Hospital and Massachusetts Institute of Technology have developed a targeted drug-delivery system that’s based on a combination of ultraviolet (UV) light and short, single strands of DNA called aptamers. The study is published in the Proceedings of the National Academy of Sciences (PNAS).
Aptamers hold appeal as drug delivery tools, or as drugs themselves, because they’re small size, penetrate tissues rapidly and resist enzymatic breakdown in the bloodstream. They’re readily synthesized, can be tagged onto drugs or other therapeutic molecules and can be designed to stick to specific targets similar to how an antibody would.
Their downside, however, is that they spread easily through the body and tend to accumulate in normal tissues, such as liver and kidneys. Thus, it’s hard to get enough aptamers to the site of the diseased tissue to have a therapeutic effect, and one can get off-target effects.
DNA and RNA aptamers are very useful, and have been widely used for biomedical applications like sensing, targeted imaging and drug delivery. To use them for targeted tumour therapy the team needed to improve their targeting efficiency.
The research team’s solution was to use light. They engineered a complementary short DNA strand, called an oligonucleotide, containing chemical bonds that break in UV light. In the absence of UV, the oligonucleotide and the aptamer stick together, stopping the aptamer from binding to its target.
In the presence of UV, though, the oligonucleotide’s light-sensitive bonds break, snapping it into even smaller DNA pieces that float away, giving the liberated aptamer a chance to bind to its target cells. In the rest of the body, the aptamer isn’t activated. The specific effect of the aptamer is gained only where light is shone which allows great spatial and temporal control over where the therapeutic action takes place.
The research team tested the approach’s utility in breast cancer cell lines and in a live mouse model of breast cancer, using an aptamer targeted to the protein nucleolin, found on the surface of many kinds of cancer cells.
In both systems, the aptamer alone easily bound to nucleolin and penetrated cancerous cells. Adding the oligonucleotide kept the aptamer from binding to its target, until the researchers turned on a UV laser, breaking up the oligonucleotide and freeing the aptamer to bind to nucleolin again demonstrating the approach’s power in a live animal.
The researchers found they could readily control accumulation of the oligonucleotide-bound aptamers in tumours simply by shining their UV light on the mice. They also noted that the method significantly reduced the amount of aptamer accumulating in the liver and kidneys relative to the tumours.
The team state that there are very few demonstrations of something like this working in vivo. It’s the kind of work that brings together two different areas, aptamers and light activation, that don’t ordinarily mix.
The team adds that this method could potentially complement other light-activated drug technologies the lab has developed, like drug-loaded nanoparticles that squeeze out their payload when exposed to UV light, or gold nanoparticles that heat up in near-infrared light to cook diseased cells.
The team summise that aptamers could be tagged to passive particles, ones that don’t react to light, or to particles that are triggered by the same or different wavelengths. Those are some of the kinds of future approaches the team is planning.
Source: Boston Children’s Hospital