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Biotechnology

Tumor microenvironment and targeted therapies

João Nuno Moreira

PhD, Group Leader

Sergio Simões

PhD, Associate Professor

Anália do Carmo

PhD, MD

Teresa Martins

PhD, Aux.Researcher

Rita Oliveira

PhD, Post-Doc

Nuno Fonseca

PhD, Aux.Researcher

Marta Pereira

Teresa Abreu

PhD Student

Ana Filipa Cruz

PhD Student

Ana Rita Ribeiro

PhD Student

Mariangela Natale

PhD Student

Mariana Biscaia

PhD Student

Scientific activity has been focused on the design of targeted entities, namely lipid-based nanosystems for drug and nucleic acid delivery, addressing the impact on the tumor microenvironment and cancer cells, both at the cellular and molecular level. Scientific competences include formulation and characterization of lipid nanovesicles, in vitro and in vivo mechanistic studies, in vitro cytotoxicity, biodistribution, and therapeutic testing in animal models of cancer.

The goals of the group also point towards the identification and validation of target proteins overexpressed in tumors associated with clear unmet medical needs. This aims at identifying novel pathways for drug delivery to solid tumors (and beyond the liver), combined with the demonstration of their importance for the tumorigenic process. We believe that this strategy will enable to establish the mechanism of action of the targeted strategies the members of the group have been working on, either with single or drug combinations. It will ultimately overcome the challenges posed by drug resistance and metastasis, thus leading to decrease of overall tumor burden and relapse as well, clearly benefiting cancer patients.

To further support the achievement of the referred scientific goals, and increase the translational potential of the generated knowledge, the involvement of researchers from hospitals and clinicians will be fostered at the early stages of the projects. This will be crucial to support the identified target proteins as markers for drug targeting, namely in patients-derived samples and validate the proposed targeting strategies.

Keywords:

Drug delivery

Tumor microenvironment

Solid tumors

Experimental therapeutics

Analysis of pluripotency genes and nucleolin mRNA levels (in putative breast cancer stem cells, CSC)
(N.A. Fonseca et al. / Biomaterials 69 (2015) 76-88)

Research Lines:

•   Identify pathways for drug delivery to solid tumors (and beyond the liver).

•   Engineering strategies to temporal and special delivery of drug combinations targeting different components of the tumor microenvironment.

•   Delivery of macromolecules to solid tumors.

•   Novel anticancer targeted strategies to boost intratumoral immune system.

Intracellular trafficking of siRNA encapsulated in Lipid NanoParticles (LNP)
(L. Gomes-da-Silva et al. / Nanomedicine 8(9) (2013) 1397-1413)

Selected Publications

Abreu, T. R., Fonseca, N. A., Gonçalves, N., & Moreira, J. N. (2020). Current challenges and emerging opportunities of CAR-T cell therapies. J Control Release, 319, 246–261. https://doi.org/10.1016/j.jconrel.2019.12.047

Romano, Sofia, Fonseca, N., Simões, S., Gonçalves, J., & Moreira, J. N. (2019). Nucleolin-based targeting strategies for cancer therapy: From targeted drug delivery to cytotoxic ligands. Drug Discovery Today, 24(10), 1985–2001. https://doi.org/10.1016/j.drudis.2019.06.018

Romano, S., Moura, V., Simoes, S., Moreira, J. N.*, & Goncalves, J.* (2018). Anticancer activity and antibody-dependent cell-mediated cytotoxicity of novel anti-nucleolin antibodies. Sci Rep, 8(1), 7450. https://doi.org/10.1038/s41598-018-25816-8. *Corresponding authors.

Gregorio, A. C., Fonseca, N. A., Moura, V., Lacerda, M., Figueiredo, P., Simoes, S., Dias, S., & Moreira, J. N. (2016). Inoculated Cell Density as a Determinant Factor of the Growth Dynamics and Metastatic Efficiency of a Breast Cancer Murine Model. PLoS One, 11(11), e0165817. https://doi.org/10.1371/journal.pone.0165817

Fonseca, N. A., Rodrigues, A. S., Rodrigues-Santos, P., Alves, V., Gregorio, A. C., Valerio-Fernandes, A., Gomes-da-Silva, L. C., Rosa, M. S., Moura, V., Ramalho-Santos, J., Simoes, S., & Moreira, J. N. (2015). Nucleolin overexpression in breast cancer cell sub-populations with different stem-like phenotype enables targeted intracellular delivery of synergistic drug combination. Biomaterials, 69, 76–88. https://doi.org/10.1016/j.biomaterials.2015.08.007

Fonseca, N. A., Gomes-da-Silva, L. C., Moura, V., Simoes, S., & Moreira, J. N. (2014). Simultaneous active intracellular delivery of doxorubicin and C6-ceramide shifts the additive/antagonistic drug interaction of non-encapsulated combination. J Control Release, 196, 122–131. https://doi.org/10.1016/j.jconrel.2014.09.024

Fonseca, N. A., Gregorio, A. C., Valerio-Fernandes, A., Simoes, S., & Moreira, J. N. (2014). Bridging cancer biology and the patients’ needs with nanotechnology-based approaches. Cancer Treat Rev, 40(5), 626–635. https://doi.org/10.1016/j.ctrv.2014.02.002

Gomes-da-Silva, L. C., Fernandez, Y., Abasolo, I., Schwartz, S., Jr., Ramalho, J. S., Pedroso de Lima, M. C., Simoes, S., & Moreira, J. N. (2013). Efficient intracellular delivery of siRNA with a safe multitargeted lipid-based nanoplatform. Nanomedicine (Lond), 8(9), 1397–1413. https://doi.org/10.2217/nnm.12.174

Gomes-da-Silva, L. C., Fonseca, N. A., Moura, V., Pedroso de Lima, M. C., Simões, S., & Moreira, J. N. (2012). Lipid-based nanoparticles for siRNA delivery in cancer therapy: Paradigms and challenges. Acc. Chem. Res., 45(7), 1163–1171. https://doi.org/10.1021/ar300048p

Moura, V., Lacerda, M., Figueiredo, P., Corvo, M. L., Cruz, M. E., Soares, R., de Lima, M. C., Simões, S., & Moreira, J. N. (2012). Targeted and intracellular triggered delivery of therapeutics to cancer cells and the tumor microenvironment: Impact on the treatment of breast cancer. Breast Cancer Res. Treat., 133(1), 61–73. https://doi.org/10.1007/s10549-011-1688-7

GROUP LEADER AND PRINCIPAL INVESTIGATOR

João Nuno Moreira, PhD

ORCID

CiênciaID

João Nuno Moreira is Assistant Professor with Habilitation and Tenure and group leader at CNC, Univ of Coimbra. Has published 65 papers in high-impact journals as Biomaterials (IF:10.293) or Acc Chem Res (IF:20.323), and has lectured 147 talks by invitation. 3/10 patents granted in USA and 2/10 granted in Europe. Co-founded TREAT U, SA, start-up from CNC&UC. His group has developed a nanotechnology awarded with the Orphan Drug Designation for the treatment of human mesothelioma, by both EMA and FDA.

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Funded by ERDF - European Regional Development Fund through COMPETE 2020 and National Funds via FCT - Fundação para a Ciência e Tecnologia, under projects POCI-01-0145-FEDER-007440 e UIDB/04539/2020.