Laboratoire de Physique et Chimie des Nano-objets

Institut National des Sciences Appliquées
135 avenue de Rangueil, 31077 TOULOUSE CEDEX 4 - FRANCE
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Home page > LPCNO > Groups > Receptors and Therapeutic Targeting of Cancers > Research topics > Cancer targeted therapies

Cancer targeted therapies

The recognition that cancer is a heterogeneous disease and the validation of new targets enables the development of personalized medicine and targeted therapies. However, selective delivery of anti-cancer agents to tumor sites remains an important challenge.

The emergence of ligand-targeted nanomedicines represents a new opportunity in oncology. We wish to exploit over-expression of G-protein coupled receptors in endocrine tumors and their ligand-induced endocytosis to deliver magnetic nanoparticules to tumors. We have developed a strategy of nanotherapy by taking advantage of the ability of cancer cells over-expressing GPCRs to internalize receptor-bound agonists. A nanoplatform composed of magnetic nanoparticles grafted with a CCK2R peptidic agonist was synthesized. We showed that this nanoplatform specifically recognizes tumoral cells expressing CCK2R, undergoes internalization and trafficking to lysosomes. Exposure of tumoral cells containing nanoparticules to an alternating magnetic field caused cell death (30% of the population) in absence of perceptible temperature rise. Cell death occurred via a lysosomal death pathway which has recently emerged as an efficient way to kill apoptosis resistant cancer cells

During the next 5 years:

1- We will conduct study in order to increase tumor targeting efficiency and cell death rate in vitro and in vivo. Iron oxide NPs will be substituted with NPs of high thermal power synthesized at LPCNO/CNRS/INSA (Toulouse). New knowledge acquired with this project should contribute to evaluate the therapeutic value of lysosomal death pathway triggered by NPs/magnetic field to treat endocrine tumors as well as its translation to a wide variety of cancers using adequate targets. NPs will be multifunctionalized by grafting peptides targeting successively αvβ3/5 integrins and neuropilin-1 which have been reported to enhance tumor homing and penetration of pharmaceutics and/or by grafting NPs with a combination of peptidic ligands of receptors over-expressed in tumors.

2- We will study mechanisms of cell death. The role of NPs heating in lysosomes, ROS, lysosomal enzymes, caspases, cell cycle etc…, will be investigated on living cells using molecular thermometers, fluorescent markers of signaling pathways, pharmacological inhibitors, SiRNAs.

3- We will launch in vivo tests on orthotopic pancreatic endocrine tumor xenografts and on MEN1-/- mice model of endocrine tumors (coll. Dr P Bertolino, Lyon Cancer Research Centre, INSERM);

National and international collaborations

Prof JC Reubi, Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, University of Berne, Berne, Switzerland;

Prof. JM Devaud, Université Paul Sabatier, Centre de Recherches sur la Cognition Animale (CRCA) CNRS UMR 5169, Toulouse, France

Dr Bertolino Philippe Cancer Research Center-Lyon (CRCL), Inserm U1052, CNRS UMR5286, Univ. Claude Bernard Lyon I, Lyon, France

Dr Irina Tikhonova, Molecular Therapeutics, School of Pharmacy, Queen’s University of Belfast, North Ireland, UK

Dr Arnau Cordomi, Laboratori de Medicina Computacional, Unitat de Bioestadı´stica, Facultat de Medicina, Universitat Auto`noma de Barcelona, 08193 Barcelona, Spain

Prof Laurence Motte, Université Paris 13, Laboratoire CSPBAT "Chimie, Structures, Propriétés de Biomatériaux et d’Agents Thérapeutiques", CNRS UMR7244, Paris, France.

Professor Helmut Maecke, Department of Nuclear Medicine, University of Friburg, Freiburg, Germany

Doctors Michel Baltas and Joelle Azema, CNRS, LSPCMIB, UMR-5068, Toulouse, France.