BioBilbao 9-12 July 2016
ICREA / Universitat de Barcelona
Departament de Química Inorgànica
Research group QBI
Martí i Franquès 1-11
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Launch of the Association Science2 (www.sci2.org)
Research in the Gamez Group is focused on the exploitation of the variety and richness of Coordination Chemistry (allowing unlimited combinations between organic ligands and metal ions) to tackle two important health issues, i.e. cancer and Alzheimer's disease.
medicinal inorganic chemistry - bio-inorganic chemistry - amyloid-beta - peptide-based drugs - copper - Reactive oxygen species (ROS) - structure-targeted biomolecular recognition - DNA structures - theragnostics - nanoparticles
Cancer and Alzheimer’s disease (AD) represent two major chronic diseases that are in the top ten leading causes of mortality worldwide and there incidence will increase exponentially in the coming decades, as the result of population ageing. Hence, our main research goals are aimed at applying new strategies for the development of efficient therapeutic tools against these two important public health issues.
The development of new anticancer drugs is of paramount importance for Society because this disease (actually cancer represents a broad group of various diseases) remains a serious concern due to the fact that successful approaches for its effective treatment are still limited. One of the new research trends that are rapidly growing (thanks to its clearly high potential) in this area of Medicinal Chemistry consists in using metal-based drugs. The development of drugs based on coordination compounds (metal complexes) offers the possibility of great structural versatility (as they are generated from the combination of different metal ion(s) with distinct ligand(s)), compared to purely organic molecules.
In that context, the main objectives of our current investigation are divided in three main parts, namely
(i) the design and preparation of small, highly cytotoxic metal-based molecules and their nanoencapsulation in nano-objects that can be functionalized (drug delivery and targeting);
(ii) the development of novel metallodrugs in a structure-targeted approach to interact with DNA supramolecules, e.g. three-way junctions or G-quadruplexes (cancer-cell-selective agents);
(iii) the generation of photoswitchable metal complexes based on the photo-modification of the ligands (an unprecedented approach in photoactivated chemotherapy ‒ PACT ‒, which is currently metal centred).
AD is a slowly progressive neurological disorder, in which neurodegeneration is believed to progress for 20 to 30 years before clinical onset, and which predominant symptoms are impairment in cognition and profound memory loss. The AD-affected brain suffers from metal-ion homeostasis (metallostasis), which gives rise to the production of amyloid-β aggregates (SPs) and oxidative stress, two associated signs of AD pathology. To date, all clinical trials targeting amyloid β have failed; however, some clinical trials targeting metal interactions with amyloid β (particularly with copper) have all shown benefit for patients. Actually, targeting metals represents a tractable avenue for an AD-modifying therapy, and approaches targeting metals warrant fundamental investigation as well as studies in large-scale clinical trials.
Our innovative approach consists in designing and preparing selective (fluorescent) peptide-based copper chelators and conjugating them to emissive nanoparticles (quantum dots, gold nanoparticles, etc...). Such peptide-decorated nanoparticles allow the detection of copper and its brain location (fluorescent probe), and the re-establishment of normal metallo-trafficiking, therefore reducing oxidative stress (Metal Protein Attenuating Compound); these nanocompounds therefore act as AD theranostic (therapy + diagnosis) agents.