ABSTRACT
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.
Subject(s)
Aniline Compounds/pharmacology , Mitochondria/drug effects , Photochemotherapy , Photons , Photosensitizing Agents/pharmacology , Porphyrins/pharmacology , Aniline Compounds/chemistry , Cations/chemical synthesis , Cations/chemistry , Cations/pharmacology , Cell Death/drug effects , Dose-Response Relationship, Drug , HT29 Cells , Humans , Molecular Structure , Photosensitizing Agents/chemical synthesis , Photosensitizing Agents/chemistry , Porphyrins/chemistry , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
We report the properties of glycoconjugated porphyrin dimers behaving as highly sensitive ratiometric temperature sensors in water. This effect results from interactions between carbohydrate and water altering molecular relaxation kinetics leading to temperature sensitive dual emission. These dimers are robust ratiometric fluorescent probes over a large temperature window (20-90 °C).
Subject(s)
Dimerization , Glycoconjugates/chemistry , Porphyrins/chemistry , TemperatureABSTRACT
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.
Subject(s)
Aniline Compounds/chemical synthesis , Colonic Neoplasms/chemistry , Colonic Neoplasms/drug therapy , Glycoconjugates/chemical synthesis , Photosensitizing Agents/chemistry , Photosensitizing Agents/therapeutic use , Porphyrins/chemical synthesis , Singlet Oxygen/chemistry , Aniline Compounds/chemistry , Biological Evolution , Cell Line, Tumor , Dimerization , Glycoconjugates/chemistry , Humans , Photochemotherapy , Photons/therapeutic use , Porphyrins/chemistry , Spectrum AnalysisABSTRACT
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.
Subject(s)
Glycoconjugates/chemistry , Glycoconjugates/pharmacology , Metalloporphyrins/chemistry , Metalloporphyrins/pharmacology , Neoplasms/drug therapy , Photosensitizing Agents/chemistry , Photosensitizing Agents/pharmacology , Cell Line, Tumor , Dimerization , Glucose/chemistry , Glucose/pharmacokinetics , Glucose/pharmacology , Glycoconjugates/pharmacokinetics , Humans , Lactose/chemistry , Lactose/pharmacokinetics , Lactose/pharmacology , Mannose/chemistry , Mannose/pharmacokinetics , Mannose/pharmacology , Metalloporphyrins/pharmacokinetics , Neoplasms/metabolism , Photochemotherapy , Photosensitizing Agents/pharmacokinetics , Singlet Oxygen/metabolismABSTRACT
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.
Subject(s)
Bystander Effect/drug effects , Colorectal Neoplasms/drug therapy , Photochemotherapy/methods , Photosensitizing Agents/pharmacology , Porphyrins/pharmacology , Animals , Apoptosis/drug effects , Cell Count , Diffusion Magnetic Resonance Imaging , Female , Mice , Mice, Nude , Xenograft Model Antitumor AssaysABSTRACT
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.
Subject(s)
Apoptosis/drug effects , Photochemistry/methods , Photosensitizing Agents/pharmacology , Polyamines/pharmacology , Porphyrins/pharmacology , Apoptosis/radiation effects , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Line , Cell Line, Tumor , Female , Humans , Keratinocytes/cytology , Keratinocytes/metabolism , Photosensitizing Agents/chemical synthesis , Photosensitizing Agents/chemistry , Phototherapy/methods , Polyamines/chemical synthesis , Polyamines/chemistry , Porphyrins/chemical synthesis , Porphyrins/chemistry , Spermidine/chemistry , Spermidine/pharmacology , Spermine/chemistry , Spermine/pharmacology , StereoisomerismABSTRACT
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.
Subject(s)
DNA Cleavage , DNA/chemistry , Photochemistry/methods , Polyamines/chemistry , Porphyrins/chemistry , Animals , Phototherapy , Structure-Activity RelationshipABSTRACT
The 2-methoxy derivative of estradiol is currently in Phase II clinical trial as an anticancer agent while the 4-methyl derivative has been shown to interact with cytoplasmic and nuclear estrogen receptors in rat pituitary gland and hypothalamus. We hypothesize that the 16alpha-(18)F-analogs of these estrogens could be suitable radiotracers to evaluate action mechanisms of the parent compounds. In this study we report the synthesis of the 16alpha-(18)F and 16alpha-(19)F-analogs of the A-ring substituted estradiols in high yield via stereoselective opening of the intermediate 16beta,17beta-O-cyclic sulfones with [(18)F]F(-) or F(-) followed by deprotection.
Subject(s)
Estradiol/analogs & derivatives , Positron-Emission Tomography , Radiopharmaceuticals/chemistry , Radiopharmaceuticals/chemical synthesis , Estradiol/chemical synthesis , Estradiol/chemistry , Isotope Labeling/methodsABSTRACT
This paper reports the synthesis of new chlorin-polyamine conjugates designed to improve the targeting of cancer cells. Photocytotoxic activity of these photosensitizers was tested against human chronic myelogenous leukemia cells (K562) and compared to the effects of Photofrin II and chlorin e6.
Subject(s)
Photosensitizing Agents/chemical synthesis , Photosensitizing Agents/toxicity , Polyamines/chemistry , Polyamines/toxicity , Porphyrins/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Proliferation/radiation effects , Humans , Molecular Structure , Photosensitizing Agents/chemistry , Polyamines/chemical synthesisABSTRACT
An efficient five-step synthesis method was developed to obtain tritolylporphyrin and protoporphyrin IX polyamine conjugates. These compounds were composed of either one polyamine unit (spermidine or spermine) covalently tethered to monocarboxyphenyl tritolylporphyrin or two molecules of polyamines borne by protoporphyrin IX. In each compound, an aliphatic spacer arm is linked to the N(4) polyamine position. Photocytotoxicity of these new compounds was evaluated against K562 human chronic myelogenous leukemia cells and compared to Photofrin II; protoporphyrin IX polyamine conjugates exhibited much stronger photocytocicity than Photofrin II and were shown to readily induce necrosis in treated cells.
