In this Neuronet spotlight on early-career researcher interview, we speak with Ilaria Ottonelli, who currently studies innovative nanomedicines for brain and retinal targeting at the University of Modena and Reggio Emilia. We asked Ilaria about her career, research, as well as about challenges & opportunities in her field.
What made you decide to follow a career in science?
Since I was a kid, I have always been fascinated by anything related to science: chemistry, biology, and medicine in particular. I was what everyone considered a “nerdy” little girl. While others were playing with dolls and action figures or playing sports, I was looking at leaves and insects under a toy microscope, mixing powders that I found in the house just to see what happened, and reading from the encyclopaedia as a bedtime story.
Studying science now continues to make me feel like that child. It keeps me curious about the world around us and its mechanisms, and I hope to never lose that sentiment. These feelings are what made me go into it and continue to push me forward in this career.
What do you enjoy most about doing research?
I appreciate the everyday life and challenges as a researcher: I enjoy lab activities, sharing my expertise with students, as well as staying informed on the latest discoveries in my field. But the thing that really makes the difference for me is the perspective that the research that I am doing now could improve the health and the life of people in need. The possibility to have a positive impact in the life of other people really inspires me to get up every day and work to my fullest potential.
What are tunnelling nanotubes and how could they be involved in the development of diseases in the brain?
Tunnelling nanotubes (TNTs) are a form of cellular communication that was firstly discovered in the early 2000s. These are really thin bridges that connect two cells, allowing for the direct exchange of any kind of material from one to the other. It is probably a mechanism of survival. For example, when a cell is suffering from high concentration of something toxic, TNTs can reduce the toxicity of one cell by diluting it between numerous other cells. Another example would be that a cell with damaged organelles could receive healthy ones from other cells nearby in order to survive.
Now, since TNTs are triggered when a cell is suffering, they are often overexpressed in the case of diseases as well. This unfortunately results in the spreading of various diseases, such as Glioblastoma, Alzheimer’s, Parkinson’s, Huntington’s, and prion diseases. They have also been shown to play an important role in the formation of metastases, and the spreading of viral infections.
What are nanomedicines, and how do they contribute to medicines development?
Nanomedicines are nano-sized carriers that can help overcome limitations of classical therapies for various diseases. These structures, for example, can improve the availability of a drug in the bloodstream by increasing its solubility and reducing its irritant properties, which are often major issues in the case of chemotherapeutics; with nanomedicines it is also possible to use classes of drugs such as proteins and enzymes, as they can protect these molecules from degradation, thus increasing therapeutic efficacy.
Another advantage of nanomedicines is that they can be formulated to prolong the release of the drug for days after the administration. This allows for a reduction in the number of administrations needed and an increase in patient compliancy. Lastly, they can be designed to selectively release the drug in a specific organ: in particular, we are investigating nanomedicine that can reach the brain, which is usually difficult to reach due to physiological barriers, concentrating the beneficial activity of the drugs at the diseased site to avoid negative effects in surrounding cells and tissues.
You recently published a scientific article as part of research, funded through the Innovative Medicines Initiative’s IM2PACT project.
How are TNTs connected to nanomedicine research?
As I mentioned before, TNTs can transfer materials from one cell to another. We also know that they are capable of transporting drugs from one cell to another, and this includes nanomedicines. This discovery has opened major questions in the field: whenever we think to specifically treat a diseased cell with our nanomedicines, could they be transferred to other cells? What happens if the receiving cell is healthy and doesn’t need the drug we loaded in the nanomedicine? Could TNTs be used to help spread them to the surrounding diseased cells? Starting from these initial concerns, we noticed that so many other questions are still unanswered: are all nanomedicines transported via TNTs at the same extent? What characteristics of nanomedicines (or NMeds) trigger their transport from cell to cell? Do different cells transfer differ amounts of NMeds? And more importantly, can we tune the transfer of NMeds via tunneling nanotubes, by changing the characteristics of the NMeds? These questions are still unanswered, but represent the path towards fully exploiting the potential of NMeds for more effective treatments.
What potential do you see in investigating tunnelling nanotubes for medicines development?
Since the formation of tunnelling nanotubes is linked to the spreading of various diseases, knowledge of the mechanisms that lead to their formation, and the possibility to selectively modulate their formation rate could represent the first step towards novel therapeutic approaches. In the case of glioblastoma, for example, which is one of the most aggressive brain tumours, inhibition of the formation of TNTs could significantly improve the clinical development of the disease, by hampering the spreading of the cancer and metastases.
Glioblastoma is also sadly known for its high rate of recurrencies: after surgery, the few cancerous cells that are not completely removed can recruit healthy cells via TNTs leading to the formation of a second tumour. In this case, reducing the number of TNTs formed could be dramatically beneficial, both by limiting the development of the tumour, and reducing the risk of recurrencies. Thanks to their advantages, nanomedicines could represent a promising tool in this perspective, with the final goal of ameliorating existing therapies and creating novel approaches for the treatment of various diseases, including brain tumours, Alzheimer’s, and Parkinson’s disease.
What are the challenges for the road ahead?
Tunnelling nanotubes have a great potential in medicine, as they are involved in several diseases. Unfortunately, they are still poorly researched. One of the main challenges linked to the investigation of TNTs lays in the difficulty in imaging them: they are so thin and fragile, that often manipulation of samples and classic imaging techniques are too aggressive and disrupt their structure. Some progress has been made in this direction, but more must be done. We need to understand how these connections form, what triggers their formation, and how nanomedicines are involved in these patterns. After that, we can design nanomedicines that selectively exploit these mechanisms to reduce mortality and improve the prognosis of brain tumours and neurodegenerative disorders.
Ottonelli, I.; Caraffi, R.; Tosi, G.; Vandelli, M. A.; Duskey, J. T.; Ruozi, B. Tunneling Nanotubes: A New Target for Nanomedicine? International Journal of Molecular Sciences 2022, 23(4), 2237. doi:10.3390/ijms23042237
Ottonelli, I.; Duskey, J.T.; Rinaldi, A.; Grazioli, M.V.; Parmeggiani, I.; Vandelli, M.A.; Wang, L.Z.; Prud’homme, R.K.; Tosi, G.; Ruozi, B. Microfluidic Technology for the Production of Hybrid Nanomedicines. Pharmaceutics 2021, 13, 1495, doi:10.3390/pharmaceutics13091495.
Duskey, J.T.; da Ros, F.; Ottonelli, I.; Zambelli, B.; Vandelli, M.A.; Tosi, G.; Ruozi, B. Enzyme Stability in Nanoparticle Preparations Part 1: Bovine Serum Albumin Improves Enzyme Function. Molecules 2020, 25, 4593, doi:10.3390/molecules25204593.
Duskey, J.T.; Ottonelli, I.; Rinaldi, A.; Parmeggiani, I.; Zambelli, B.; Wang, L.Z.; Prud’homme, R.K.; Vandelli, M.A.; Tosi, G.; Ruozi, B. Tween® Preserves Enzyme Activity and Stability in PLGA Nanoparticles. Nanomaterials 2021, 11, 2946, doi:10.3390/nano11112946.