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Researchers at the University of Illinois Urbana-Champaign have developed an innovative approach to combat leukemia using DNA aptamers that target cancer stem cells, thought to be responsible for relapses of the disease.
These aptamers are short strands of DNA that can identify and bind to specific cancer-related molecules, much like antibodies, but with the added capability of delivering therapeutic agents directly to the targeted cells. Remarkably, the aptamers also possess cytotoxic properties, further aiding in the elimination of cancer stem cells, according to the study led by Professor Xing Wang and reported in the journal Advanced Functional Materials.
“This research highlights a method to address the underlying issues of leukemia,” Wang explained. “Conventional targeted therapies frequently struggle with issues of toxicity and effectiveness. Our aptamers are designed to specifically identify and induce the death of leukemia stem cells.”
Leukemia, alongside other blood cancers, presents unique challenges for treatment compared to solid tumors. The cancerous cells circulate freely throughout the body, rendering surgical options ineffective and creating a high likelihood of relapse due to the presence of these elusive stem cells. Abhisek Dwivedy, a postdoctoral researcher and lead author of the study, emphasized that although these stem cells represent a small subset of cancer cells, they can evade treatment by migrating to the bone marrow, where they remain hidden but capable of resurgence.
“Eliminating these stem cells is crucial in the treatment of leukemia and other hematological malignancies. Any remaining stem cells pose a risk for relapse and the development of secondary cancers,” added Dwivedy.
The research team began their work by identifying DNA aptamers that specifically locate markers on the surface of acute myeloid leukemia stem cells, aiming to address the disease on a more granular level.
“A significant finding of our study is that targeting two markers rather than one improves selectivity,” Wang noted. “Existing antibody-drug conjugates for blood cancers typically focus on a single marker, which can also be present in healthy cells, leading to unwanted toxicity. Our approach, using a dual-target strategy, focuses on markers predominantly found in leukemia cells and their stem cells, enhancing specificity.”
Subsequently, the researchers connected these aptamers with the chemotherapy agent daunorubicin. The aptamers are designed to transport the drug directly to cancer cells, where they release it intracellularly, maximizing its therapeutic effect.
“This targeted delivery is particularly beneficial for daunorubicin, as it does not easily penetrate cell membranes. However, our aptamers are capable of facilitating its entry,” Dwivedy explained.
To assess the effectiveness of their drug-carrying aptamers, the researchers conducted experiments on leukemia cell cultures and in live mice models. The results showed that after 72 hours, the aptamers alone reduced cancer cell populations by 40 percent, indicating their inherent toxicity. When combined with daunorubicin, the aptamer-drug conjugate was able to eliminate cancer cells using a dosage 500 times lower than typically required for the drug. In mouse models, the aptamer delivery method demonstrated equivalent effectiveness at a dosage one-tenth of the standard therapeutic level, suggesting a synergistic effect when delivering the drug via aptamers.
“We found these results particularly promising, as outcomes observed in cultures don’t always translate to live subjects. However, we noted significant tumor reduction and survival rates in treated mice without off-target effects,” Wang reported.
Looking ahead, the research team aims to broaden their repertoire of drug-delivering aptamers by identifying specific marker combinations for various cancers and exploring the potential to associate aptamers with other therapeutic agents.
“Each cancer cell has distinctive surface biomarkers. By identifying markers that are unique to different cancers, we can expand targeting capabilities across various cancer types. Additionally, pairing drugs with DNA molecules tends to be more effective than with proteins, which could enhance our drug delivery methods,” Dwivedy concluded.
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