A new water-soluble conjugate, consisting of a chlorin-e 6 photosensitizer part, a 4-arylaminoquinazoline moiety with affinity to epidermal growth factor receptors, and a hydrophilic β-D-maltose fragment, was synthesized starting from methylpheophorbide-a in seven steps. The prepared conjugate exhibited low levels of dark cytotoxicity and pronounced photoinduced cytotoxicity at submicromolar concentrations in vitro, with an IC 50 (dark)/IC 50 (light) ratio of ∼368 and a singlet oxygen quantum yield of about 20%. In tumor-bearing Balb/c nude mice, conjugate 1 preferentially accumulates in the tumor tissue. Irradiation of the nude mice bearing A431 xenograft tumors after intravenous administration of the prepared conjugate with a relatively low light dose (50 J/cm 2 ) produced an excellent therapeutic effect with profound tumor regression and low systemic toxicity.
Tumor oxygenation and hemoglobin content are the key indicators of the tumor status which can be efficiently employed for prognosis of tumor development and choice of treatment strategy. We report on monitoring of these parameters in SKBR-3 (human breast adenocarcinoma) tumors established as subcutaneous tumor xenografts in athymic nude mice by diffuse optical spectroscopy (DOS). A simple continuous wave fiber probe DOS system is employed. Optical properties extraction approach is based on diffusion approximation. Statistically significant difference between measured values of normal tissue and tumor are demonstrated. Hemoglobin content in tumor increases from 7.0 ± 4.2 μM to 30.1 ± 16.1 μM with tumor growth from 150 ± 80 mm 3 to 1300 ± 650 mm 3 which is determined by gradual increase of deoxyhemoglobin content while measured oxyhemoglobin content does not demonstrate any statistically significant variations. Oxygenation in tumor falls quickly from 52.8 ± 24.7% to 20.2 ± 4.8% preceding acceleration of tumor growth. Statistical analysis indicated dependence of oxy-, deoxy-and total hemoglobin on tumor volume ( p < 0.01). DOS measurements of oxygen saturation are in agreement with independent measurements of oxygen partial pressure by polarography (Pearson's correlation coefficient equals 0.8).
Modern radiation therapy of malignant tumors requires careful selection of conditions that can improve the effectiveness of the treatment. The study of the dynamics and mechanisms of tumor reoxygenation after radiation therapy makes it possible to select the regimens for optimizing the ongoing treatment. Diffuse optical spectroscopy (DOS) is among the methods used for non-invasive assessment of tissue oxygenation. In this work DOS was used for in vivo registration of changes in oxygenation level of an experimental rat tumor after single-dose irradiation at a dose of 10 Gy and investigation of their possible mechanisms. It was demonstrated that in 24 h after treatment, tumor oxygenation increases, which is mainly due to an increase in the oxygen supply to the tissues. DOS is demonstrated to be efficient for study of changes in blood flow parameters when monitoring tumor response to therapy.
The aim of the investigation was to study the biodistribution of amino-amide chlorin e 6 derivative conjugate with cobalt bis-dicarbollide as a potential boron transporter for the tasks of boron neutron-capture therapy.Materials and Methods. The experiments were carried out on Balb/c mice with induced murine colon carcinoma CT-26. Amino-amide chlorin e 6 derivative conjugate with cobalt bis-dicarbollide was administered intravenously, the dose being 5 and 10 mg/kg body mass. The sampling for microscopic study of the drug uptake in ex vivo organs and tissues was performed 3 h after the administration.Results. Characteristic nanoconjugate fluorescent peak was found in most organs under study, significant selectivity of the compound being noticed. A high uptake level was recorded in the liver, spleen and lung tissue. At the dose of 5 mg/kg, the drug content in a tumor was not different from that in muscular tissue and skin; maximum uptake was found in the liver. If the dose was increased up to 10 mg/kg, the nanoconjugate content in a tumor appeared to be comparable with that in the liver, the tumor/muscle ratio of fluorescent signals was ~3.Conclusion. The study showed the prospects for using photosensitizer conjugate (chlorin е 6 ) with boron particles as a means to deliver boron into a tumor. The level of the preparation uptake in tumor tissue depends on a dose.
The necessary precondition for efficient boron neutron capture therapy (BNCT) is control over the content of isotope 10B in the tumor and normal tissues. In the case of boron-containing porphyrins, the fluorescent part of molecule can be used for quantitative assessment of the boron content. Study Objective: We performed a study of the biodistribution of the chlorin e6-Cobalt bis(dicarbollide) conjugate in carcinoma-bearing Balb/c mice using ex vivo fluorescence imaging, and developed a mathematical model describing boron accumulation and release based on the obtained experimental data. Materials and Methods: The study was performed on Balb/c tumor-bearing mice (CT-26 tumor model). A solution of the chlorin e6-Cobalt bis(dicarbollide) conjugate (CCDC) was injected into the blood at a dose of 10 mg/kg of the animal’s weight. Analysis of the fluorescence signal intensity was performed at several time points by spectrofluorimetry in blood and by laser scanning microscopy in muscle, liver, and tumor tissues. The boron content in the same samples was determined by mass spectroscopy with inductively coupled plasma. Results: Analysis of a linear approximation between the fluorescence intensity and boron content in the tissues demonstrated a satisfactory value of approximation reliability with a Spearman’s rank correlation coefficient of r = 0.938, p < 0.01. The dynamics of the boron concentration change in various organs, calculated on the basis of the fluorescence intensity, enabled the development of a model describing the accumulation of the studied compound and its distribution in tissues. The obtained results reveal a high level of correspondence between the model and experimental data.
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