Vancouver Researchers Build Radioactive DNA Molecules for Future Precision Cancer Treatments
Vancouver researchers have created a new way to build radioactive DNA molecules using enzymes that could help reimagine how radiolabeled drugs are built. Using enzymes that normally copy genetic material, scientists at UBC Chemistry and the BC Cancer Research Institute programmed synthetic DNA to carry cancer-fighting isotopes in precise patterns, opening the door to developing drugs that could both image tumors and destroy them with the same molecule.
The work represents a natural progression for new applications in nucleic acid technologies, which have been central to molecular biology since the Human Genome Project. Whereas previous examples of radioactive DNA used isotopes like phosphorus-32 for research, this new platform employs medically relevant metals, including some already approved for treating cancer, that can be delivered to patients.
“We’ve essentially repurposed the cell’s DNA-copying machinery to build radiopharmaceuticals,” said Antonio Wong, PhD candidate at BC Cancer and UBC, the lead author on the project who did all of the experimental work and helped conceive key experiments. “The enzymatic process takes less than 10 minutes and gives us unprecedented control over how many radioactive atoms go into each molecule and exactly where they’re positioned.”
Why it matters
Cancer touches nearly every family – driving the need for better treatments that improve outcomes and quality fo life. The new method harnesses DNA’s natural precision to build what researchers call “theranostic” drugs, molecules that both diagnose and treat disease simultaneously.
As radioactive drugs continue to evolve with increasing promise in treating cancers with great precision, new challenges involve getting of more than one medically relevant radioisotope into molecules of biological and therapeutic interest. Here, DNA provides an ideal solution to this challenge; by using the enzymes that make it and tricking them into incorporating more than one kind of radioisotope into the DNA, we can now synthesize multi-radiometallated molecules with defined compositions.
“This work erases traditional boundaries between DNA chemistry and radiopharmaceutical development. We’ve kicked off a new platform for biomanufacturing the next-generation of radiotherapeutics where we exploit the information content of nucleic acids to program the incorporation of medical isotopes within designed molecules,” Dr. David Perrin, Professor of Department of Chemistry commented, adding, “what’s special about this technology is the potential for readily being able to incorporate more than one radioactive metal isotope to apply more than one radio-theranostic modality”
How they did it
The work, a collaboration between Dr. David Perrin, UBC and Dr. François Bénard, Distinguished Scientist and Vice President Research, BC Cancer Research Institute, builds on decades of enzymatic DNA synthesis but introduces a crucial innovation: modifying DNA’s building blocks to carry metal-chelating molecules that grip radioactive isotopes.
The team synthesized modified versions of two DNA letters (C and T) attached to molecular “cages” that hold metals. They then loaded these cages with five different metals, including gallium-68 (used in PET imaging), lutetium-177 (used in FDA-approved cancer therapies), and terbium-161 (an emerging therapeutic isotope).
When mixed with natural DNA-copying enzymes and a template strand, these radioactive building blocks are incorporated into new DNA strands following the template’s instructions, just as cells copy their genomes. The DNA sequence itself becomes the programming language that dictates which radioactive metals go where.
Using mass spectrometry sensitive enough to detect metals at parts-per-trillion concentrations, the researchers confirmed that metal ratios in the final products matched the template sequences exactly. Radioactive imaging further validated that clinically relevant isotopes were incorporated with high efficiency and specificity.
Crucially, the radioactive DNA molecules retained their ability to recognize and bind to complementary DNA strands, a property essential for targeting specific genetic sequences in living systems. The current study demonstrates the chemistry platform itself: showing that enzymatic synthesis can incorporate multiple radioactive metals into DNA with sequence-defined precision. The team has not yet tested these molecules in preclinical models which will be essential to determine whether the approach can deliver on its therapeutic promise.
From theory to proof-of-principle
The breakthrough required resources that neither institution could provide alone. BC Cancer contributed specialized radiochemistry facilities and expertise in nuclear medicine, while UBC brought synthetic chemistry capabilities and enzymatic expertise.
“This is exactly the kind of discovery that becomes possible when you pool specialized equipment and knowledge across institutions,” Wong noted. “The radioisotope handling, mass spectrometry, and molecular biology techniques we needed don’t typically exist under one roof.”
The collaboration also bridges two fields, nucleic acid chemistry and nuclear medicine, that have historically operated independently.
Next steps
The team’s immediate focus is on pre-clinical studies to test these radioactive DNA molecules in laboratory models and understand how they behave in biological systems. The long-term vision is to develop the platform into clinical tools: a goal that will require extensive pre-clinical validation and clinical trials. This invention is expected to increase the diversity of for new radiotracer design that should eventually improve patient outcomes through better imaging, more effective therapies, or theranostic combinations of both.
Success will depend on continued partnerships between chemists, biologists, clinicians, and industry, exactly the kind of cross-disciplinary collaboration that made this breakthrough possible. Still, significant hurdles will need to be addressed including validation in pre-clinical animal cancer models and refinement of (radio)synthetic methods to generate significant quantities of radiometallated DNA to show real applications against cancer.
"Nucleic acids are versatile building blocks and this technology can be used to create unique 3D structures that can interact with various proteins expressed in cancer cells such as receptors or enzymes." says Dr. François Bénard. "This technology opens up exciting new possibilities for nuclear medicine applications, from diagnosis to treatment."
About the research
The study, published in Angewandte Chemie International Edition, was supported by the Natural Sciences and Engineering Research Council of Canada (NSERC), the New Frontiers in Research – Transformation (NFRF-T) Fund, and other agencies. Antonio Wong conducted the research under the joint supervision of Dr. François Bénard (BC Cancer, Department of Basic and Translational Research; UBC, Department of Radiology) and Dr. David Perrin (UBC, Department of Chemistry).
Read the full paper in Angewandte Chemie International Edition here.