Introduction
We consider ourselves dreamers. Theriac is our attempt to make a difference in the lives of patients with Glioblastoma. We understand that Theriac making it into the market is still a far-fetched dream. Nevertheless, our preliminary but noble work will be sure to inspire more researchers and companies to invest in rare cancer therapy and diagnosis. These diseases are rare but no patient should be alone. This page is a sneak peek into our vision.
Molecular mechanism
Theriac is a two-step theranostic approach. It consists of two types of hairpins, the first hairpin (Y-shaped) detects at the same time two different cancer biomarkers (miR-21 and miR-10b). In this way, discrimination of cancer cells from healthy ones is possible. At the same time, by attaching the two microRNAs, Theriac prevents them from acting in favor of cancer cells, achieving a first-to-go attempt of therapy. As analyzed in our design page, inhibition of miR-21 and miR-10b in GBM cancer cells could lead to inhibition of metastasis and cancer cells’ death.
Only after the detection of both microRNAS, and through changes in the secondary structure, the final and more specialized therapeutic molecules will be released. This procedure is called HCR and leads to the release of two siRNAs that target key molecules of cancer cells’ metabolism. Through this intervention, Theriac will cause apoptosis to both cancer cells and cancer stem cells, reducing the size of the tumour and minimizing the possibility of recurrence.
Administration
Theriac hairpins will be uploaded to a nanocarrier, with a magnetic core surrounded by a lipid membrane. The composition of the lipid membrane will be similar to those of glial cells to achieve better recognition of GBM cancer cells. The magnetic core will enhance the MRI signal giving the opportunity for real-time monitoring, detection of distant tumor loci, and treatment regiment adjustment.
Theriac will be administrated in the form of aerosol intranasally. The brain is protected by the blood-brain barrier (BBB) which doesn't allow most of the therapeutic molecules to reach GBM tumours. Nose-to-brain delivery offers a promising alternative to systemic delivery. It enables the direct transfer of therapeutic drugs to the CNS via the trigeminal or olfactory nerves, avoiding the BBB.
Theriac will be administrated after surgery (if that possible) or, instead of it, in cases where surgery is not feasible. If surgery is successful, Theriac will not be activated because there will not be left any cancer cells. Unfortunately, in most cases, due to the high metastasized profile of the GBM cells, the surgery is not successful and a lot of cancer cells are left behind. In those cases, due to overexpression of the microRNAs, Theriac will be activated and kill the cancer cells and cancer stem cells left behind.
Safety
Theriac will be a theranostic approach with a high safety profile. It will be activated only in GBM cancer cells, due to the absence of expression of miR-10b in healthy neural and glial cells. However, the two selected microRNAs are overexpressed under other comorbidities of CNS, too. Thus, some contraindications should be taken into consideration before or during Theriac’s administration, such as strokes and severe brain injuries.
Regarding the selected siRNAs, even if Theriac is for some reason activated in healthy cells, it will cause no harm. The targeted mRNAs (and proteins) are overexpressed in GBM and are necessary for the proliferation of cancer cells. In healthy cells, their expression is minimum and can be replaced by other proteins, too. Moreover, Theriac is a personalized therapeutic approach, meaning that the siRNAs released will be proportional to the size of the tumour.
Regarding the nanocarrier, caution should be given to possible toxicity due to Ferrum. To bypass this problem, we choose as prototypes FDA-approved magnetic nanoparticles with a concentration of Ferrum that doesn’t cause increased brain toxicity or oxidative stress. Moreover, we took into consideration different sizes of the nanocarrier to achieve better and safer transportation. One of the biggest challenges to nasal drug delivery is overcoming barriers posed by the nasal mucosal lining and the enzymes present in the nasal cavity. The ability of the nasal tissues to metabolize drugs is something that cannot be overlooked (Krishnamoorthy & Mitra, 1998).
Neural Network
We also developed a software tool to monitor the patient in real-time and assist the medical professional using Theriac. Our neural network is trained to intentify MRI images from patients with GBM, evaluate the current stage of the disease, and possibly, the effect of a potential treatment. Our nanocarriers, due to their Ferrum oxide core, will enhance the MRI signal in the areas they reach. Common therapies are causing false images in MRI scans called pseudoprogression due to edema caused by damage to near healthy cells. Theriac has a high specificity for GBM cells thus, no pseudoprogression will occur.
Outcome
In total, Theriac will offer a personalized theranostic approach with a high safety profile. A more accurate and well-tolerated therapy accompanied by better monitoring techniques, according to bibliography, can increase the 5-year survival rate from up to 15% percent, saving many lives. It will take many years and more than a lot of money for such a product to come onto the market. An integral part of Theriac’s future implementation is the founding of Theriac’s platform. Our dream and passion are to make breakthrough research possible and accessible by everyone. One step closer to democratizing research and implementing Theriac, our innovative approach to our entrepreneurship page we hope to fascinate you!
References
Keller, L.-A., Merkel, O., & Popp, A. (2021). Intranasal drug delivery: opportunities and toxicologic challenges during drug development. Drug Delivery and Translational Research. https://doi.org/10.1007/s13346-020-00891-5
Pires, A., Fortuna, A., Alves, G., & Falcão, A. (2009). Intranasal Drug Delivery: How, Why and What for? Journal of Pharmacy & Pharmaceutical Sciences, 12(3), 288. https://doi.org/10.18433/j3nc79
Krishnamoorthy, R., & Mitra, A. K. (1998). Prodrugs for nasal drug delivery. Advanced Drug Delivery Reviews, 29(1-2), 135–146. https://doi.org/10.1016/s0169-409x(97)00065-3
McMartin, C., Hutchinson, L. E., Hyde, R., & Peters, G. E. (1987). Analysis of structural requirements for the absorption of drugs and macromolecules from the nasal cavity. Journal of Pharmaceutical Sciences, 76(7), 535–540. https://doi.org/10.1002/jps.2600760709