Research Projects 

Tackling cancer stem cells: a challenge and an opportunity to advance in anti-cancer therapy (CANCEL_STEM, POCI-01-0145-FEDER-016390); PROGRAMAS DE ATIVIDADES CONJUNTAS (PAC).

Aging, Stress and Chronic Diseases: From Mechanisms to Therapeutics; PROJETO INTEGRADO BrainHealth2020 (CENTRO-01-0145-FEDER-000008).


External Collaborations

Professor Nejat Duzgunes, Department of Biomedical Sciences, University of the Pacific, San Francisco, USA

Professor Ernst Wagner, Department of Pharmacy, Ludwig-Maximilians University, Munich, Germany

Professor Peter Canoll and Dr. Jeffrey Bruce, Columbia University Irving Medical Center, New York, USA

Dr Anne Régnier-Vigouroux, Faculty of Biology, University Johannes Gutenberg-Mainz, Germany

Professor Bo Nystrom, Department of Chemistry, University of Oslo, Norway

Professor Faustino Mollinedo, Centro de Investigaciones Biológicas - CIB, Consejo Superior de Investigaciones Cientificas - CSIC, Madrid, Spain

Professor Salette Reis, REQUIMTE, Chemistry Department, Pharmacy Faculty, Porto University, Portugal

Professor Paula Gomes, UCIBIO-REQUIMTE, Chemistry and Biochemistry Department, Porto University, Portugal

Professor Maria do Rosário Domingues, Centro de Espectroscopia de Massa, QOPNA, Chemistry Department, University of Aveiro, Portugal

Professor Cristina Carvalho and Professor Maria Alexandra Brito, Instituto de Investigação do Medicamento – iMed, University of Lisbon, Portugal 

Having as a central mission to generate innovative gene and lipid therapies aimed at fighting brain diseases, namely brain cancer, the research developed in our group has been guided by the following objectives:

•    Identification of new molecular targets for the treatment of brain diseases, namely at the transcriptome and lipidome level in the ill cells. 

•    Evaluation of the therapeutic efficacy of the developed gene therapy approaches and study of the molecular and cellular mechanisms associated to the therapeutic response, in cell and animal models of disease. 
•    Study of the role of glioblastoma (GBM) stem-like cells in tumor progression and identification of new molecular targets involved in the renewal and differentiation of tumor stem-like cells. 
•    Study of the communication between tumor and immune cells and identification of therapeutic targets involved in the tumor-specific immune environment. 

In parallel, in order to guarantee efficiency in gene therapy interventions, our group has also been enrolled in more fundamental research, with the following objectives:

•    Development of novel nanosystems based on lipids, surfactants, peptides and polymers, as technological platforms for efficient and specific delivery of different nucleic acids in target cells/tissues.

•    Physico-chemical characterization of the nanosystems and mechanistic studies of their interaction with target-cells, including cell internalization and intracellular traffic.
•    Application of the developed nanosystems in targeted gene therapy approaches using animal models of brain diseases, including GBM, towards potential clinical translation. 


 

Keywords:
gene therapy
lipid therapy
functionalized nanosystems
targeted nuclei acid delivery
brain cancer

Research Lines:

1.    Development of a targeted therapeutic approach towards glioblastoma pathogenesis:  modulation of the activity of key miRNAs combined with new generation anti-angiogenic chemotherapy 

2.    A membrane lipid therapy-based approach for glioblastoma and other brain diseases:  modulation of membrane lipid composition by addressing key-enzymes of lipid metabolism using RNA interference technology.

3.    Development of immunotherapeutic strategies for glioblastoma:  Evaluation of their efficacy in immunocompetent human cerebral organoid models.

Morais, C.M., Cardoso, A.M., Aguiar, L., Vale, N., Nóbrega, C., Zuzarte, M., Gomes, P., Pedroso de Lima, M.C. and Jurado, A.S. (2020). Lauroylated histidine-enriched S413-PV peptide as an efficient gene silencing mediator in cancer cells. Pharmaceutical Research 37, 188-206. https://doi.org/10.1007/s11095-020-02904-x.

Cardoso, A.M., Sousa, M., Morais, C.M., Oancea-Castillo, L.R., Régnier-Vigouroux, A., Rebelo, O., Tão, H., Barbosa, M., Pedroso de Lima, M.C., and Jurado, A.S. (2019). MiR-144 overexpression as a promising therapeutic strategy to overcome glioblastoma cell invasiveness and resistance to chemotherapy. Human Molecular Genetics, 28, 2738-2751. https://doi.org/10.1093/hmg/ddz099.

Morais, C.M., Cunha, P.P., Melo, T., Cardoso, A.M., Domingues, P., Domingues, M.R., Pedroso de Lima, M.C. and Jurado, A.S. (2019). Glucosylceramide synthase silencing is detrimental to glioblastoma cells when combined with axitinib. Human Molecular Genetics, 28, 3664-3679 https://doi.org/10.1093/hmg/ddz152.

Morais, C.M., Cardoso, A.M., Cunha, P.P., Aguiar, L., Vale, N., Lage, E., Pinheiro, M., Nunes, C., Gomes, P., Reis, S., Castro, M.M.C.A., Pedroso de Lima, M.C, and Jurado, A.S. (2018). Acylation of the S413-PV cell-penetrating peptide as a means of enhancing its capacity to mediate nucleic acid delivery: Relevance of peptide/lipid interactions. Biochimica et Biophysica Acta Biomembranes, 1860(12), 2619-2634. https://doi.org/10.1016/j.bbamem.2018.10.002. 

Cunha, P.P., Costa, P.M., Morais, C.M., Lopes, I.R., Cardoso, A.M., Cardoso, A.L., Mano, M., Jurado, A.S., and Pedroso de Lima, M.C. (2017). High-throughput screening uncovers miRNAs enhancing glioblastoma cell susceptibility to tyrosine kinase inhibitors. Human Molecular Genetics, 26(22), 4375-4387. https://doi.org/10.1093/hmg/ddx323

Viegas, A.T., Guedes, J., Oliveira, A.R., Cardoso, A.M., and Cardoso, A.L. (2017). MiRNAs: New Biomarkers and Therapeutic Targets in Dementia. Current Pharmaceutical Design, 23 (5), 669-692. https://doi.org/10.2174/1381612823666170111094702. 

Conceição, M., Mendonça, L., Nóbrega, C., Gomes, C., Costa, P., Hirai, H., Moreira, J.N., Pedroso de Lima, M.C., Manjunath, N., Almeida, and L.P. (2016). Intravenous administration of brain-targeted stable nucleic acid lipid particles alleviates Machado-Joseph disease neurological phenotype. Biomaterials, 82, 124-137. https://doi.org/10.1016/j.biomaterials.2015.12.021

Cardoso A.M, Guedes, J., Cardoso, A.L., Morais, C., Cunha, P., Viegas, A.T., Costa, R., Jurado A.S. and M.C. Pedroso de Lima, M.C. (2016). Recent trends in nanotechnology toward CNS diseases: Lipid-based nanoparticles and exosomes for targeted therapeutic delivery, In K. Al-Jamal (Ed) International Review of Neurobiology: Nanotechnology and the Brain, Elsevier, 130, 1-40. https://doi.org/10.1016/bs.irn.2016.05.002

Costa, P.M, Cardoso, A.L., Mano, M., Pedroso de Lima, M.C. (2016) MicroRNAs in glioblastoma: Role in pathogenesis and opportunities for targeted therapies. CNS & Neurological Disorders-Drug Targets, 14, 222-238. https://doi.org/ 10.2174/1871527314666150116123610

Costa P.M., Cardoso A.L., Custódia C., Cunha P., Pereira de Almeida L. and Pedroso de Lima M.C. (2015). MiRNA-21 silencing mediated by tumor-targeted nanoparticles combined with sunitinib: A new multimodal gene therapy approach for glioblastoma. Journal of Controlled Release, 207, 31-39. https://doi.org/10.1016/j.jconrel.2015.04.002