bacteriochlorin and Neoplasms

The review summarizes the chemistry of the third generation of photosensitizers, namely, the derivatives of natural bacteriochlorophyll a, for photodynamic treatment of cancer. The compounds of this class strongly absorb light at lambda=770-850 nm. This unique property opens new therapeutic opportunities due to deeper tissue penetration of light, thereby increasing the photodamage for tumor eradication. Analyzed are the modifications of bacteriochlorophyll a, that improve physico-chemical characteristics of compounds and enhance accumulation in tumors. Focusing on the delivery of photosensitizers to the tumor site and to specific intracellular compartments, we describe the conjugates of bacteriochlorophyll a, derivatives with carbohydrate and protein carriers. Boronated bacteriochlorins can be used in both photodynamic and boron neutron capture therapy.

Topics: Antineoplastic Agents; Bacteriochlorophyll A; Humans; Models, Biological; Neoplasms; Photochemotherapy; Photosensitizing Agents; Porphyrins

Pyroptosis is increasingly considered a new weathervane in cancer immune therapy. However, triggering specific pyroptotic tumor cell death while preserving normal cells still remains a major challenge. Herein, a brand-new pyroptosis inducer, copper-bacteriochlorin nanosheet (Cu-TBB), is designed. The synthesized Cu-TBB can be activated to an "on" state in the tumor microenvironment with glutathione (GSH) overexpression, leading to the release of Cu

Topics: Cell Line, Tumor; Copper; Glutathione; Humans; Immunotherapy; Neoplasms; Porphyrins; Pyroptosis; Tumor Microenvironment

Photo-induced cytotoxicity and antitumor activity of a series of dual function agents for photodynamic therapy (PDT) and fluorescent imaging based on bacteriochlorin photosensitizer conjugated with various naphthalimide fluorophores was studied in vitro using murine tumor cells of S37 sarcoma and in vivo on mice bearing murine S37 sarcoma. Upon irradiation at the absorption maximum of the photosensitizer, the activity of conjugates was as high as in the case of individual bacteriochlorin, while an additional excitation of the naphthalimide fragment led to an increase in the PDT efficacy due to resonance energy transfer from the fluorophore to photosensitizer. The fluorescence contrast and specific cytotoxic activity measurements indicate that the conjugate of bacteriochlorin with 3,4-dimethoxestyrene-substituted naphthalimide is the most promising agent for the application as theranostic in PDT.

Topics: Animals; Cell Line, Tumor; Lasers; Mice; Naphthalimides; Neoplasms; Optical Imaging; Photochemotherapy; Photosensitizing Agents; Porphyrins; Tissue Distribution; Transplantation, Homologous

Photodynamic therapy (PDT) is currently one of the most promising methods of cancer treatment. However, this method has some limitations, including a small depth of penetration into biological tissues, the low selectivity of accumulation, and hypoxia of the tumor tissues. These disadvantages can be overcome by combining PDT with other methods of treatment, such as radiation therapy, neutron capture therapy, chemotherapy, etc. In this work, potential drugs were obtained for the first time, the molecules of which contain both photodynamic and chemotherapeutic pharmacophores. A derivative of natural bacteriochlorophyll a with a tin IV complex, which has chemotherapeutic activity, acts as an agent for PDT. This work presents an original method for obtaining agents of combined action, the structure of which is confirmed by various physicochemical methods of analysis. The method of molecular modeling was used to investigate the binding of the proposed drugs to DNA. In vitro biological tests were carried out on several lines of tumor cells: Hela, A549, S37, MCF7, and PC-3. It was shown that the proposed conjugates of binary action for some cell lines had a dark cytotoxicity that was significantly higher (8-10 times) than the corresponding metal complexes of amino acids, which was explained by the targeted chemotherapeutic action of the tin (IV) complex due to chlorin. The greatest increase in efficiency relative to the initial dipropoxy-BPI was found for the conjugate with lysine as a chelator of the tin cation relative to cell lines, with the following results: S-37 increased 3-fold, MCF-7 3-fold, and Hela 2.4-fold. The intracellular distribution of the obtained agents was also studied by confocal microscopy and showed a diffuse granular distribution with predominant accumulation in the near nuclear region.

Topics: A549 Cells; Coordination Complexes; HeLa Cells; Humans; MCF-7 Cells; Neoplasms; Photochemotherapy; Photosensitizing Agents; Porphyrins; Tin

Near infrared (NIR) fluorescent probes are attractive tools for biomedical in vivo imaging due to the relatively deeper tissue penetration and lower background autofluorescence. Activatable probes are turned on only after binding to their target, further improving target to background ratios. However, the number of available activatable NIR probes is limited. In this study, we introduce two types of activatable NIR fluorophores derived from bacteriochlorin: chlorin-bacteriochlorin energy-transfer dyads and boron-dipyrromethene (BODIPY)-bacteriochlorin energy-transfer dyads. These fluorophores are characterized by multiple narrow excitation bands with relatively strong emission in the NIR. Targeted bacteriochlorin-based antibody or peptide probes have been previously limited by aggregation after conjugation. Polyethylene glycol (PEG) chains were added to improve the hydrophilicity without altering pharmacokinetics of the targeting moieties. These PEGylated bacteriochlorin-based activatable fluorophores have potential as targeted activatable, multicolor NIR fluorescent probes for in vivo applications.

Topics: Animals; Antibodies, Monoclonal; Boron Compounds; Cell Line, Tumor; Fluorescent Dyes; Heterografts; Humans; Mice; Neoplasms; Optical Imaging; Polyethylene Glycols; Porphyrins

This paper presents a primary screening of bacteriochlorin-type compounds with aminoamide, propyl and carbohydrate substituents aimed for development a new generation photosensitizers (PS) for photodynamic therapy of malignant tumors. Absorption and fluorescence spectral characteristics of the compounds, their storage stability in solutions under dark conditions and light exposure, photo-induced and dark cytotoxicity against human HEp2 tumor cells have been studied. It has been shown that the dyes with aminoamide substituents have an absorbtion maximum at 754±2 nm in the long wavelength region and they are not stable during storage (the specific fluorescence intensity decreased by 33-56% during 24 hours). The long wavelength region absorption of the propyl and carbohydrate substituted compounds varied in the range 780-831 nm, they were stable in solutions during storage and under light irradiation. Except the dye with a carbohydrate residue in the exocycle E, all PS exhibited the high photo-induced activity and low level of the dark cytotoxicity. The highest photo-induced cytotoxicity was observed for compounds with aminoamide substituents inthe macrocyclic ring (IC 50 values ranged from 17 nM to49 nM after 2 hour incubation with PS followed by exposure to the 10 J/cm 2 dose of red light). Taking into account the totality of the physico-chemical and biological properties, as well as manufacturability of production, O-propyloxime-N-propoxybacteriopurinimide methyl ester was chosen as the most promising candidate compound for further investigations.. Proveden pervichnyĭ skrining substantsiĭ-fotosensibilizatorov (FS) bakteriokhlorinovogo riada s aminoamidnymi, propil'nym i uglevodnymi zamestiteliami; on vkliuchal otsenku spektral'nykh kharakteristik dannykh soedineniĭ, ikh ustoĭchivost' pri khranenii v rastvore v zatemnennykh usloviiakh i pri svetovom vozdeĭstvii, a takzhe izuchenie fotoindutsirovannoĭ aktivnosti i tsitotoksichnosti na opukholevykh kletkakh NEr2. Po rezul'tatam absorbtsionnogo i fluorestsentnogo analizov krasiteli s aminoamidnymi zamestiteliami imeiut maksimum pri 754±2 nm, ne stabil'ny pri khranenii (v techenie sutok otmechali snizhenie intensivnosti fluorestsentsii na 33-56%); soedineniia s propil'nym i uglevodnymi zamestiteliami pogloshchaiut v oblasti 780-831 nm i kharakterizuiutsia stabil'nost'iu pri khranenii i obluchenii. Vse FS, krome krasitelia s uglevodnym ostatkom v ékzotsikle E, obladaiut fotoindutsirovannoĭ aktivnost'iu pri otsutstvii temnovoĭ toksichnosti. Naibolee vysokaia fotoaktivnost' zaregistrirovana u soedineniĭ s aminoamidnymi fragmentami v makrotsiklicheskom kol'tse (pri 2-kh chasovoĭ inkubatsii IC 50 sostavliala ot 17 nM do 49 nM). Uchityvaia sovokupnost' fiziko-khimicheskikh i biologicheskikh svoĭstv, a takzhe tekhnologichnost' polucheniia i stabil'nost' pri khranenii i obluchenii, dlia dal'neĭshikh issledovaniĭ s tsel'iu sozdaniia fotosensibilizatora novogo pokoleniia dlia fotodinamicheskoĭ terapii zlokachestvennykh novoobrazovaniĭ vybran metilovyĭ éfir O-propiloksim-N-propoksibakteriopurpurinimida.

Topics: Cell Line, Tumor; Drug Screening Assays, Antitumor; Humans; Neoplasms; Photochemotherapy; Photosensitizing Agents; Porphyrins

Bacteriochlorin derivatives are promising photosensitive agents for photodynamic therapy (PDT) of tumors. In the current study, the photodynamic activity of a novel bacteriochlorin derivative, cis-2, 3, 12, 13-tetracarboxymethyl-5, 10, 15, 20-tetraphenyl bacteriochlorin (TCTB), was evaluated both in vitro and in vivo.. Physicochemical characteristics of the novel photosensitizer were measured. The efficiency of TCTB-PDT in vitro was analyzed by MTT assay, clonogenic assay and in situ trypan blue exclusion test. The intracellular distribution of photosensitizer was detected with laser scanning confocal microscopy. The accumulation of TCTB in human malignant tumor cells was measured by fluorescence spectrometer, and the pathway of cell death was analyzed by flow cytometry. S180 tumor model was used to evaluate the anti-tumor effects of TCTB-PDT. And histopathological study was also used to confirm the anti-tumor effect.. TCTB shows a singlet oxygen quantum yield of 0.56 and displays a characteristic long wavelength absorption peak at 732 nm. The accumulation of TCTB increased in time-dependent manner, and it was found in cytoplasm and nuclear membranes. In vitro PDT using TCTB and Nd:YAG laser showed drug concentration-, laser dose-dependent cytotoxicity to human esophageal cancer Eca-109 cells. In mice bearing osteosarcoma S180 tumors, the combined use of 10 mg/kg TCTB and 120 J/cm(2) showed superior anti-tumor activity. Histology examination of tumor tissues revealed that PDT using TCTB and the Nd:YAG laser induced tumor cells shrunken and necrotic.. In in vitro and in vivo studies, we found that TCTB has excellent anti-tumor effect. It suggests that TCTB is a potential photosensitizer of PDT for cancer.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Humans; Mice; Neoplasms; Photochemotherapy; Photosensitizing Agents; Porphyrins

A series of four stable synthetic bacteriochlorins was tested in vitro in HeLa cells for their potential in photodynamic therapy (PDT). The parent bacteriochlorin (BC), dicyano derivative (NC)(2)BC and corresponding zinc chelate (NC)(2)BC-Zn and palladium chelate (NC)(2)BC-Pd were studied. Direct dilution of a solution of bacteriochlorin in an organic solvent (N,N-dimethylacetamide) into serum-containing medium was compared with the dilution of bacteriochlorin in Cremophor EL (CrEL; polyoxyethylene glycerol triricinoleate) micelles into the same medium. CrEL generally reduced aggregation (as indicated by absorption and fluorescence) and increased activity up to tenfold (depending on bacteriochlorin), although it decreased cellular uptake. The order of PDT activity against HeLa human cancer cells after 24 h incubation and illumination with 10 J cm(-2) of near-infrared (NIR) light is (NC)(2)BC-Pd (LD(50)=25 nM) > (NC)(2)BC > (NC)(2)BC-Zn ≈ BC. Subcellular localization was determined to be in the endoplasmic reticulum, mitochondria and lysosomes, depending on the bacteriochlorin. (NC)(2)BC-Pd showed PDT-mediated damage to mitochondria and lysosomes, and the greatest production of hydroxyl radicals as determined using a hydroxyphenylfluorescein probe. The incorporation of cyano substituents provides an excellent motif for the enhancement of the photoactivity and photostability of bacteriochlorins as PDT photosensitizers.

Topics: Animals; Coordination Complexes; Glycerol; HeLa Cells; Humans; Neoplasms; Palladium; Pharmaceutical Vehicles; Photochemotherapy; Photosensitizing Agents; Porphyrins; Zinc

New halogenated and sulfonated bacteriochlorins and their analogous porphyrins are employed as photosensitizers of singlet oxygen and the superoxide ion. The mechanisms of energy and electron transfer are clarified and the rates are measured. The intermediacy of a charge-transfer (CT) complex is proved for bacteriochlorins, but excluded for porphyrins. The energies of the intermediates and the rates of their interconversions are measured, and are used to obtain the efficiencies of all the processes. The mechanism of formation of the hydroxyl radical in the presence of bacteriochlorins is proposed to involve a photocatalytic step. The usefulness of these photosensitizers in the photodynamic therapy (PDT) of cancer is assessed, and the following recommendations are given for the design of more effective PDT protocols employing such photosensitizers: 1) light doses should be given over a more extended period of time when the photosensitizers form CT complexes with molecular oxygen, and 2) Fe(2+) may improve the efficiency of such photosensitizers if co-located in the same cell organelle assisting with an in vivo Fenton reaction.

Topics: Neoplasms; Photochemotherapy; Porphyrins; Singlet Oxygen; Superoxides

Chlorin and bacteriochlorin derivatives of 5,10,15,20-tetrakis(2-chloro-5-sulfophenyl)porphyrin have intense absorptions in the phototherapeutic window, high water solubility, high photostability, low fluorescence quantum yield, long triplet lifetimes, and high singlet oxygen quantum yields. Biological studies revealed their negligible dark cytotoxicity, yet significant photodynamic effect against A549 (human lung adenocarcinoma), MCF7 (human breast carcinoma) and SK-MEL-188 (human melanoma) cell lines upon red light irradiation (cutoff λ<600 nm) at low light doses. Time-dependent cellular accumulation of the chlorinated sulfonated chlorin reached a plateau at 2 h, as previously observed for the related porphyrin. However, the optimal incubation time for the bacteriochlorin derivative was significantly longer (12 h). The spectroscopic, photophysical, and biological properties of the compounds are discussed in relevance to their PDT activity, leading to the conclusion that the bacteriochlorin derivative is a promising candidate for future in vivo experiments.

Topics: Cell Line, Tumor; Halogenation; Humans; Neoplasms; Photochemotherapy; Photosensitizing Agents; Porphyrins; Spectrometry, Fluorescence; Water

Conjugates of bacteriochlorin p and chlorin e(6) with cobalt bis(dicarbollide) anion [3,3'-Co(1,2-C(2)B(9)H(11))(2)](-) were synthesized using different synthetic approaches. The boronated bacteriochlorin p was prepared by reaction of bacteriochlorin N-amino cycloimide with, bis(dicarbollide)-based carboxylic acid. The boronated chlorin e(6) conjugates were obtained by both "click reaction" of containing alkyne group chlorine with azide derivative of cobaltacarborane and reaction of chorin-based amines with cyclic oxonium derivative of cobalt bis(dicarbollide).

Topics: Boron Compounds; Boron Neutron Capture Therapy; Humans; Molecular Structure; Neoplasms; Photochemotherapy; Porphyrins; Radiation-Sensitizing Agents