Project title

siRNA incorporation in a lipid/micelle-based nanocarrier as a strategy to restore E-cadherin expression and eradicate advanced breast cancer metastatic phenotype

Scientific Coordinator's name:

Mafalda Castro Ascensão Marques Videira

Scientific Coordinator's e-mail:

mvideira@ff.ul.pt

Principal R&D Unit:

iMed.UL/FFUL

Other R&D Units involved in the project:

Associação para a Investigação Biomédica e Inovação em Luz e Imagem (AIBILI); Institut d’Investigació Biomèdica de Bellvitge (IDIBELL); School of Pharmacy and Chemistry, Ludwig-Maximilians-University (LMU)

Project keyword(s)

Epithelial-Mesenchymal Transition; E-cadherin; Akt2 siRNA nanocarrier; Twist modelation

Short abstract and comments

Cell growth signal transduction, angiogenesis, metastasis and cell cycle regulation are, in our days, different targets that can be explored to improved cancer therapies and consequently, to improve the efficacy/safety profile of the biotech molecules. This knowledge in cell biology has been integrated into strategies for developing new biotechnological products as well as new drug delivery systems (DDS) in order to improve their availability in the relevant site of action. Tumour invasive behaviour is dependent on the disruption of cell-cell junctions, and frequently a partial or total loss of E-cadherin (E-cad) expression, a potent invasion-suppressing tumour protein. In epithelial cells E-cad molecules form small junction complexes cadherin-catenin, which then expand to establish stable adherents junctions. Epithelial mesenchymal transitions (EMT), is associated with the silencing of E-cad expression and further expression of EMT related molecules, such as Akt2 and Twist, crucial for progression of non-invasive into a malignant metastatic carcinomas, due to a polarity and adhesion loss between adjacent cells. This mechanism, found in various human solid tumours, correlates with loss of differentiation characteristics and acquisition of a more invasive and metastatic phenotype. The critical role of cell transcriptional factors, such as Akt2 and Twist, in a number of mechanisms underlying the acquisition of metastatic potential at late stages of epithelial tumour progression, has been increasingly recognised in the past few years. It is described in literature that one of the Akt2/Twist modulation pathways drives the silencing of E-cad. Our proposal is based on the assumption that, the impairment of the AKT2 expression trough the intracellular presence of a siRNA will provide a strategy to silencing Twist thus restoring E-cad expression. However, silencing mediated siRNA strategy is ultimately defined by its intracellular availability and its ability to interact with the molecular pathways. Until now the major obstacle to the clinical use of siRNA for cancer therapy is their poor bioavailability. Nanotechnology, particularly strategies related with biotech’s loading nanocarriers, might change their cellular availability and therefore open new therapeutic opportunities. The development of an effective drug-nanocarrier against breast cancer lung metastasis has been a major goal of our group in the past few years. The major goal of this project is to correlate Akt2 siRNA-nanocarriers delivery to the cancer cells and the expression of the E-cad de-regulated mechanism. The development and full characterization of stable and effective nanocarriers intended for subcutaneous administration, and the evaluation of its ability to target cancer cells in breast cancer will be the ultimate aim of this project. The study has been designed in order to achieve improved outcomes in breast cancer therapy and to obtain significant progress in the clinical application of biotech molecules.

Potential uses/indications

Cancer therapy; Gene therapy; Intracellular drug Delivery