Spotlight: PHC Protea Programme 2022-2024

SCIENCE AND INNOVATION

Development and Evaluation of Theranostic Nanocrystals for the Treatment of Triple Negative Breast Cancer:

An Innovative Nanotechnology Project Serving Our Health

CONTEXT

The most common cancer worldwide is breast cancer with 2.3 million cases recorded [1]. Furthermore, breast cancer is the leading cause of mortality among women. Triple Negative Breast Cancer (TNBC) affects women more aggressively than other types of breast cancer, with a higher risk of developing metastases, particularly in the brain [2]. This metastatic cancer is then unresectable and therefore requires treatment, which can be physical (radiotherapy), chemical (chemotherapy), or biological (immunotherapy). New generations of oncology treatments aim to co-administer different therapeutic agents to achieve an improvement in antitumor efficacy and, ultimately, increase the survival rate of patients. In the context of TNBC treatment, Trodelvy is the first targeted chemotherapy through a combined chemo-/immunotherapy treatment, thus reflecting a paradigm shift for anticancer therapies [3]. Indeed, it is an original combination: sacituzumab govitecan [4, 5], which results from the conjugation of a human IgG1 kappa Trop-2 antibody (anti-Trop-2) with a chemotherapy drug (SN-38, a topoisomerase I inhibitor) via a cleavable chemical bridge. This antibody-drug conjugate (ADC) was approved by the FDA and EMA respectively in 2020 and 2021. The results are promising in terms of improving the survival rate of patients and resolving cancer. However, if one refers to the published clinical trial data [6], surprisingly, it turns out that the side effects compared to conventional chemotherapy are much more significant for the cohort of patients treated with Trodelvy. The antitumor efficacy of Trodelvy thus comes at the expense of the comfort of these patients. Moreover, over the past seven years, peptide therapies (e.g., ADCs, antibodies) have represented about 29% of cancer treatments, compared to 63% for small organic molecule chemotherapy (Figure 1). Indeed, the latter are more stable during drug formulation and storage processes.

OBJECTIVES

The research team propose to develop a new formulation of this chemotherapy, in the form of co-nanocrystals encapsulated in a stabilizing and functionalizable polymeric matrix. This nanotechnology, unlike conventional ADCs, will increase the active substance load, optimize drug stealthiness in vivo, target tumor cells, and release the active substance only after internalization of the anticancer agent into tumor cells [8]. Furthermore, the association with a fluorophore such as BODIPY will allow tracking both the internalization and tissue biodistribution of chemotherapy in real-time by near-infrared NIR-II technology, without invasive surgical procedures during in vivo evaluations. This new nanotechnology will thus contribute to the development of an innovative theranostic tool (combination of therapy and diagnosis) in the treatment of triple negative breast cancer, a tool with better therapeutic response and reduced side effects.

TEAMS

This project was initiated thanks to funding from the PHC Protéa bilateral program between France and South Africa. It has enabled the pooling of skills by two partners specializing in nanocrystallization at the international level. The French partner, UTCBS (Unité des Technologies Chimiques et Biologiques pour la Santé, UFR Pharmacie, Faculté de Santé, Université Paris Cité), was the first to develop the “bottom-up” approach with a minimal amount of stabilizing agent to formulate nanocrystals [9, 10], specifically etoposide nanocrystals, a topoisomerase II inhibitor overexpressed in cells of certain tumor microenvironments compared to healthy tissues [11, 12]. The South African partner, PSL (Pharmaceutical Sciences Laboratory, Faculty of Health, Sefako Makgatho University of Pretoria), specializes in co-crystallization of pharmaceutical molecules [13, 14].

Thus, the TN2BCT project will allow the integration of skills developed by each laboratory in order to propose one of the innovative nanomedicines internationally, while meeting the regional specificities of breast cancer, particularly regarding the disparity in the 5-year survival rate. Indeed, this survival rate was 88% in France in 2020 compared to 40% in South Africa, linked to an ethnic-geographical delay in diagnosis as suggested by the analysis of breast cancer incidence and mortality rates in the two countries.

References

[1] Cancer Tomorrow estimate. https://gco.iarc.fr/tomorrow/en

[2] A. Kadamkulam Syriac, N. S. Nandu, J. P. Leone. Central nervous system metastases from triple-negative breast cancer: current treatments and future prospective. Breast Cancer: Targets Ther. 2022, 14, 1-13. https://doi.org/10.2147/BCTT.S274514

[3] X. Zhang, A. C. Huang, F. Chen, H. Chen, L. Li, N. Kong, W. Luo, J. Fang. Novel development strategies and challenges for anti-Her2 antibody-drug conjugates. Antib. Ther., 2022, 5, 18-29. https://doi.org/10.1093/abt/tbac001

[4] N. Joubert, A. Beck, C. Dumontet, C. Denevault-Sabourin. Antibody-drug conjugates: The last decade. Pharmaceuticals, 2020, 13, 245. https://doi.org/10.3390/ph13090245

[5] A. Bardia, S. M. Tolaney, K. Punie, D. Loirat, M. Oliveira, K. Kalinsky, A. Zelnak, P. Aftimos, F. Dalenc, S. Sardesai, E. Hamilton, P. Sharma, S. Recalde, E. C. Gil, T. Traina, J. O’Shaughnessy, J. Cortes, M. Tsai, L. Vahdat, V. Diéras, L. A. Carey, H. S. Rugo, D. M. Goldenberg, Q. Hong, M. Olivo, L. M. Itri, S. A. Hurvitz. Biomarker analyses in the phase III ASCENT study of sacituzumab govitecan versus chemotherapy in patients with metastatic triple-negative breast cancer. Ann. Oncol., 2021, 32, 1148-1156. https://doi.org/10.1016/j.annonc.2021.06.002

[6] A. Bardia, S. A. Hurvitz, S. M. Tolaney, D. Loirat, K. Punie, M. Oliveira, A. Brufsky, S. D. Sardesai, K. Kalinsky, A. B. Zelnak, R. Weaver, T. Traina, F. Dalenc, P. Aftimos, F. Lynce, S. Diab, J. Cortés, J. O’Shaughnessy, V. Diéras, C. Ferrario, P. Schmid, L. A. Carey, L. Gianni, M. J. Piccart, S. Loibl, D. M. Goldenberg, Q. Hong, M. S. Olivo, L. M. Itri, H. S. Rugo. Sacituzumab govitecan in metastatic triple-negative breast cancer. N. Engl. J. Med., 2021, 384, 1529-1541. https://doi.org/10.1056/NEJMoa2028485

[7] M. Lorscheider, A. Gaudin, J. Nakhlé, K.-L. Veiman, J. Richard, C. Chassaing. Challenges and opportunities in the delivery of cancer therapeutics: update on recent progress. Ther. Deliv., 2021, 12, 55-76. https://doi.org/10.4155/tde-2020-0079

[8] B. Martin Couillaud, P. Espeau, N. Mignet, Y. Corvis. State of the art of pharmaceutical solid forms from crystal property issues to nanocrystals formulation. ChemMedChem, 2019, 14, 8-23. https://doi.org/10.1002/cmdc.201800612

[9] L. Castillo Henríquez, B. Bahloul, K. Alhareth, F. Oyoun, M. Frejková, K. Kostka, T. Etrych, L. Kalshoven, A. Guillaume, N. Mignet, Y. Corvis. Step-by-step standardization of the bottom-up semi-automated nanocrystallization of pharmaceuticals: A Quality by Design and Design of Experiments joint approach. Small, 2024, 2306054. https://doi.org/10.1002/smll.202306054

[10] P. Ma, J. Seguin, N. K. Ly, L. Castillo Henríquez, E. Plansart, K. Hammad, R. Gahoual, H. Dhôtel, C. Izabelle, B. Saubamea, C. Richard, V. Escriou, N. Mignet, Y. Corvis. Designing fisetin nanocrystals for enhanced in cellulo anti-angiogenic and anticancer efficacy. Int. J. Pharm.: X, 2022, 4, 100138. https://doi.org/10.1016/j.ijpx.2022.100138

[11] B. Martin, N. Mignet, Y. Corvis. Preparation of nanosuspension comprising nanocrystals of active pharmaceutical ingredients with little or no stabilizing agents. PCT Int. Appl. (2020), WO 2020043735 A1 20200305. https://patents.google.com/patent/WO2020043735A1/en

[12] B. Martin, J. Seguin, M. Annereau, T. Fleury, R. Laï-Kuen, G. Neri, A. Lam, M. Bally, N. Mignet,
Y. Corvis. Preparation of parenteral nanocrystal suspensions of etoposide from the excipient free dry state of the drug to enhance in vivo antitumoral properties. Sci. Rep., 2020, 10, 18059. https://doi.org/10.1038/s41598-020-74809-z

[13] B. A. Witika, M. Aucamp, L. L. Mweetwa, P. A. Makoni. Application of fundamental techniques for physicochemical characterizations to understand post-formulation performance of pharmaceutical nanocrystalline materials. Crystals, 2021, 11, 310. https://doi.org/10.3390/cryst11030310

[14] B. A. Witika, V. J. Smith, R. B. Walker. Quality by design optimization of cold sonochemical synthesis of zidovudine-lamivudine nanosuspensions. Pharmaceutics, 2020, 12, 367. https://doi.org/10.3390/pharmaceutics12040367

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