Guillaume Garcia

Synthesis and Characterization of Glycoconjugated Porphyrin Triphenylamine Hybrids for Targeted Two-Photon Photodynamic Therapy

In order to avoid side effects at the time of cancer eradication to the patients, the selectivity of treatments has become of strategic importance. In the case of photodynamic therapy (PDT), two-photon absorption combined with active targeting of tumors could allow both spatial and chemical selectivity. In this context, we present the synthesis, spectroscopic, and biological properties of a series of porphyrin-triphenylamine hybrids with excellent singlet oxygen production capacities and good two-photon absorption.

Carbohydrate-conjugated porphyrin dimers: synthesis and photobiological evaluation for a potential application in one-photon and two-photon photodynamic therapy.

We report the synthesis of bioconjugated zinc porphyrin dimers 1a-e designed as photosensitizers for one-photon and two-photon excited photodynamic therapy. These macrocycles are substituted with carbohydrate units (glucose, mannose, lactose) in order to target tumor cells over-expressing lectin membrane receptors. Polarity, singlet oxygen production and in vitro photocytotoxicity are studied to determine their photodynamic therapy potentiality.

DNA photocleavage by porphyrin-polyamine conjugates

A series of polyamine-porphyrin conjugates bearing two (cis or trans position) or four units of spermidine or spermine was synthesized. We studied the binding of these cationic porphyrins to calf thymus DNA by the means of UV-vis spectroscopy and we investigated their ability to cleave plasmid DNA in the presence of light. DNA binding and DNA photocleavage abilities were found to depend on structural characteristics as (a) the relative positions of the side chains on the porphyrin ring and (b) the nature of the attached side chains (spermidine or spermine). DNA cleavage was also studied in the presence of a singlet oxygen quencher (NaN(3)) and in the presence of a hydroxyl radical scavenger (mannitol). Singlet oxygen was the major species responsible for the cleavage of DNA previously observed. Collectively, these data show that polyamine-porphyrin conjugates could be promising phototherapeutic agents.

Photodynamic effects of porphyrin–polyamine conjugates in human breast cancer and keratinocyte cell lines

Porphyrin-polyamine conjugates bearing two (cis or trans position) or four spermidine or spermine units were synthesized. We studied the photostability, the hydrophilic/lipophilic balance of porphyrin-polyamine derivatives and the production of singlet oxygen. All these compounds possess physicochemical features required for their use in PDT. Then, we investigated the photocytotoxic efficacy of these porphyrin-polyamine derivatives and the cell death pathway implicated. All compounds appear to be more efficient than Photofrin® to induce HaCat and MCF7 cell death, essentially by apoptosis. Collectively, these data show that porphyrin-polyamine conjugates could be promising phototherapeutic agents.

PDT induced bystander effect on human xenografted colorectal tumors as evidenced by sodium MRI

BACKGROUND Previous in vivo studies on photodynamic therapy (PDT)-treated, high cellular density tumors showed evidences of a bystander effect accompanying the therapy, cellular death continuing beyond the limits of the photochemical reactions in time and space. This process is generated by the initially damaged cells on the light pathway. The aim of this study was to determine if the bystander effect may be induced as well in colorectal xenografted tumors (less compact structure) and if the cellular signaling depends primarily on cellular proximity or not. METHODS The photosensitizer was a glycoconjugated, meso substituted porphyrin derivative synthesized at Institut Curie. The longitudinal follow-up of the tumors was carried out by (23)Na/(1)H MRI, ideal imaging modality for mapping the extracellular compartment. Two regimens were followed in order to target either blood vessels alone or blood vessels and cancer cells simultaneously. RESULTS The antivascular PDT did not succeed to arrest the tumors growth at the end of the follow-up. For double targeting PDT, we managed to stop the tumoral evolution. Sodium MRI evidenced a bystander effect. CONCLUSION The results obtained showed that the bystander effect is more difficult to induce for the type of colorectal tumors used in this work. It needs a double treatment, 4 days apart, in order to be promoted.

Design of an amphiphilic porphyrin exhibiting high in vitro photocytotoxicity

A porphyrin monosubstituted by three triethyleneglycol chains grafted on a pentaerythritol skeleton was designed to display an optimized amphiphilicity for an enhanced cellular uptake and thus to exert enhanced photocytotoxicity. This porphyrin proved to be an excellent photosensitiser with submicromolar IC50.

Dendrimeric-like hexadecahydroxylated zinc phthalocyanine: Synthesis and evaluation of photodynamic efficiency

The design of a dendrimeric-like diglycerol-tetrasubstituted Zn(II) phthalocyanine resulted in a remarkably water-soluble compound due to the presence of 16 hydroxyls. Several parameters relevant to evaluate the photodynamic efficiency of a potentiel photosensitizer such as: aggregation behavior, fluorescence properties, singlet oxygen generation, binding to a carrier protein model (Bovine Serum Albumin) and partition coefficient have been measured. Biocompatibility was demonstrated by dark cytotoxicity in in vitro experiments. The absence of phototoxicity can be explained by an elevated hydrophilicity. All the collected data have confirmed that this new substitution pattern is promising to be used on phthalocyanines aiming at being photodynamic therapy agents.

Mitochondria-targeted cationic porphyrin-triphenylamine hybrids for enhanced two-photon photodynamic therapy

The proof of concept for two-photon activated photodynamic therapy has already been achieved for cancer treatment but the efficiency of this approach still heavily relies on the availability of photosensitizers combining high two-photon absorption and biocompatibility. In this line we recently reported on a series of porphyrin-triphenylamine hybrids which exhibit high singlet oxygen production quantum yield as well as high two-photon absorption cross-sections but with a very poor cellular internalization. We present herein new photosensitizers of the same porphyrin-triphenylamine hybrid series but bearing cationic charges which led to strongly enhanced water solubility and thus cellular penetration. In addition the new compounds have been found localized in mitochondria that are preferential target organelles for photodynamic therapy. Altogether the strongly improved properties of the new series combined with their specific mitochondrial localization lead to a significantly enhanced two-photon activated photodynamic therapy efficiency.