Introduction
Glioblastoma drew our team’s attention when we were looking for a project. It is a type of cancer that grows in our brains and is very lethal. This type of cancer is one of the most aggressive malignancies. It is often called incurable due to its high mortality. Treatments already exist, yet, we need new ones with better patient outcomes.
Statistics of GBM show it is the most common malignant tumour in an adult's brain. Only 5–6 out of 100 glioblastoma patients survive 5 years after diagnosis. This is the lowest survival rate of all types of cancer. A patient is usually expected to live for about 15 months. This short life expectancy can affect the patient’s physical and mental health, so it is a dual problem. Glioblastoma concerns 3 per 100,000 people around the world every year (Ostrom et al. 2018), so it is a rare type of cancer.
The current methods of treatment are surgery, radiotherapy, and chemotherapy. Surgery cannot be perfect. It is difficult for the neurosurgeon to distinguish between tumor cells and healthy tissue. So, we cannot completely remove the tumour, which means local recurrence. Chemotherapy and radiotherapy often mean chemoresistance and burdening side effects (Grochans et al. 2022). GBM patients often suffer a relapse because of ineffective treatments. That means a worse prognosis (Mirzaei et al. 2021). It is obvious there is room for improvement in GBM treatments, and research is necessary.
The inspiration
We came across a paper describing a process called Hybridization Chain Reaction (HCR). This new method of sequence amplification has many advantages, e.g. it needs no enzymes. The technique is based on the recognition and hybridization between different types of hairpins. We decided to alter these hairpins to carry therapeutic molecules. That way, this process could be a tool in a new therapeutic approach for GBM (Evanko et al. 2004).
Our project
We designed "Theriac", a molecular theranostic tool, based on the HCR technique, that will be uploaded in a nanocarrier for its delivery to the brain.
Theranostics combine therapy and diagnosis. In our case diagnosis is about the detection of biomarkers and patient monitoring. This detection causes the release of a molecule called ‘’initiator’’. The initiator triggers hybridization chain reactions of HCR Hairpins. Due to these reactions therapeutic molecules, siRNAs are released. These molecules can interrupt biomolecular pathways and suppress tumour growth.
In more detail, Theriac consists of two types of hairpins. The Y-type hairpin, consists of 3 DNA strands and detects 2 biomarkers. These biomarkers are 2 microRNAs that glioblastoma cancer cells overexpress. This process releases the initiator. This initiator changes the secondary structure of the HCR hairpins. The initiator is complementary to the 5' of the first HCH-Hairpin (H1). After hybridization of H1 and iniatiator, H1 unfolds and attaches H2 hairpin, which in turn attaches H3. H3 after unfolding is binding with H4 Wich the then can cause unfolding of H1, etc. In every circle (H1-H4) 2 siRNAs are released.
We aim to load this molecular mechanism to a nanocarrier. This way it can reach metastatic cells in areas of the brain the surgeon cannot. Besides, the nanocarrier could amplify the MRI signal, helping the process of monitoring.
Theriac targets GBM in a precise way, suggesting a new approach to GBM therapy with a high safety profile and fewer side effects (Ma et al. 2019; Gong et al. 2021).
Figure 1. Y Mechanism
Figure 2. HCR Mechanism
References
Evanko, D. Hybridization chain reaction. Nat Methods 1, 186 (2004). https://doi.org/10.1038/nmeth1204-186a
Grochans, S., Cybulska, A. M., Simińska, D., Korbecki, J., Kojder, K., Chlubek, D., & Baranowska-Bosiacka, I. (2022). Epidemiology of Glioblastoma Multiforme–Literature Review. Cancers, 14(10). https://doi.org/10.3390/cancers14102412
Mirzaei, S., Mahabady, M. K., Zabolian, A., Abbaspour, A., Fallahzadeh, P., Noori, M., Hashemi, F., Hushmandi, K., Daneshi, S., Kumar, A. P., Aref, A. R., Samarghandian, S., Makvandi, P., Khan, H., Hamblin, M. R., Ashrafizadeh, M., & Zarrabi, A. (2021). Small interfering RNA (siRNA) to target genes and molecular pathways in glioblastoma therapy: Current status with an emphasis on delivery systems. Life sciences, 275, 119368. https://doi.org/10.1016/j.lfs.2021.119368
Ostrom, Q. T., Gittleman, H., Truitt, G., Boscia, A., Kruchko, C., & Barnholtz-Sloan, J. S. (2018). CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2011–2015. Neuro-Oncology, 20(Suppl 4), iv1. https://doi.org/10.1093/neuonc/noy131
