Fabienne Dumoulin

Light-Triggered Liposomal Release: Membrane Permeabilization by Photodynamic Action

Photosensitized damage to liposome membranes was studied by using different dye-leakage assays based on fluorescence dequenching of a series of dyes upon their release from liposomes. Irradiation of liposomes with red light in the presence of a photosensitizer, trisulfonated aluminum phthalocyanine (AlPcS(3)), resulted in the pronounced leakage of carboxyfluorescein, but rather weak leakage of sulforhodamine B and almost negligible leakage of calcein from the corresponding dye-loaded liposomes. The same series of selectivity of liposome leakage was obtained with chlorin e6 that appeared to be more potent than AlPcS(3) in bringing about the photosensitized liposome leakage. Electrically neutral zinc phthalocyanine tetrasubstituted with a glycerol moiety (ZnPcGlyc(4)) was less effective than negatively charged AlPcS(3) in provoking the light-induced liposome permeabilization. On the contrary, both ZnPcGlyc(4) and AlPcS(3) were much more effective than chlorin e6 in sensitizing gramicidin channel inactivation in planar bilayer lipid membranes, thus showing that relative photodynamic efficacy of sensitizers can differ substantially for damaging different membrane targets. The photosensitized liposome permeabilization was apparently associated with oxidation of lipid double bonds by singlet oxygen as evidenced by the mandatory presence of unsaturated lipids in the membrane composition for the photosensitized liposome leakage to occur and the sensitivity of the latter to sodium azide. The fluorescence correlation spectroscopy measurements revealed marked permeability of photodynamically induced pores in liposome membranes for such photosensitizer as AlPcS(3).

Click chemistry: the emerging role of the azide-alkyne Huisgen dipolar addition in the preparation of substituted tetrapyrrolic derivatives

The review aims at being an exhaustive summary of the use of Huisgen azide-alkyne dipolar addition in the synthesis of tetrapyrrolic compounds, mainly porphyrins, phthalocyanines, chlorins and bacteriochlorins.

Monoglycoconjugated phthalocyanines: Effect of sugar and linkage on photodynamic activity

BACKGROUND Click chemistry can be advantageously used to graft carbohydrates on phthalocyanines which are potent photosensitisers, but the effect of the presence of triazole moieties on photodynamic efficiency was not investigated systematically to date. The nature and linkage of the sugar were investigated in order to define structure-activity relationships. METHOD Two sets of monoglycoconjugated water-soluble phthalocyanines have been designed and their photodynamic activity and uptake investigated in HT-29 human colon adenocarcinoma cells. Carbohydrates: galactose, mannose or lactose were grafted onto Zn(II) phthalocyanines either by glycosylation or by click reaction. RESULTS The triazole linkage formed by click conjugation lowered the biological efficiency for mannose and galactose, compared to classical glycosylation grafting. The mannose conjugate formed by glycosylation was the most photodynamically active, without correlation with the photosensitiser cell uptake.

Amphiphilic carbohydrate–phthalocyanine conjugates obtained by glycosylation or by azide–alkyne click reaction

Two series of amphiphilic carbohydrate–phthalocyanine conjugates have been prepared either by glycosylation or by copper-catalyzed click coupling. A common precursor, a hydroxylated phthalocyanine, was directly glycosylated or converted into an azido derivative before undergoing grafting of propargyl–carbohydrates by click reaction.

Improved photodynamic efficacy of Zn(II) phthalocyanines via glycerol substitution.

Phthalocyanines are excellent photosensitizers for photodynamic therapy as they have strong absorbance in the near infra-red region which is most relevant for in vivo activation in deeper tissular regions. However, most phthalocyanines present two major challenges, ie, a strong tendency to aggregate and low water-solubility, limiting their effective usage clinically. In the present study, we evaluated the potential enhancement capability of glycerol substitution on the photodynamic properties of zinc (II) phthalocyanines (ZnPc). Three glycerol substituted ZnPc, 1–3, (tetra peripherally, tetra non-peripherally and mono iodinated tri non-peripherally respectively) were evaluated in terms of their spectroscopic properties, rate of singlet oxygen generation, partition coefficient (log P), intracellular uptake, photo-induced cytotoxicity and vascular occlusion efficiency. Tetrasulfonated ZnPc (ZnPcS4) was included as a reference compound. Here, we showed that 1–3 exhibited 10–100 nm red-shifted absorption peaks with higher molar absorptivity, and at least two-fold greater singlet oxygen generation rates compared to ZnPcS4. Meanwhile, phthalocyanines 1 and 2 showed more hydrophilic log P values than 3 consistent with the number of glycerol attachments but 3 was most readily taken up by cells compared to the rest. Both phthalocyanines 2 and 3 exhibited potent phototoxicity against MCF-7, HCT-116 and HSC-2 cancer cell-lines with IC50 ranging 2.8–3.2 µM and 0.04–0.06 µM respectively, while 1 and ZnPcS4 (up to 100 µM) failed to yield determinable IC50 values. In terms of vascular occlusion efficiency, phthalocyanine 3 showed better effects than 2 by causing total occlusion of vessels with diameter <70 µm of the chorioallantoic membrane. Meanwhile, no detectable vascular occlusion was observed for ZnPcS4 with treatment under similar experimental conditions. These findings provide evidence that glycerol substitution, in particular in structures 2 and 3, is able to improve the photodynamic properties of ZnPc.

Design of a Gd-DOTA-Phthalocyanine Conjugate Combining MRI Contrast Imaging and Photosensitization Properties as a Potential Molecular Theranostic

The design and synthesis of a phthalocyanine – Gd‐DOTA conjugate is presented to open the way to novel molecular theranostics, combining the properties of MRI contrast imaging with photodynamic therapy. The rational design of the conjugate integrates isomeric purity of the phthalocyanine core substitution, suitable biocompatibility with the use of polyoxo water‐solubilizing substituents, and a convergent synthetic strategy ended by the use of click chemistry to graft the Gd‐DOTA moiety to the phthalocyanine. Photophysical and photochemical properties, contrast imaging experiments and preliminary in vitro investigations proved that such a combination is relevant and lead to a new type of potential theranostic agent.

4,5-, 3,6-, and 3,4,5,6-tert-Butylsulfanylphthalonitriles: synthesis and comparative structural and spectroscopic analyses

Three tert-butylsulfanylphthalonitriles have been prepared with optimized synthetic procedures. Their comparative structural analyses have been completed, with a focus on IR and NMR spectroscopy and refined X-ray structural data. Miscellaneous parameters such as UV absorption, melting points, and related polarity of the compounds are summarized.

Preparation of N-bridged diiron phthalocyanines bearing bulky or small electron-withdrawing substituents

The synthesis of novel μ-nitrido diiron phthalocyanine with electron-withdrawing substituents is reported: μ-nitrido tetra-methylsulfonylphthalocyanine (13), μ-nitrido tetra-ethylsulfonylphthalocyanine (14), μ-nitrido tetra-adamantylsulfonylphthalocyanine (15), μ-nitrido tetra-cyclohexylsulfonylphthalocyanine (16). These complexes were characterized by ESI-MS, UV-vis, FT-IR and EPR techniques. The state of these complexes depends on the size of the substituents. Complexes 13 and 14 bearing small methylsulfonyl and ethylsulfonyl substituents are cationic (PcFeIVNFeIVPc)+N3- complexes while complexes 15 and 16 with bulkier adamantylsulfonyl and cyclohexylsulfonyl substituents are formally neutral PcFeIIINFeIVPc complexes which can be represented as PcFe(+3.5)NFe(+3.5)Pc.

Amphiphilic galactosylated phthalocyanines

Two amphiphilic Ni phthalocyanines bearing a hydrophilic galactose head facing six hydrophobic thiohexyl chains are described. The place of the glycosylation step on the overall synthetic pathway is discussed. For the first time, phthalocyanines are used as acceptors in glycosylation reactions, in excellent yields.

Octasolketal-substituted phthalocyanines: synthesis and systematic study of metal effect and substitution pattern on 13C NMR

A complete series of solketal octasubstituted phthalocyanines have been synthesized, with peripheral (β) or non-peripheral (α) substitution pattern. Their 13C NMR and UV-vis properties are compared relatively to this substitution pattern or the nature of the central metal (Ni, Zn or H2).