Periodic Reporting for period 1 - TEMPER (Thermal Evaluation of specific drug delivery with Molecularly imprinted nanoParticles developed against Estrogen Receptor)
Reporting period: 2021-04-01 to 2023-03-31
The overall objective of the project is to improve drug delivery of anti-cancer agents for breast cancer. Current methods lead to drug resistance and debilitating side effects, including severe neurotoxicity, due to the drugs also affecting healthy cells and not just cancer cells. This limits both drug efficacy and has a severe impact on quality of life of patients. We will develop novel nano carriers (based on polymers) that can overcome these issues. In particular, we aim to improve breast cancer treatment in developing countries where mortality rates are still too high, by developing a low-cost system that can be manufactured at scale.
Breast cancer is highly heterogeneous and therefore each patient requires a personalised approach. We have decided to focus on breast cancers that are positive for oestrogen receptor, which accounts for ~70% of breast cancer cases. To develop a system for selective drug delivery for breast cancer cells positive for oestrogen receptor, the following objectives had to be achieved:
-Develop polymer carriers with a dual functionality: they can selective target oestrogen receptor on breast cancer cells and release the drug (doxorubicin) when binding to the cell occurs;
-Characterise this system and compare it to the current state-of-the-art;
-Determine drug efficacy and selectivity of drug delivery in 2D cell lines systems of the polymers loaded with doxorubicin compared to when doxorubicin is used without any carrier system;
-Apply the materials to 3D cell line systems, which are more representative for breast cancer growth in human tissue.
Breast cancer is highly heterogeneous and therefore each patient requires a personalised approach. We have decided to focus on breast cancers that are positive for oestrogen receptor, which accounts for ~70% of breast cancer cases. To develop a system for selective drug delivery for breast cancer cells positive for oestrogen receptor, the following objectives had to be achieved:
-Develop polymer carriers with a dual functionality: they can selective target oestrogen receptor on breast cancer cells and release the drug (doxorubicin) when binding to the cell occurs;
-Characterise this system and compare it to the current state-of-the-art;
-Determine drug efficacy and selectivity of drug delivery in 2D cell lines systems of the polymers loaded with doxorubicin compared to when doxorubicin is used without any carrier system;
-Apply the materials to 3D cell line systems, which are more representative for breast cancer growth in human tissue.
We have determined the affinity of the polymers for oestrogen receptor is similar compared to normal antibodies, and thus high selectivity can be guaranteed. This affinity is not impacted by incorporating the drug in the system.
Once this was established, assays were performed to show drug loading over time in two cell lines, one positive for oestrogen receptor, and one negative (another type of breast cancer cells). It was clear that the drug-loaded polymers showed temporal release of doxorubicin and were both more efficient and more selective in killing oestrogen positive breast cancer cells, as evidenced by higher cytotoxicity. Selective binding of the polymers to oestrogen receptor was also confirmed with confocal imaging. This did not just enable quantification of the results, it was also clearly shown that the polymers can enter the nucleus, which explains why the efficacy of the drug is enhanced. This is the first system that uses these specific (double imprinted) polymers for targeting a receptor that is present in the nucleus. During the secondment at UCL, the drug efficacy was also tested in 3D cell lines that are more representative of cancer growth in the human body. We have performed the experiments but are awaiting the analysis of the imaging. This will increase the novelty of the work as normally researchers do not go beyond 2D cell studies.
There have been several papers that have been written on drug delivery as part of this Marie Curie fellowship. Besides collaboration with UCL, there was also collaboration with the University of Sheffield, Guru Nanak Dev University in India and FH Krems in Austria; the Marie Curie fellow supervised an exchange student from Krems and published the results that were obtained on using alternative polymer-based systems for drug delivery. The results have been presented at several conferences and will be presented at an international conference in Las Vegas in July 2023, which is considered one of the most prestigious conferences on drug delivery in the world. The Marie Curie fellow was also able to attract an additional 10k in funding via internal sources for an ongoing collaboration with UCL.
We are now writing up the final results that include the studies in 3D models and aim to submit a manuscript this summer. The results have been presented to industrial partner MIP Discovery on several occasions and one member of MIP Discovery will be included as co-author on the upcoming publication.
Once this was established, assays were performed to show drug loading over time in two cell lines, one positive for oestrogen receptor, and one negative (another type of breast cancer cells). It was clear that the drug-loaded polymers showed temporal release of doxorubicin and were both more efficient and more selective in killing oestrogen positive breast cancer cells, as evidenced by higher cytotoxicity. Selective binding of the polymers to oestrogen receptor was also confirmed with confocal imaging. This did not just enable quantification of the results, it was also clearly shown that the polymers can enter the nucleus, which explains why the efficacy of the drug is enhanced. This is the first system that uses these specific (double imprinted) polymers for targeting a receptor that is present in the nucleus. During the secondment at UCL, the drug efficacy was also tested in 3D cell lines that are more representative of cancer growth in the human body. We have performed the experiments but are awaiting the analysis of the imaging. This will increase the novelty of the work as normally researchers do not go beyond 2D cell studies.
There have been several papers that have been written on drug delivery as part of this Marie Curie fellowship. Besides collaboration with UCL, there was also collaboration with the University of Sheffield, Guru Nanak Dev University in India and FH Krems in Austria; the Marie Curie fellow supervised an exchange student from Krems and published the results that were obtained on using alternative polymer-based systems for drug delivery. The results have been presented at several conferences and will be presented at an international conference in Las Vegas in July 2023, which is considered one of the most prestigious conferences on drug delivery in the world. The Marie Curie fellow was also able to attract an additional 10k in funding via internal sources for an ongoing collaboration with UCL.
We are now writing up the final results that include the studies in 3D models and aim to submit a manuscript this summer. The results have been presented to industrial partner MIP Discovery on several occasions and one member of MIP Discovery will be included as co-author on the upcoming publication.
This is the first time that this specific drug delivery system has been used to target receptors that are present in the nucleus. Due to the versatility of the polymers used, it is expected that this can be expanded beyond breast cancer. For instance, we are planning to work on pancreatic cancer going forward. The developed drug nano carriers are low-cost and there is potential to develop these at medium scale. Thus, it could be considered an interesting alternative to current cancer treatments, which can have significant impact on patient outcome. Moreover, we aim to facilitate knowledge exchange with other groups that are working in this field and have established a lasting collaboration with a group in India, where mortality rates of breast cancer are still high.
We are also working with our industrial partner to consider commercialisation of the system.
We are also working with our industrial partner to consider commercialisation of the system.