Bernard Loock

Mannose-targeted mesoporous silica nanoparticles for photodynamic therapy.

Functionalisation of MSN with mannose for PDT applications dramatically improved the efficiency of PDT on breast cancer cells.

Cancer therapy improvement with mesoporous silica nanoparticles combining targeting, drug delivery and PDT.

The synthesis of mesoporous silica nanoparticles (MSN) covalently encapsulating fluoresceine or a photosensitizer, functionalized with galactose on the surface is described. Confocal microscopy experiments demonstrated that the uptake of galactose-functionalized MSN by colorectal cancer cells was mediated by galactose receptors leading to the accumulation of the nanoparticles in the endosomal and lysosomal compartments. The MSN functionalized with a photosensitizer and galactose were loaded with the anti-cancer drug camptothecin. Those MSN combining drug delivery and photodynamic therapy were tested on three cancer cell lines and showed a dramatic enhancement of cancer cell death compared to separate treatments.

Silicalites and Mesoporous Silica Nanoparticles for photodynamic therapy

The synthesis of silicalites and Mesoporous Silica Nanoparticles (MSN), which covalently incorporate original water-soluble photosensitizers for PDT applications is described. PDT was performed on MDA-MB-231 breast cancer cells. All the nanoparticles showed significant cell death after irradiation, which was not correlated with (1)O(2) quantum yield of the nanoparticles. Other parameters are involved and in particular the surface and shape of the nanoparticles which influence the pathway of endocytosis. Functionalization with mannose was necessary to obtain the best results with PDT due to an active endocytosis of mannose-functionalized nanoparticles. The quantity of mannose on the surface should be carefully adjusted as a too high amount of mannose impairs the phototoxicity of the nanoparticles. Fluorescein was also encapsulated in MCM-41 type MSN in order to localize the nanoparticles in the organelles of the cells by confocal microscopy. The MSN were localized in lysosomes after active endocytosis by mannose receptors.

Multifunctionalized mesoporous silica nanoparticles for the in vitro treatment of retinoblastoma: Drug delivery, one and two-photon photodynamic therapy

In this work, we focused on mesoporous silica nanoparticles (MSN) for one photon excitated photodynamic therapy (OPE-PDT) combined with drug delivery and carbohydrate targeting applied on retinoblastoma, a rare disease of childhood. We demonstrate that bitherapy (camptothecin delivery and photodynamic therapy) performed with MSN on retinoblastoma cancer cells was efficient in inducing cancer cell death. Alternatively MSN designed for two-photon excited photodynamic therapy (TPE-PDT) were also studied and irradiation at low fluence efficiently killed retinoblastoma cancer cells.

23Na MRI longitudinal follow-up of PDT in a xenograft model of human retinoblastoma

BACKGROUND Photodynamic therapy is an established cancer treatment in which a photosensitizing agent is activated by exposure to light thus generating cytotoxic reactive oxygen species that cause cellular damage. METHODS A new photosensitizer synthesized at Curie Institute was used to treat retinoblastoma xenografts in mice, a glycoconjugated meso substituted porphyrin derivative, that showed some retinoblastoma cell affinity. The longitudinal follow-up of the tumors was carried out by (23)Na MRI (without adding exogenous contrast agents) to map the extracellular compartment and to characterize cell packing. Two regimens were followed to target either blood vessels alone or blood vessels and cancer cells simultaneously. RESULTS AND CONCLUSIONS Only the protocol targeting both cancer cells and blood vessels effectively induces cellular death, confirmed by histology at the end of the experiment. Sodium MRI evidences a huge change in the cellular density of tumors only 24h after a double targeting (vascular and cellular) PDT treatment. We suggest that this change was possibly due to a bystander effect that can be promoted by the intercellular signaling favored by the high cellular density of retinoblastoma. These results indicate that non-invasive (23)Na imaging (which detects the tumor response to treatment from very early stages) in association with non-mutagenic therapies represents an effective option for tailored and individualized clinical treatments.

A Strategy for the Targeting of Photosensitizers. Synthesis, Characterization, and Photobiological Property of Porphyrins Bearing Glycodendrimeric Moieties

This paper describes the conception, synthesis, and characterization of new tetrapyrrolic chromophores bearing glycodendrimeric moieties inducing a potential increase of tumor targeting by a cluster effect. Two families of monoglycodendrimeric photosensitizers bearing three glycosyl units were designed, prepared with an acceptable overall efficiency and characterized by NMR, UV-visible, and fluorescence spectroscopies. The polarity and log P were evaluated by HPLC and the stir-flask method, respectively. The in vitro photoefficiency against two human tumor cell lines was assessed. The presence of the glycodendrimeric group does not appear to increase the tumor in vitro targeting.

Synthesis of interlocked basket handle porphyrins

Abstract The synthesis and the characterization by UV-visible and 1 H NMR spectroscopic analyses of interlocked basket handle porphyrins in which the two subunits are assembled by the Cu(I) complex of phenanthroline residues inserted into superstructures are reported.

Both-faces hindered porphyrins. Part 1. Synthesis and characterization of basket-handle porphyrins and their iron complexes

The synthesis of the ‘both-faces’ hindered porphyrins using two different methods is reported. These so-called ‘basket-handle’ porphyrins (BHP) are derived from 5,10,15,20-tetraphenylporphyrin in which two opposite phenyl groups are bridged by alkylene or arylene-p-bisalkylene chains. In addition to the desired compounds [the cross-trans-linked isomer (7)], two other isomers were obtained [adjacent-trans-linked (8) and adjacent-cis-linked (9)]. These were separated by t.l.c. on silica gel and then individually characterized. The structural assignment of the three isomers in the five series studied was based on the 1H n.m.r. spectra of the free bases and of their iron(II) complexes.

Both-faces hindered porphyrins. Part 3. Synthesis and characterization of internally five-co-ordinated iron(II) basket handle porphyrins derived from 5,10,15,20-tetrakis(o-aminophenyl)porphyrin

The synthesis of a series of so-called amide ‘hanging base’ porphyrins (10), (14) and (18). derived from 5,10,15,20-tetrakis(o-aminophenyl)porphyrin (αβαβ-atropisomer)(3), in which one of the faces is hindered by an alkylene or an arylene-p-bisalkylene bridge and the other face is bridged by a pyridine-3,5-diyl-bisalkyleneoran imidazolyl-alkylene chain, is described. The structural assignment of the various compounds is based on the 1H n.m.r. spectra of the free bases, and of their zinc(II) and iron(II) complexes. Unlike the ether ‘hanging base’ metalloporphyrins, the metallic ion of amide ‘hanging base’ porphyrins is actually five-co-ordinated by the proximal base. Furthermore, not only is the equilibrium pyridine plane orientation dependent on the length of its linking chain, but the bridging forces the amide protons to point toward the centre of the macrocyle core. These structural properties are potential factors which may affect the binding of dioxygen. The synthesis of a bis-pyridine ‘basket handle’ porphyrin is also reported.

Assignment of N(Pyrrole)-Sensitive Raman Bands of 2-Methylimidazole and Bisimidazole Complexes of Ferroetioporphyrin

Abstract Resonance Raman spectra of 2-methylimidazole and bisimidazole complexes of (14N-pyrrole)4-and of (15N-pyrrole)4-ferroetioporphyrin were obtained using a 441.6 nm excitation. It is shown that the low-frequency bands, II (204 or 257 cm−1), IV (334 or