boron and Colonic-Neoplasms

The conjugation of maleimide-functionalized closo-dodecaborate (MID) to transferrin (TF), which has no free SH cysteine residue, proceeded at room temperature for 12 h in PBS buffer (pH = 7.4). MID-TF conjugates were accumulated into the cells in the time- and concentration-dependent manners through the TF receptor mediated mechanism. In vivo biodistribution study of MID-TF conjugates in colon 26-bearing mice revealed the time-dependent selective accumulation of MID-TF conjugates into tumor very similar to that of MID-BSA. The tumor boron concentration of MID-BSA was higher than that of MID-TF conjugates (62 ppm vs. 20 ppm at a dose of 30 mg [B]/kg) 12 h after administration, suggesting that the EPR effect is not remarkably observed in the case of MID-TF conjugates because TF has smaller molecular weight than BSA (48 kDa vs. 68 kDa).

Topics: Animals; Boron; Boron Neutron Capture Therapy; Carrier Proteins; Colonic Neoplasms; Drug Delivery Systems; HeLa Cells; Heterografts; Humans; Maleimides; Mice; Receptors, Transferrin; Tissue Distribution; Transferrin

Boron neutron capture therapy (BNCT) is a unique anticancer technology that has demonstrated its efficacy in numerous phase I/II clinical trials with boronophenylalanine (BPA) and sodium borocaptate (BSH) used as

Topics: Animals; Boron; Boron Neutron Capture Therapy; Brain Neoplasms; Cell Line, Tumor; Colonic Neoplasms; Disease Models, Animal; Intracellular Space; Mannose; Melanoma, Experimental; Mice; Optical Imaging; Rats; Tissue Distribution; Toxicity Tests

Polymers containing pyrrolopyrrole aza-BODIPY (PPAB) and thiophene-bridged BODIPY dimers (TBD) having poly(ethylene glycol) (PEG) or PEGylated hyaluronic acid (HA) were prepared by facile conjugation approaches. Self-assemblies consisting of TBD-conjugated polymers more efficiently generated photoacoustic (PA) signals than PPAB-PEG conjugate upon irradiation with near-infrared pulsed laser light. Among dye-conjugated polymers examined, TBD-HA-PEG conjugates efficiently generated photoacoustic signals, 1.49-1.83 times stronger than that of commercially available indocyanine green (ICG). We found that the following two factors are essential to enhance PA signals from self-assemblies: (1) the formation of strongly interacting TBD aggregates and (2) enhancement of the elastic modulus of self-assemblies by conjugating TBDs with HA. TBD-conjugated HA derivatives circulated in blood vessels for a longer time (15.6 ± 4.9% injected dose (ID) in blood 24 h after injection) and more specifically accumulated in tumor tissues (17.8 ± 3.5% ID/g in tumor 24 h after injection) than ICG-conjugated HA derivatives, visualizing a tumor site more clearly. The cell uptake experiment of dye-HA conjugates indicates that ICG-conjugated polymers internalized into cells or merged with cell walls to emit strong fluorescence, while TBD-conjugated polymers were not internalized into cells. Because the disassembly of the TBD-conjugated HA derivatives is suppressed, aggregated TBDs emit weak fluorescence but efficiently generate strong PA signals in tumor tissues.

Topics: Animals; Boron; Colonic Neoplasms; Coloring Agents; Hyaluronic Acid; Indocyanine Green; Mice; Mice, Inbred BALB C; Mice, Nude; Optical Imaging; Photoacoustic Techniques; Polymers; Spectroscopy, Near-Infrared; Tumor Cells, Cultured

A method for the synthesis of cholesterol-metallacarborane conjugates bearing cobalt, iron and chromium was developed. Effective incorporation of the cholesterol conjugate bearing cobalt into liposome membrane was revealed. Using the metallacarborane-encrusted liposomes as boron delivery system in vivo biodistribution experiments in tumor-bearing mice, high accumulation and selective delivery of boron into tumor tissues was observed. The results demonstrate that the cholesterol-metallacarborane conjugates can be considered as a potential candidate for boron delivery vehicle in BNCT.

Topics: Animals; Boron; Boron Neutron Capture Therapy; Cell Line, Tumor; Cholesterol; Chromium; Cobalt; Colonic Neoplasms; Drug Carriers; Female; Iron; Liposomes; Mice; Tissue Distribution

Boron neutron capture therapy (BNCT) is a binary radiotherapy based on thermal-neutron irradiation of cells enriched with (10)B, which produces α particles and (7)Li ions of short range and high biological effectiveness. The selective uptake of boron by tumor cells is a crucial issue for BNCT, and studies of boron uptake and washout associated with cell survival studies can be of great help in developing clinical applications. In this work, boron uptake and washout were characterized both in vitro for the DHDK12TRb (DHD) rat colon carcinoma cell line and in vivo using rats bearing liver metastases from DHD cells. Despite a remarkable uptake, a large boron release was observed after removal of the boron-enriched medium from in vitro cell cultures. However, analysis of boron washout after rat liver perfusion in vivo did not show a significant boron release, suggesting that organ perfusion does not limit the therapeutic effectiveness of the treatment. The survival of boron-loaded cells exposed to thermal neutrons was also assessed; the results indicated that the removal of extracellular boron does not limit treatment effectiveness if adequate amounts of boron are delivered and if the cells are kept at low temperature. Cell survival was also investigated theoretically using a mechanistic model/Monte Carlo code originally developed for radiation-induced chromosome aberrations and extended here to cell death; good agreement between simulation outcomes and experimental data was obtained.

Topics: Animals; Apoptosis; Boron; Boron Neutron Capture Therapy; Cell Line, Tumor; Colonic Neoplasms; Isotopes; Male; Metabolic Clearance Rate; Radiopharmaceuticals; Rats; Tissue Distribution; Treatment Outcome

Potential boron neutron capture therapy (BNCT) agents have been designed on the basis of the evidence about translocator protein (TSPO) overexpression on the outer mitochondrial membrane of tumor cells. The structure of the first TSPO ligand bearing a carborane cage (compound 2d) has been modified in order to find a suitable candidate for in vivo studies. The designed compounds were synthesized and evaluated for their potential interaction with TSPO and tumor cells. In vitro biological evaluation showed in the case of fluoromethyl derivative 4b a nanomolar TSPO affinity very similar to that of 2d, a significantly lower cytotoxicity, and a slightly superior performance as boron carrier toward breast cancer cells. Moreover, compound 4b could be used as a ¹⁹F magnetic resonance imaging (MRI) agent as well as labeled with ¹¹C or ¹⁸F to obtain positron emission tomography (PET) radiotracers in order to apply the "see and treat" strategy in BNCT.

Topics: Adenocarcinoma; Animals; Binding Sites; Boranes; Boron; Boron Neutron Capture Therapy; Brain; Breast Neoplasms; Carrier Proteins; Cell Line, Tumor; Colonic Neoplasms; Crystallography, X-Ray; Female; Fluorine Radioisotopes; Gene Expression; Magnetic Resonance Imaging; Male; Mitochondria; Models, Molecular; Positron-Emission Tomography; Protein Binding; Quinolines; Rats; Receptors, GABA-A; Structure-Activity Relationship

A series of boronated cationic copolymers, composed of different ratios of acrylamide, N-acryloyl-3-aminophenylboronic acid and N-acryloyl-diaminoethane (the cationic moiety), were prepared with the intention of localizing boron neutron capture therapy (BNCT) in experimentally induced polyps on the luminal side of the gut of the rat. The goals of this study were to: (a) test the effect of cationization of the boronated copolymers on their uptake by polyps and normal adjacent epithelium; (b) compare the whole rat body distribution of aminophenylboronic acid (APB) and polymeric APB after local application; (c) measure the effect of micro-environmental parameters such as pH, the presence of mucin and cations on the interaction between the APB-copolymers and the epithelium of the rat intestines. Direct analysis of tissue boron levels showed that polymeric APB-uptake was higher in the colonic polyps than in the surrounding normal tissues. Free APB, however, was found in similar quantities in both. When tested in the normal jejunum and colon of the rat, polymeric APB uptake was directly proportional to the molar content of the cationic monomer in the copolymers. The presence of magnesium ions, free boron cationic monomer and mucin interfered with this uptake in a concentration-dependent manner. The uptake was pH-independent at pH 5, 7 and 10. APB accumulation in the colon polyps was inversely proportional to the cationic monomer content in the copolymers, suggesting an increased amount of mucus around the polyps, which probably impeded the electrostatic attachment of the polymer to the malignant tissue. The use polymeric APB for targeting BNCT in perioperative treatment of colorectal carcinoma is suggested, especially in the cases of microscopic residual disease after curative resection.

Topics: 1,2-Dimethylhydrazine; Acrylamide; Animals; Boron; Boron Neutron Capture Therapy; Boronic Acids; Carcinogens; Cations; Colon; Colonic Neoplasms; Drug Carriers; Intestinal Mucosa; Jejunum; Mucins; Polymers; Rats; Rats, Inbred Strains; Tissue Adhesives

For the study on boron neutron capture therapy, the whole-body sections of tumor-bearing mice infused with 10B attached to CR-39 plastic track detectors were exposed to thermal and cold neutron beams. Neutron capture autoradiographic images obtained by the cold neutron irradiation were extremely superior in quality to those of the thermal neutron beams. From the autoradiographic images, the 10B reaction dose of the neutron-induced particles was estimated using the differential LET distribution.

Topics: Animals; Autoradiography; Body Burden; Boron; Boron Neutron Capture Therapy; Colonic Neoplasms; Isotopes; Men; Mice; Neutrons; Organ Specificity; Radiometry; Radionuclide Imaging; Radiopharmaceuticals; Radiotherapy Dosage; Tissue Distribution; Whole-Body Counting

The cytotoxic effect of boron neutron capture therapy (BNCT) is due to a nuclear reaction between 10B and thermal neutrons. It is necessary to accumulate the 10B atoms to the tumor cells selectively for effective BNCT. In order to achieve an accurate measurement of 10B concentrations in the biological samples, we employed a technique of neutron capture autoradiography (NCAR) of the sliced whole-body samples of tumor bearing mice using CR-39 plastic track detectors. The CR-39 detectors attached with samples were exposed to thermal neutrons in the thermal column of the TRIGA II reactor at the Institute for Atomic Energy, Rikkyo University and thermal neutron facility of Paul Scherer Institute(PSI). We obtained NCAR images for mice injected intravenously by 10B-PEG liposome, 10B-transferrin-PEG liposome, or 10B-bare liposome. The 10B concentrations in the tumor tissue of mice were estimated by means of alpha-track density measurements. In this study, we can increase the accumulation of 10B atoms in the tumor tissues by binding polyethylene-glycol chains to the surface of liposome, which increase the retention in the blood flow and escape the phagocytosis by reticulo-endothelial systems. Therefore, we will be able to apply NCAR technique for selection of effective 10B carrier in BNCT for cancer.

Topics: Animals; Autoradiography; Boron; Boron Neutron Capture Therapy; Colonic Neoplasms; Drug Delivery Systems; Isotopes; Liposomes; Mice; Mice, Inbred BALB C; Mice, Nude; Neutrons; Polyethylene Glycols; Radionuclide Imaging; Radiopharmaceuticals; Tissue Distribution

Sulfhydryl boron hydride (BSH) (10B enriched) is presently used for boron neutron capture therapy of malignant gliomas. BSH must be close to the target cells to be effective in the inactivation of cell proliferation because of the short range of the reaction products (5-9 microns). Clinical experience indicates that BSH is taken up in gliomas but it is not known to which structures it binds at the cellular level. In vitro tests on monolayer cultured cells have indicated that BSH does not bind, or only shows very weak binding, to single isolated cells. It is possible that BSH accumulates in tumor regions due to the special conditions in poorly vascularized tumor tissue, such as low pO2, low extracellular pH, metabolic gradients, and degenerative changes. To test this we incubated three types of multicellular tumor spheroids with BSH for different times and analyzed both penetration and binding. The spatial distribution of 10B in sections of the spheroids was analyzed by neutron capture autoradiography. We found extensive accumulation of 10B in the central regions of both glioma and colon carcinoma spheroids. The accumulation closely followed the pattern of the degenerative changes which were characterized by massive necrosis in the central regions of the colon carcinoma spheroids and by a continuously increasing frequency of pyknotic nuclei as a function of depth in the glioma spheroids. The accumulation of 10B in the prostatic carcinoma spheroids was much lower. The penetration assay, based on freeze-drying and vapor fixation, showed that BSH penetrated easily since 10B equilibrated within 5-15 min in the studied spheroids. Thus, the low accumulation in the prostatic carcinoma spheroids was not due to penetration difficulties. The results of the present study on cellular spheroids and the results from previous studies on transplanted tumors support the observation that BSH penetrates easily into the degenerative tumor areas and that 10B, for some tumor types, might accumulate in these regions as a result of the BSH administration.

Topics: Autoradiography; Borohydrides; Boron; Brain Neoplasms; Carcinoma; Colonic Neoplasms; Glioma; Humans; Isotopes; Male; Prostatic Neoplasms; Sulfhydryl Compounds; Tumor Cells, Cultured

The theoretical basis for boron neutron capture therapy (BNCT) derives from the reaction that occurs when a stable isotope, boron-10, is irradiated with thermal neutrons to produce an unstable intermediate, boron-11, which then undergoes instantaneous nuclear fission to yield lithium-7 and alpha particles.

Topics: Antibodies, Monoclonal; Boron; Colonic Neoplasms; Humans; Neutrons; Radioisotopes; Rectal Neoplasms