Scientists are using microcellular drones to deliver lung cancer-killing drugs

In a study conducted by researchers at NUS Yong Loo Lin School of Medicine, extracellular vesicles loaded with customizable anticancer antisense oligonucleotides suppressed cancer growth.

Lung cancer, particularly non-small cell lung cancer (NSCLC) – the most common subtype of cancer affecting patients who do not smoke – is a leading cause of cancer mortality and the second most commonly diagnosed cancer worldwide. The rapid and inevitable emergence of drug resistance mechanisms caused by cancer mutations is occurring far faster than the development of small molecule drugs. This phenomenon increases the urgency for a new, adaptable, safe and effective cancer therapeutic that can be developed, tested and validated in a short time.

A team of researchers led by Assistant Professor Minh Le from the Institute of Digital Medicine (WisDM) and the Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore (NUS Medicine) has successfully demonstrated that nano-sized particles exist in cells like Substances released by red blood cells could be used as drug delivery platforms to deliver antisense oligonucleotide molecules (ASO) that target cancer cells in the lungs, thereby suppressing cancer progression.

This study was conducted in collaboration with the Cancer Science Institute of Singapore (CSI Singapore) at NUS, the Agency for Science, Technology and Research (A*STAR), the National Cancer Center Singapore (NCCS) and Duke-NUS Medical School .

Asst Prof Minh Le said: “Mutated epidermal growth factor receptors (EGFRs) are the most common cause of lung cancer in the Asian population. Therefore, we focused on fighting lung cancer caused by mutated EGFR. Currently, drugs known as tyrosine kinase inhibitors are the standard of care, and they work by inhibiting the mutated EGFR protein to stop the cancer from progressing. Because the cancer cells may continue to mutate and resist these drugs, we looked for a more effective way to fight the cancer.”

In the study published in eBioMedicineThe authors hoped for ASOs to not only overcome the problem of drug resistance but also contribute to the development of precision medicine.

Precision medicine tailors treatment individually to the patient and their disease, in contrast to “one-size-fits-all” broad-spectrum therapy. ASOs are molecules that attach to a specific part of a ribonucleic acid (RNA) and can inhibit irregular activities. ASOs are a flexible tool that can be easily redesigned to target and correct problems in different genes. This advantage is critical in the context of NSCLC as it is known to develop resistance to tyrosine kinase inhibitors.

Additionally, the ASOs can be customized to target unique mutations based on each individual patient's cancer profile. However, some disadvantages of ASOs are that they are easily broken down in the bloodstream, resulting in diluted treatment at tumor sites. A method that captures the ASOs and delivers them directly to the tumor site provides a solution.

To achieve this, the researchers used extracellular vesicles (EVs) derived from human red blood cells as natural carriers to deliver the anti-cancer ASOs to the tumor site. To target the ASO-loaded EV to the tumor site, EGFR targeting moieties were attached to the surface of the EVs. This prepared the EV to locate the cancer cells.

Furthermore, the ASO-loaded EVs were shown to exhibit potent anticancer effects in various lung cancer models, including patient-derived cells. The specific design of ASOs allows them to suppress mutated EGFR while leaving normal EGFR unaffected. They also showed that the ASO-loaded RBCEVs possess potent anticancer effects against TKI-resistant cancer cells.

Associate Professor Tam Wai Leong, deputy managing director of the A*STAR Genome Institute of Singapore (A*STAR GIS) and co-author of the study, said: “The innovative use of extracellular vesicles as a delivery vehicle for nucleic acid therapeutics.” The ability to precisely target mutant EGFR cancer cells Eliminating them while sparing normal tissue will enable tailored treatment for individual patients. This is an important step towards combating cancer drug resistance and advancing the application of personalized cancer medicine. “

Professor Goh Boon Cher, Deputy Director of CSI Singapore, Professor of Medicine at NUS Medicine and one of the study's authors, added: “This work is instrumental in pioneering new avenues for the precise delivery of therapeutic RNA to tumor cells “To destroy them.” It is a proof of concept that can be applied to other areas of cancer treatment.”