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NANORESISTANCEFP7-PEOPLE-IAPP: NANORESISTANCE 286125

Duration: November 2011 - October 2015

Funding: € 1,400.000

Principal Investigator: A. Odysseos.

NANORESISTANCE introduces for the first time (i) receptor -independent targeting of Epidermal Growth Factor Receptor-kinase activity, (ii) nuclear delivery of anti-Epidermal Growth Factor Receptor therapy with novel grafting techniques and (iii) the deciphering of resistance and lack of responsiveness to anti-EGFR therapies in the preclinical setting with mathematical models of interstitial biodistribution. This work defines an unprecedented integrated approach for the comprehensive management of failure to anti-EGFR therapy and treatment monitoring. This partnership will play a structuring role by allowing researchers to acquire key skills equally relevant to the public and private sectors including cutting edge nanobiotechnology techniques for fabrication of nanotheranostic conjugates for targeted nuclear drug delivery and imaging, pioneering approaches for intracellular targeting with carbon nanotubes (CNT), innovative mathematical models and assessment of biodistribution, state-of-the-art Surface Plasmon Resonance for assessing drug-target interactions, emerging technologies for in vivo protein-protein and theranostic compound-protein interaction with Bimolecular Fluorescence Complementation Assays (BIFCs).These parallel approaches provide a promising innovative solution in the multifaceted challenge of the overall resistance to anti-EGFR therapies. This will be achieved with the development of multimodal CNT-based nanoplatforms carrying the fluorescent conjugates of EGFR inhibitors intracellularly independently of EGFR extracellular recognition. This system will further deliver anti-EGFR and fluorescent attributes to the nucleus. The partnership offers and a well-structured scheme of complementary skills highly inspired by the entrepreneurial spirit of academicians and research commitment of the industrial partners securing significant impact on their employability in their sector.



PATHCHOOSERDuration: October 2013 - September 2017

Funding: € 3,178.803

Lead of Training: A. Odysseos

Nanomedicine offers capability to significantly change the course of treatment for lifethreatening diseases. Many of the most significant current therapeutic targets, to be viable in practice, require the efficient crossing of at least one biological barrier. However, the efficient and controlled crossing of the undamaged barrier is difficult. The range of small molecules that can successfully do so (via diffusive or other non-specific processes) is limited in size and physiochemical properties, greatly restricting the therapeutic strategies that may be applied. In practice, after several decades of limited success, there is a broad consensus that new multidisciplinary, multi-sectoral strategies are required. Key needs include detailed design and understanding of the bionano-interafce, re-assessment of in vitro models used to assess transport across barriers, and building regulatory considerations into the design phase of nanocarriers. The overarching premises of the PathChooser ITN are that (i) significant advances can only be made by a more detailed mechanistic understanding of key fundamental endocytotic, transcytotic, and other cellular processes, especially biological barrier crossing; (ii) elucidating the Mode of Action / mechanism of successful delivery systems (beyond current level) will ensure more rapid regulatory and general acceptance of such medicines. Paramount in this is the design and characterization of the in situ interface between the carrier system and the uptake and signalling machinery. (iii) inter-disciplinary knowledge from a range of scientific disciplines is required to launch a genuine attack on the therapeutic challenge. The PathChooser ITN program of research and training will equip the next generation of translational scientists with the tools to develop therapies for a range of currently intractable (e.g. hidden in the brain) and economically unviable diseases (e.g. orphan diseases affecting a limited population).


Nanofiber projectFunding: €137.688

Partner and Deputy Coordinator, A. Odysseos

Adaptation of Nanofiber Electrospinning for Rapid Prototyping: A mesoscale-resolution electrospinning RP system based on a 3-axis CNC machine was set up and configured. A collector for layered deposition based on spraying of graphite microparticles in sacrificial intermediate layers was tested, as well as a polystyrene foil mask on the target to patern electrospun areas The innovative idea of structuring of the electrospun fiber membrane surface to conform to the epithelial geometry of intestinal tissue by patterned electrochemical roughening of the metal foil target, onto which the fibers are deposited during electrospinning, was introduced. For software integration, an electrospinning process-structure database was assembled by parametric studies for cellulose acetate , and is to be combined with imaging software (STL format) for tissue geometry encoding .
Tissue model design 1 was based on surgical collection of 37 tissue specimens at the Nicosia General Hospital, with tissues already imaged by optical microscopy, SEM and 3D laser scanning, white-light profilometry and X-ray microtomography, with SEM proving the most appropriate technique. Fabrication of tissue scaffolds was performed at the HO with SEM parametric studies for electrospinning of fiber membranes made of CA (also with PANI), PEO, PLLA and PEO/PLLA mixtures. Functional analysis was realized with dynamic mechanical analysis (DMA) and rheological analysis of a great variety of CA nanofiber membranes. SEM analysis was performed on the cell-cultured scaffolds for subsequent intestinal tissue processing and engineering. Tissue phantom have been developed with intestinal cells incorporated in a collagen mixture. The partners introduced the family of vitamin E derivatives (tocopherols-tocotrienols) as a new super-family of growth and differentiation factors in the normal intestinal cell.


Theranostic projectDuration: June. 2012 - May. 2014

Funding: € 178.803

Project Coordinator: C. Pitris ; Partner: A. Odysseos

This project brings together expertise in medical optics and optoelectronics, magnetics, coordinate Lanthanide chemistry, bio-organic synthesis and molecular oncology, aiming at introducing a break-through solution for the overall management of colorectal cancer and potentially other malignancies expressing the epidermal growth factor family of receptors (EGFR). The solutions is based on prototype metal-based functionalized compounds engaging cutting-edge synthetic and complexation approaches. Initially, a panel of kinetically stable prototype lanthanides complexes with potent (a) optical (e.g near infrared spectroscopic) and (b) magnetic /relaxation properties will be designed and synthesized as building blocks for heterometallic arrays and subsequently the lanthanide complexes will be functionalized to a series of biologically active bimodal theranostic agents with anti-EGFR recognizing and inhibiting properties. Functionalization of the probes with the recognizing and therapeutic ligands (i.e. anilinoquinazolines) will increase the molecular size, thus optimizing proton relaxivity and magnetic efficacy. Diagnostic specificity will be assessed by ERB-B1 recognition and internalization of the compounds on (a) cell monolayers and (b) 3-dimensional tissue phantoms of cell lines differentially expressing ERB-B1 under inverted NIR microscope. Highly sensitive and efficacious compounds will be considered for further development as theranostic agents for early detection and therapy of CRC in subsequent pre-clinical models with the application of multimodal Molecular Imaging. This approach enables the quantitative imaging of defined cancer biomarkers in a non-invasive manner, aiding in lesion detection, patient stratification, new drug development and validation, dose optimization and treatment monitoring.


COST CM1106 1This COST Action aims to unite researchers with expertise in rational drug design and the medicinal chemistry of synthetic and natural compounds with biomedical investigators dedicated to the understanding the mechanisms governing drug resistance in cancer stem cells. Cancer stem cells (CSC) are a subpopulation of cells within tumors that exhibit enhanced tumor-initiating attributes and are a major contributing factor to current cancer therapy failure. The CSC phenotypic state comprises distinct molecular and functional differences that underpin resistance to current treatments and the unique ability spread and to seed new tumors throughout the body.

COST CM1106 2This insight necessitates an entirely new approach to cancer drug development to effectively target tumor CSCs. Through exchange of information, experience and expertise, researcher mobility and fostering new collaboration between chemistry and biology groups, the Action endeavours to develop new, effective methods for identifying novel compounds and drug candidates that target drug-resistant cancer stem cells.


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