Nanoparticles as vehicles for delivery of photodynamic therapy agents Denise Bechet 1* , Pierre Couleaud 2* , Ce ´ line Frochot 2, 3 , Marie-Laure Viriot 2, 3 , Franc ¸ois Guillemin 1, 3 and Muriel Barberi-Heyob 1, 3 1 Centre de Recherche en Automatique de Nancy, Nancy-University, CNRS, Centre Alexis Vautrin, Brabois, Avenue de Bourgogne F-54511 Vandœuvre-le ` s-Nancy, France 2 DCPR, De ´ partement de Chimie Physique des Re ´ actions, Nancy-University, CNRS, 1 rue Grandville, F-54001 Nancy, France 3 GDR 3049 ‘Me ´ dicaments Photoactivables – Photochimiothe ´ rapie (PHOTOMED)’, France Photodynamic therapy (PDT) in cancer treatment involves the uptake of a photosensitizer by cancer tissue followed by photoirradiation. The use of nanoparticles as carriers of photosensitizers is a very promising approach because these nanomaterials can satisfy all the requirements for an ideal PDT agent. This review describes and compares the different individual types of nanoparticles that are currently in use for PDT appli- cations. Recent advances in the use of nanoparticles, including inorganic oxide-, metallic-, ceramic-, and bio- degradable polymer-based nanomaterials as carriers of photosensitizing agents, are highlighted. We describe the nanoparticles in terms of stability, photocytotoxic efficiency, biodistribution and therapeutic efficiency. Finally, we summarize exciting new results concerning the improvement of the photophysical properties of nanoparticles by means of biphotonic absorption and upconversion. Introduction: bio-nanotechnology opens new avenues for photodynamic therapy Photodynamic therapy (PDT) is now well established as a clinical treatment modality for various diseases, including cancer and particularly for the treatment of superficial tumours (e.g. oesophagus, bladder, melanoma) [1]. This treatment involves the administration of a photosensitizer. After a predefined time-interval to allow the photosensi- tizer to accumulate in the tumour tissue, the irradiation of the tumour site with non-thermal light (635–760 nm) leads to the formation of an excited photosensitizer. The com- bined action of the excited triplet photosensitizer and molecular oxygen results in the formation of singlet oxygen ( 1 O 2 ), which is thought to be the main mediator of cellular death induced by PDT [2]. PDT has been shown to induce both apoptosis and necrosis. The one disadvantage of photoactivable molecules is their low absorbance in the optical window for photosensitizer excitation, which reduces their efficiency in terms of 1 O 2 production. Of the major proteins in blood that absorb light, the most important quantitatively is haemoglobin, which absorbs light up to wavelengths of 600 nm, meaning that tissues must be illuminated at wavelengths higher than this to ensure a good penetration of light. At wavelengths higher Review Glossary Absorption cross section: the absorption coefficient divided by the number of molecular entities contained in a volume of the absorption medium along the light path. In the case of biphotonic excitation, it is a two photon absorption (TPA) cross-section. Biocompatibility: the quality of not having toxic or injurious effects on biological systems. How nanomaterials interact with the human body and, eventually, how those interactions determine the clinical success of a medical device. Biodegradable polymer-based nanoparticles: organic nanoparticles made of polymer that can be degraded in a biological environment. This occurs mainly by hydrolysis or enzymatic reactions. Ceramic-based nanoparticles: inorganic nanoparticles with porous character- istics made mainly of silica, titania or alumina. Diffusion magnetic resonance imaging (MRI): diffusion MRI enables the study of water diffusion in a variety of environments (e.g. biological tissues). Diffusion MRI can be performed at various time points after treatment to monitor changes in tumour diffusion and tumour growth. After PDT, for instance, brain cells die, trapping water molecules inside them (cellular pumps are no longer functioning). Doped nanoparticles: nanoparticles (usually silica) doped with a large number of dye molecules (either organic or inorganic). There can be tens of thousands of dye molecules inside a single silica particle. Drug loading: amount of photosensitizer in nanoparticles divided by the amount of nanoparticles, usually expressed as a percentage. Entrapment efficiency: drug loading divided by the theoretical drug loading (expressed as a percentage). Hyperthermia therapy: a type of treatment in which body tissue is exposed to high temperatures to damage cancer cells or to make them more sensitive to the effects of radiation and certain anticancer drugs. Metallic nanoparticles: nanoparticles made of metal, such as gold or silver. Multifunctional nanoparticles: nanoparticles with different units (e.g. targeting units, imaging agents) or nanoparticles that have several functions (therapy, diagnosis). Nanoparticles: the term nanoparticle is generally used to refer to a small particle with all three dimensions measuring less than 1000 nanometres. Photocytotoxicity: effect on cell survival dependent upon the incident level of light (toxic effect on cells induced by absorption of light). Photosensitization: the process by which a photochemical or photophysical alteration occurs in one molecular entity as a result of initial absorption of radiation by another molecular entity called a photosensitizer. Photosensitizer (or a photosensitizing agent): light-sensitive molecule that can activate an alteration in another molecular entity. Photodynamic therapy is based on the formation of singlet oxygen from triplet oxygen by a photosensitizer. Singlet oxygen gives rise to peroxidative reactions that can cause cell damage and death. Photothrombic: PDT-induced thrombosis. Photothrombic efficacy is visually assessed for each CAM according to the vessel closure efficacy. Quantum yield: The number of defined events that occur per photon absorbed by the system. Scintillation luminescent nanoparticles: nanoparticles that can be stimulated by X-rays or other radiation sources and will generate light Two-photon absorption (TPA) or excitation (TPE): excitation resulting from successive or simultaneous absorption of two photons by an atom or a molecular entity. The simultaneous two-photon absorption can also be called biphotonic excitation. Upconversion: a nonlinear optical effect in which light frequency is increased. Corresponding author: Barberi-Heyob, M. (m.barberi@nancy.fnclcc.fr) * These authors contributed equally to this review. 612 0167-7799/$ – see front matter ß 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.tibtech.2008.07.007 Available online 17 September 2008