FP7Реинтеграция2015–2018

MEMOTUMCELLMACH · Metallodrugs to Modulate Tumour Cell Machinery

7РП — „Хора“ (Действия „Мария Кюри“)

Период: 2015-01-01 → 2018-12-31
Финансиране от ЕС: 100 000 €
Участници: 1
Схема: MC-CIG

Линиите свързват координатора с партньорите.

Накратко на български

Металоорганични молекулни превключватели от рутений, осмий и иридий се тестват за активиране в зависимост от киселинността (pH) в клетките. Това помага за по-точното насочване на лекарствата към туморните клетки и модулирането на техните процеси.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

Metallodrugs to Modulate Tumour Cell Machinery

The general aim of this proposal is to create pH-responsive metalloorganic molecular switches capable of activation towards biomolecule interaction within cells in a pH-dependent manner. To this end, we have developed switches based on ruthenium(II), osmium(II) and iridium(III). The ruthenium sub-project has pioneered the establishment of the switchable system. In a general structure [Ru(eta6,kappa1-arene,N/O)(L^L’)]Cl2 (where L^L’ is a chelating ligand), changes in the different ligands around the metal have led to an understanding of which electronic and steric features of the different building blocks can help tailor the pH of activation. Most importantly, our design allows for deactivation upon drop in the proton concentration (increase in the pH). The dynamics of the switch have been carefully studied and have allowed us to conclude that the rates at which both processes (activation and deactivation) occur are also pH dependent. Osmium analogues have been isolated and their dynamics in aqueous solution thoroughly investigated. The osmium-arene compounds have opened up the possibility of creating intracellular proton shuttles. The iridium sub-project has also produced striking results, with cytotoxic activities in the nanomolar range, targeting capabilities at the intracellular level only matched by tagged molecules, and activation processes that hint at intracellular catalytic events. The grant has greatly contributed to the consolidation of the fellow (Dr Pizarro) and enable her to start her own research line, creating her group at the host institution, and to the establishment of new national and international collaborations.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

The past decade has seen substantial advances in our understanding of cancer molecular biology and the technologies available to study it, emphasising the importance of the molecular mechanisms of carcinogenesis in cancer research. We now face having to therapeutically aim for many less common targets rather than a few all-cancer present targets. Effective single molecular targets therapies are generally not sufficient to elicit durable clinical responses and the development of drug resistance is an increasing problem. Consideration of only a single drug–target interaction in vivo has proven to be overly simplistic.The ultimate goal of this proposal is to generate metallodrugs whose mechanism of action is understood and whose targets are identified. These multitargeting drugs would be a more realistic option by leading rational co-extinction strategies for specific cancers.Current cross-discipline trainings make possible the alliance of inorganic chemistry with cell and molecular biology. The unprecedented potential for design of metallodrugs has not been overseen and medicinal bioinorganic chemistry is rapidly expanding.This interdisciplinary proposal involves chemistry, biology and physics, with potential not only for the discovery of novel medicines for cancer treatment, but also for the development of new methodologies to modulate and deconvolute the technology behind the tumour cell machinery. By uncovering the operating principles and mechanisms of action of our metallodrugs at the nanoscale (i.e. subcellular level) we aim to inform on what biological context its destruction would lead to cell death and also to tumour regression.These metallo-medicines will exploit the extraordinary features of transition metal complexes, in particular the capability for in tumour activation, and the possibility of being loaded into nanocarriers, conferring control on the drug reactivity, and thus minimising undesired side effects, often responsible for drug failure.

Оригинален текст от CORDIS (на английски).

Участници

FUNDACION IMDEA NANOCIENCIA · MadridКоординаторИспания