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Novel targeted near-IR photosensitisers and their local and systemic antitumour effects

Ziel

Photodynamic therapy (PDT) is an innovative and efficient method for cancer treatment. It is based on the accumulation of an organic dye, a photosensitiser (PS), in malignant tissue and its local activation with light. The activated dye produces reactive oxygen species that initiate a chain of events leading to tumour destruction. Effective development of PDT requires new highly efficient and selective PSs, detailed knowledge of mechanisms of their action and advanced PDT procedures with implication of local and systemic antitumour effects. This will be the subject of the project that unites specialists in biology, chemistry and biophysics.

This interdisciplinary approach is essential in order to resolve a wide spectrum of fundamental and applied problems concerning:
(i) the synthesis of new efficient near-IR photosensitisers - chlorin (CIC) and bacteriochlorin (CIBC) derivatives with additional imide exocycle;
(ii) the targeting of these derivatives to mitochondrial benzodiazepine receptors through optimisation of the structure;
(iii) the creation of lectin targeted photosensitising molecular constructions (PS-MCs);
(iv) the design of modular recombinant PS-MCs for selective internalisation in tumour cells and directed intranuclear transport;
(v) the comprehensive investigation of physical-chemical and photobiological properties of new PSs, structure-activity relationships and peculiarities of photodynamic action in cell culture and animals;
(vi) the PDT-induced immune response and the role of immunity in elimination of disseminated cancer cells and prevention of tumour re-growth.

Biophysical properties of CIC and CIBC derivatives are a good prerequisite for the development of advanced PSs, as was demonstrated in the pilot investigations. Based on the experience gained by the project participants, a set of new PS-MCs interacting with definite molecular/organelle targets will be designed and their structures will be optimised to enhance considerably the PDT efficiency. At present there remain many fundamental gaps in understanding both specific nature of the photodynamic damage that occurs within cells and tissues, and relationships between structure of PSs and their photodynamic activity.

Different characteristics of designed PS-MCs will be studied and compared in this project. These include: spectral, photophysical and photochemical properties; intracellular and intratumour localisation; mechanisms of action in vitro and in vivo. Relationships between these characteristics, structure of the developed PSs and their overall photodynamic efficacy will be clarified.

Tumour-specific immunity is considered now as an essential part of PDT antitumour efficacy. A special emphasis will be devoted to investigation of this topic; the role of PDT-induced inflammatory/ immune reactions in prevention of local and distant recurrence of tumours will be examined. The influence of PDT with new PS-MCs on incidence of tumour metastases will be established in order to envisage and estimate possible long-term consequences of tumour treatment.

Aufforderung zur Vorschlagseinreichung

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Koordinator

Centre National de Recherche Scientifique
EU-Beitrag
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Adresse
Rue Charles Sadron
45071 Orléans Cedex 2
Frankreich

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Beteiligte (7)