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Objective: The main objective was to evaluate the anterior flexion force (AFF) and the lateral abduction force (LAF) of patients who underwent reverse shoulder arthroplasty (RSA) and to compare the measured force with that in a similar-age control group. The secondary objective was to identify prognostic factors for muscle strength recovery., Methods: Forty-two shoulders that underwent primary RSA between September 2009 and April 2020 met the inclusion criteria and were called the arthroplasty group (AG). The control group (CG) consisted of 36 patients. The mean AFF and the mean LAF were evaluated with a digital isokinetic traction dynamometer., Results: The average AFF found in the AG was 15 N, while in the CG, the average AFF was 21 N ( P  < .001). The average LAF in the AG was 14 N (standard deviation [SD] 8 N), while in the CG the average LAF was of 19 N (SD 6 N) ( P  = .002). All prognostic factors studied in the AG showed no statistical significance: dominance (AFF 0.697/LAF 0.883), previous rotator cuff repair surgery (AFF 0.786/LAF 0.821), Hamada radiological classification (AFF 0.343/LAF 0.857), magnetic resonance imaging (MRI) pre-operative evaluation of the quality of the teres minor (AFF 0.131/LAF 0.229), suture of the subscapularis at the end of the arthroplasty procedure (AFF 0.961/LAF 0.325) and postoperative complications (AFF 0.600/LAF 0.960)., Conclusion: The mean AFF was 15 N, and the mean LAF was 14 N. The comparison of AFF and LAF with a CG showed a 25% reduction in muscle strength. It was not possible to demonstrate prognostic factors for muscle strength recovery after RSA., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

We report the synthesis and investigation of an unprecedented 8-heteroaryl-fused BODIPY 4. This compound exhibits enhanced π-π stacking in the solid state, unusually large blue-shifts in the absorbance and emission spectra, and higher fluorescence quantum yield than its unfused precursor; DFT calculations suggest a small energy gap for 4 and strong electronic communication between the 8-OPh and the BODIPY core.

A series of push-pull BODIPYs bearing multiple electron-donating and electron-acceptor groups were synthesized regioselectively from 2,3,5,6,8-pentachloro-BODIPY, and characterized by NMR spectroscopy, HRMS, and X-ray crystallography. The influence of the push-pull substituents on the spectroscopic and electrochemical properties of BODIPYs was investigated. Bathochromic shifts were observed for both absorbance (up to 37 nm) and emission (up to 60 nm) in different solvents upon introduction of the push-pull moieties. DFT calculations, consistent with the spectroscopic and cyclic voltammetry studies, show decreased HOMO-LUMO energy gaps upon the installation of the push-pull moieties. BODIPY 7 bearing thienyl groups on the 2 and 6 positions showed the largest λ max for both absorption (635-653 nm) and emission (706-707 nm), but also the lowest fluorescence quantum yields. All BODIPYs were nontoxic in the dark (IC 50 > 200 μM) and showed low phototoxicity (IC 50 > 100 μM, 1.5 J/cm 2 ) toward human HEp2 cells. Despite the relatively low fluorescence quantum yields, the push-pull BODIPYS were effective for cell imaging, readily accumulating within cells and localizing mainly in the ER and Golgi. Our structure-property studies can guide future design of functionalized BODIPYs for various applications, including bioimaging and in dye-sensitized solar cells.

Three perhalogenated BODIPYs (1b-3b), bearing chloro and bromo groups at all carbon positions, were synthesized and characterized. The reactivity of BODIPY 3b was investigated under Stille cross-coupling reactions, and single crystal X-ray analysis was used to confirm the regioselectivity of the reactions. Further substitution at the boron atom produced nona-functionalized BODIPYs 7a,b, which show 676 and 739 nm emissions with 91 and 100 nm Stokes shifts, respectively.

A series of seven BODIPYs functionalized with ortho-carborane groups at the 8(meso) or 3/5(α) position were synthesized and characterized by NMR, HRMS, HPLC, and in the cases of 2b and 5b, by X-ray analysis. The BODIPYs exhibited low dark toxicity and phototoxicity toward human glioma T98G cells, and their cellular uptake varied significantly, with 5b accumulating the most and 7 the least. All BODIPYs localized mainly within the cell ER. The BODIPYs showed higher permeabilities than lucifer yellow across human hCMEC/D3 brain endothelial cell monolayers as the BBB model. Among this series, 1b showed the highest BBB permeability (Pe = 16.4 × 10(-5) cm/s), probably as a result of its lower MW (366 Da) and favorable hydrophobicity (log P = 1.5). The combination of low cytotoxicity, amphiphilicity, high boron content, high cellular uptake, and moderate BBB permeability renders these compounds promising boron delivery agents for the BNCT of brain tumors.

Chlorin e6 is a tricarboxylic acid degradation product of chlorophyll a. Four chlorin e6 bis(amino acid) conjugates were regioselectively synthesized bearing two aspartate conjugates in the 13(1),17(3)- and 15(2),17(3)-positions, or at the 13(1),15(2)via an ethylene diamine linker. One additional conjugate bearing two different amino acids, lysine at 13(1)via an ethylene diamine linker and an aspartate at 15(2)via a β-alanine linker was also synthesized. The cytotoxicity and uptake of four di(amino acid) chlorin e6 conjugates were investigated in human HEp2 cells, and compared with chlorin e6. The most cytotoxic and most taken up conjugates were the zwitterionic 13(1),15(2)-disubstituted conjugates 28 and 33; these also localized in multiple organelles. In contrast, the anionic 13(1),17(3)- and 15(2),17(3)-di-aspartyl chlorin e6 conjugates 12 and 13 showed low dark cytoxicity and lower phototoxicity compared with chlorin e6.

A facile approach using click chemistry is demonstrated for immobilization of metalloporphyrins onto the surface of silica-coated iron oxide particles. Oleic-acid stabilized iron oxide nanocrystals were prepared by thermal decomposition of iron(III) acetylacetonate. Their crystallinity, morphology, and superparamagnetism were determined using X-ray diffraction, transmission electron microscopy, and a superconducting quantum interference device. Monodisperse core-shell particles were produced in the silica-coating of iron oxide via microemulsion synthesis. Surface modification of these particles was performed in two steps, which included the reaction of silica-coated iron oxide particles with 3-bromopropyltrichlorosilane, followed by azido-functionalization with sodium azide. Monoalkylated porphyrins were prepared using the Williamson ether synthesis of commercially available tetra(4-hydroxyphenyl) porphyrin with propargyl bromide in the presence of a base. (1)H NMR and matrix-assisted laser desorption ionization confirmed the identity of the compounds. The prepared monoalkyne porphyrins were zinc-metalated prior to their introduction to azide-functionalized, silica-coated iron oxide particles in the click reaction. X-ray photoelectron spectroscopy, thermogravimetric analysis, and Fourier transform infrared spectroscopy were used to characterize the surface chemistry after each step in the reaction. In addition, particle size was determined using dynamic light scattering and microscopy. The presented methodology is versatile and can be extended to other photoreactive systems, such as phthalocyanines and boron-dipyrromethane, which may lead to new materials for optical, photonic, and biological applications.

The synthesis and in vitro evaluation of four mesoporphyrin IX-peptide conjugates designed to target EGFR, over-expressed in colorectal and other cancers, are reported. Two peptides with known affinity for EGFR, LARLLT ( 1 ) and GYHWYGYTPQNVI ( 2 ), were conjugated to mesoporphyrin IX (MPIX, 3 ) via one or both the propionic side chains, directly ( 4 , 5 ) or with a triethylene glycol spacer ( 7 , 8 ). The conjugates were characterized using NMR, MS, CD, SPR, UV-vis and fluorescence spectroscopies. Energy minimization and molecular dynamics suggest different conformations for the conjugates. SPR studies show that conjugate 4 , bearing two LARLLT with no PEG spacers, has the greatest affinity for binding to EGFR, followed by conjugate 7 with two PEG and two LARLLT sequences. Molecular modeling and docking studies suggest that both conjugates 4 and 7 can bind to monomer and dimer EGFR in open and closed conformations. The cytotoxicity and cellular targeting ability of the conjugates were investigated in human HEp2 cells over-expressing EGFR. All conjugates showed low dark- and photo-toxicities. The cellular uptake was highest for conjugates 4 and 8 and lowest for 7 bearing two LARLLT linked via PEG groups, likely due to decreased hydrophobicity. Among the conjugates investigated 4 is the most efficient EGFR-targeting agent, and therefore the most promising for the detection of cancers that over-express EGFR.

A series of β,β'-bicyclo-3,5-diaryl-BODIPYs were synthesized from the corresponding β,β'-bicyclo-3,5-diiodo-BODIPYs ( 1a,b ) via Pd(0)-mediated Suzuki cross-coupling reactions in 82-92% yields. Subsequent aromatization with DDQ afforded the corresponding β,β'-dibenzo-aryl-BODIPYs, which showed red-shifted absorptions and emissions in the near-IR range. The dibenzo-appended BODIPYs showed characteristic 1 H-, 13 C-, 11 B- and 19 F-NMR shifts, and nearly planar conformations by X-ray crystallography.

A series of four BODIPYs containing one or two ortho - or para -carborane clusters were synthesized using palladium(0)-catalyzed Suzuki cross-coupling or nucleophilic substitution reactions, at the 2,6- or the 8-positions of halogenated boron dipyrromethenes (BODIPYs). The spectroscopic, structural (including one X-ray) and in vitro BBB permeability of the BODIPYs using hCMEC/D3 brain endothelial cells were investigated.

An effective, stepwise methodology for polychlorination of BODIPY using trichloroisocyanuric acid (TCCA) in acetic acid was developed. In this way, selectively substituted di-, tri-, tetra-, and pentachloro-BODIPYs 2-5 were prepared. The pentachloro-BODIPY is shown to undergo regioselective Pd(0)-catalyzed Stille and Suzuki coupling reactions, first at the 8-position followed by the 3,5- and then the 2,6-positions; nucleophilic substitution reactions occur first at the 8- followed by the 3,5-positions, while the 2,6 are unreactive.

The asymmetric BODIPY 1 a (BODIPY=4,4-difluoro-4-bora-3a,4a-diaza-s-indacene), containing two chloro substituents at the 3,8-positions and a reactive 5-methyl group, was synthesized from the asymmetric dipyrroketone 3, which was readily obtained from available pyrrole 2 a. The reactivity of 3,8-dichloro-6-ethyl-1,2,5,7-tetramethyl-BODIPY 1 a was investigated by using four types of reactions. This versatile BODIPY undergoes regioselective Pd(0) -catalyzed Stille coupling reactions and/or regioselective nucleophilic addition/elimination reactions, first at the 8-chloro and then at the 3-chloro group, using a variety of organostannanes and N-, O-, and S-centered nucleophiles. On the other hand, the more reactive 5-methyl group undergoes regioselective Knoevenagel condensation with an aryl aldehyde to produce a monostyryl-BODIPY, and oxidation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) gives the corresponding 5-formyl-BODIPY. Investigation of the reactivity of asymmetric BODIPY 1 a led to the preparation of a variety of functionalized BODIPYs with λmax of absorption and emission in the ranges 487-587 and 521-617 nm, respectively. The longest absorbing/emitting compound was the monostyryl-BODIPY 16, and the largest Stokes shift (49 nm) and fluorescence quantum yield (0.94) were measured for 5-thienyl-8-phenoxy-BODIPY 15. The structural properties (including 16 X-ray structures) of the new series of BODIPYs were investigated., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A series of boron-disubstituted O-BODIPYs were synthesized, and their structures and spectroscopic properties were investigated using both computational and experimental methods. Three methods were investigated for the preparation of 4,4-dimethoxy-BODIPYs bearing electron-donating or electron-withdrawing 8-aryl groups: method A employs refluxing in the presence of NaOMe/MeOH, method B uses AlCl3 in refluxing dichloromethane followed by addition of methanol as nucleophile, and method C involves activation of the BODIPYs using TMSOTf in refluxing toluene followed by addition of methanol. The yields obtained depend on the method used and the structure of the starting BODIPYs; for example, 1a and 3a were most efficiently prepared using method C (98 and 70%, respectively), while 2a was best prepared by method A (50%). Methods B and C were employed for the synthesis of seven new 4,4-dialkoxy-BODIPYs. 4,4-Dipropargyloxy-BODIPY 1e reacted under Cu(I)-catalyzed alkyne-azide Huisgen cycloaddition conditions to produce 4,4-bis(1,2,3-triazole)-BODIPY 4 in 78% yield. The substitution of the fluorides for alkoxy groups on the BODIPYs had no significant effect on the absorption and emission wavelengths but altered their fluorescence quantum yields. Among this series of dialkoxy-BODIPYs, the 4,4-dipropargyloxy 1e and its corresponding bis(1,2,3-triazole) 4 show the largest quantum yields in toluene and THF, respectively.

A series of five mono-styryl and their corresponding symmetric di-styryl-2,6-diiodo-BODIPYs containing indolyl, pyrrolyl, thienyl or tri(ethylene glycol)phenyl groups were synthesized using Knoevenagel condensations. The yields for the condensation reactions were improved up to 40% using microwave irradiation (90°C for 1h at 400W) due to lower decomposition of BODIPYs upon prolonged heating. The spectroscopic, structural (including the X-ray of a di-styryl-2,6-diiodo-BODIPY) and in vitro properties of the BODIPYs were investigated. The extension of π-conjugation through the 3,5-dimethyls of the known phototoxic 2,6-diiodo-BODIPY 1 produced bathochromic shifts in the absorption and emission spectra, in the order of 63-125nm for the mono-styryl- and 128-220nm for the di-styryl-BODIPYs in DMSO. The largest red-shifts were observed for the indolyl-containing BODIPYs while the largest fluorescence quantum yields were observed for the tri(ethyleneglycol)phenylstyryl-BODIPYs. Among this series, only the mono-styryl-BODIPYs were phototoxic (IC50=2-15μM at 1.5J/cm(2)), and were observed to localize preferentially in the cell ER and mitochondria. On the other hand, the di-styryl-BODIPYs were found to have low or no phototoxicity (IC50>100μM at 1.5J/cm(2)). Among this series of compounds BODIPY 2a shows the most promise for application as photosensitizer in PDT., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Carboranyl-containing chlorins have emerged as promising dual sensitizers for use in both photodynamic therapy (PDT) and boron neutron capture therapy (BNCT), by virtue of their known tumor affinity, low cytotoxicity in dark conditions, and their strong absorptions in the red region of the optical spectrum. Tetrakis(p-carboranylthio-tetrafluorophenyl)chlorin (TPFC) is a new synthetic carboranyl-containing chlorin of high boron content (24% by weight). To evaluate TPFC's applicability as sensitizer for both PDT and BNCT, we performed an in vitro and in vivo study using F98 rat glioma cells and F98 rat glioma-bearing brain tumor models. For the in vivo BNCT study, we used boronophenylalanine (BPA), which is currently used in clinical BNCT studies, via intravenous administration (i.v.) and/or used TPFC via convection-enhanced delivery (CED), a method for local drug infusion directly into the brain. In the in vitro PDT study, the cell surviving fraction following laser irradiation (9 J/cm(2) ) was 0.035 whereas in the in vitro BNCT study, the cell surviving fraction following neutron irradiation (thermal neutron = 1.73 × 10(12) n/cm(2) ) was 0.04. In the in vivo BNCT study, the median survival time following concomitant administration of BPA (i.v.) and TPFC (CED) was 42 days (95% confidence interval; 37-43 days)., (© 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.)

Catalytic hydrogenation of dibenzyl 5-dipyrroketone-2,9-dicarboxylates followed by decarboxylative iodination affords a 2,9-diiododipyrroketone which gives a 2,5,9-trichlorodipyrromethene hydrochloride after nucleophilic addition/elimination, with adventitious chloride to replace the two iodide groups. Treatment with BF3·Et2O gives a 3,5,8-trichloro-BODIPY that readily undergoes regioselective Stille coupling at the 8-position, or homo/mixed couplings at the 3,8- or 3,5- and 8-positions. Stepwise and controlled replacement of the 3,5- and 8-chlorine atoms using Stille reagents results in formation of a completely unsymmetrical trisubstituted BODIPY. Several examples of unsymmetrical BODIPYs were synthesized and characterized using this methodology. Structure features of new BODIPYs are discussed within the context of 14 new X-ray structures, and photophysical parameters of all new BODIPY compounds are reported and discussed.

A series of pegylated cis -A 2 B 2 - or A 3 B-type ZnPcs, substituted on the α-positions with tri(ethylene glycol) and hydroxyl groups, were synthesized from a new bis-phthalonitrile. A clamshell-type bis-phthalocyanine was also obtained as a byproduct. The hydroxyl group of one ZnPc was alkylated with 3-dimethylaminopropyl chloride to afford a pegylated ZnPc functionalized with an amine group. All mononuclear ZnPcs were soluble in polar organic solvents, showed intense Q absorptions in DMF, and had fluorescence quantum yields in the range 0.10-0.23. The clamshell-type bis-phthalocyanine adopts mainly open shell conformations in DMF, and closed clamshell conformations in chloroform. All ZnPcs were highly phototoxic to human carcinoma HEp2 cells, particularly the amino-ZnPc mainly protonated under physiological conditions, which showed the highest phototoxicity (IC 50 = 0.5 μM at 1.5 J/cm 2 ) and dark cytotoxicity (IC 50 = 22 μM), in part due to its high cellular uptake. The ZnPcs localized in multiple organelles, including mitochondria, lysosomes, Golgi and ER.

A series of tri[(p-carboranylmethylthio)tetrafluorophenyl]porphyrin conjugates of linear and branched polyamines, glucose, arginine, tri(ethylene glycol), and Tyr-D-Arg-Phe-β-Ala (YRFA) peptide were synthesized. These conjugates were investigated for their BBB permeability in human hCMEC/D3 brain endothelial cells, and their cytotoxicity and uptake were assessed using human glioma T98G cells. For comparison purposes, a symmetric tetra[(p-carboranylmethylthio)tetrafluorophenyl]porphyrin was also synthesized, and its crystal structure was obtained. All porphyrin conjugates show low dark cytotoxicity (IC50>400 μM) and low phototoxicity (IC50>100 μM at 1.5 J/cm2) toward T98G cells. All conjugates were efficiently taken up by T98G cells, particularly the cationic polyamine and arginine conjugates, and were localized in multiple cellular organelles, including mitochondria and lysosomes. All compounds showed relatively low in vitro BBB permeability compared with that of lucifer yellow because of their higher molecular weight, hydrophobicity, and tendency for aggregation in solution. Within this series, the branched polyamine and YRFA conjugates showed the highest permeability coefficient, whereas the glucose conjugate showed the lowest permeability coefficient.

Symmetric dipyrrylketones 1 a,b were synthesized in two steps from the corresponding α-free pyrroles, by reaction with thiophosgene followed by oxidative hydrolysis under basic conditions. The dipyrrylketones produced the corresponding 5-chloro-dipyrrinium salts or 5-ethoxy-dipyrrins on reaction with phosgene or Meerwein's salt, respectively. Boron complexation of the dipyrrins afforded the corresponding 8-functionalized BODIPYs (borondipyrromethenes) in high yields. The 5-chloro-dipyrrinium salts reacted with methoxide or ethoxide ions to produce monopyrrole esters, presumably via a 5,5-dialkoxy-dipyrromethane intermediate. In contrast, 8-chloro-BODIPYs underwent a variety of nucleophilic substitutions of the chloro group in the presence of alkoxide ions, Grignard reagents, and thiols. In the presence of excess alkoxide or Grignard reagent, at room temperature or above, substitution at the boron center also occurred. The 8-chloro-BODIPY was a particularly useful reagent for the preparation of 8-aryl-, 8-alkyl-, and 8-vinyl-substituted BODIPYs in very high yields, using Pd(0) -catalyzed Stille cross-coupling reactions. The X-ray structures of eleven BODIPYs and two pyrroles are presented, and the spectroscopic properties of the synthesized BODIPYs are discussed., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Novel aza-BODIPYs with significant bathochromic shifts were designed and synthesized by installation of strong electron-withdrawing groups on the para-positions of 1,7-phenyls and electron-donating groups on the para-positions of 3,4-phenyls. These dyes show strong NIR fluorescence emissions up to 756 nm, and absorptions up to 720 nm.

A series of twenty-two BODIPY compounds were synthesized, containing various meso-phenyl and meso-thienyl groups, and their spectroscopic and structural properties were investigated using both experimental and computational methods. Further functionalization of the BODIPY framework via iodination at the 2,6-pyrrolic positions was explored in order to determine the effect of these heavy atoms on the photophysical and cytotoxicity of the meso-aryl-BODIPYs. BODIPYs bearing meso-thienyl substituents showed the largest red-shifted absorptions and emissions and reduced fluorescence quantum yields. The phototoxicity of the BODIPYs in human carcinoma HEp2 cells depends on both the presence of iodines and the nature of the meso-aryl groups. Six of the eleven 2,6-diiodo-BODIPYs investigated showed at least a sevenfold enhancement in phototoxicity (IC50 = 3.5-28 μM at 1.5 J/cm(2)) compared with the non-iodinated BODIPYs, while the others showed no cytotoxicity, while their singlet oxygen quantum yields ranged from 0.02 to 0.76. Among the series investigated, BODIPYs 2a and 4a bearing electron-donating meso-dimethoxyphenyl substituents showed the highest phototoxicity and dark/phototoxicity ratio, and are therefore the most promising for application in PDT., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

5,10,15-Triaryltetrabenzocorroles functionalized with different electron-withdrawing groups on the β,β'-fused rings have been prepared by a cross-coupling Heck procedure between octabrominated copper corrole and a terminal alkene bearing electron-withdrawing moieties. The spectroscopic characterization of these complexes showed red-shifted UV-vis absorption bands characterized by a significant band broadening. The same feature was observed in the case of NMR spectra, where low-resolution groups of signals were observed. This behavior derives from a strong tendency of these macrocycles to aggregate in solution, as has been demonstrated by an (1)H NMR study performed on one of these tetrabenzocorroles. The influence of the substituents on the fused benzene ring on the properties of the tetrabenzocorroles was investigated by electrochemistry and spectroelectrochemistry, and comparisons were made between properties of the newly synthesized compounds and those of the tetrabenzocorroles reported earlier in the literature.

Among the EGFRs, HER2 is a major heterodimer partner and also has important implications in the formation of particular tumors. Interaction of HER2 protein with other EGFR proteins can be modulated by small molecule ligands and, hence, these protein-protein interactions play a key role in biochemical reactions related to control of cell growth. A peptidomimetic (compound 5-1) that binds to HER2 protein extracellular domain and inhibits protein-protein interactions of EGFRs was conjugated with BODIPY (4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene). Conjugation of BODIPY to the peptidomimetic was investigated by different approaches. The conjugate was characterized for its ability to bind to HER2 overexpressing SKBR-3 and BT-474 cells. Furthermore, cellular uptake of conjugate of BODIPY was studied in the presence of membrane tracker and Lyso tracker using confocal microscopy. Our results suggested that fluorescently labeled compound 5-7 binds to the extracellular domain and stays in the membrane for nearly 24 h. After 24 h there is an indication of internalization of the conjugate. Inhibition of protein-protein interaction and downstream signaling effect of compound 5-1 was also studied by proximity ligation assay and Western blot analysis. Results suggested that compound 5-1 inhibit protein-protein interactions of HER2-HER3 and phosphorylation of HER2 in a time-dependent manner., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

5,10,15-Triaryltetrabenzocorrole complexes of aluminum, gallium, germanium, and phosphorus were synthesized by coordination of these metal ions in the preformed triaryltetrabenzocorrole macrocycle, opening a way to the investigation of different metal complexes. The UV-vis spectra of these derivatives exhibit a red shift and broadening of all absorption bands because of the π-extended aromatic system and distortion of the molecular framework. The electrochemical and photophysical behaviors of the free base and the metal complexes of meso-triaryltetrabenzocorrole were investigated and characterized.

Seven polyamine conjugates of a tri(p-carboranylmethylthio)tetrafluorophenylporphyrin were prepared in high yields by sequential substitution of the p-phenyl fluoride of tetrakis(pentafluorophenyl)porphyrin (TPPF), and investigated as boron delivery agents for boron neutron capture therapy (BNCT). The polyamines used were derivatives of the natural-occurring spermine with different lengths of the carbon chains, terminal primary amine groups and, in two of the conjugates, additional aminoethyl moieties. A tri(polyethylene glycol) conjugate was also synthesized for comparison purposes. The polyamine conjugates showed low dark cytotoxicity (IC(50) >400 μM) and low phototoxicity (IC(50) >40 μM at 1.5 J/cm(2)). All polyamine conjugates, with one exception, showed higher uptake into human glioma T98G cells (up to 12-fold) than the PEG conjugate, and localized preferentially in the cell ER, Golgi and the lysosomes. Our results show that spermine derivatives can serve as effective carriers of boronated porphyrins for the BNCT of tumors., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Two zinc(II) phthalocyanines (ZnPcs) were conjugated with a monoclonal antibody (MAb) directed against carcinoembryonic antigen (CEA), using an in situ activated carboxylic acid on the ZnPcs. The bioconjugate with the highest ZnPc/MAb ratio of 3 was investigated in vitro for its ability to target and fluorescently label human colorectal HT-29 cells. The ZnPc-CEA MAb 2 was observed to efficiently target HT-29 cells, about 37 times more than unconjugated ZnPc. Furthermore, in the presence of a 4-fold excess of unlabelled anti-CEA antibody, the fluorescence signal of 2 was reduced by ~90% showing that the targeting is CEA-mediated. These studies further confirm the high specificity of Pc-antibody conjugates for antigens over-expressed on tumor cells and warrant further investigations of these immunoconjugates and their derivatives for imaging of colorectal cancer.

Boron neutron capture therapy (BNCT) is a biochemically targeted radiotherapy based on the nuclear capture and fission reactions that occur when non-radioactive boron-10, which is a constituent of natural elemental boron, is irradiated with low energy thermal neutrons to yield high linear energy transfer alpha particles and recoiling lithium-7 nuclei. Clinical interest in BNCT has focused primarily on the treatment of high grade gliomas, recurrent cancers of the head and neck region and either primary or metastatic melanoma. Neutron sources for BNCT currently have been limited to specially modified nuclear reactors, which are or until the recent Japanese natural disaster, were available in Japan, United States, Finland and several other European countries, Argentina and Taiwan. Accelerators producing epithermal neutron beams also could be used for BNCT and these are being developed in several countries. It is anticipated that the first Japanese accelerator will be available for therapeutic use in 2013. The major hurdle for the design and synthesis of boron delivery agents has been the requirement for selective tumor targeting to achieve boron concentrations in the range of 20 μg/g. This would be sufficient to deliver therapeutic doses of radiation with minimal normal tissue toxicity. Two boron drugs have been used clinically, a dihydroxyboryl derivative of phenylalanine, referred to as boronophenylalanine or "BPA", and sodium borocaptate or "BSH" (Na2B12H11SH). In this report we will provide an overview of other boron delivery agents that currently are under evaluation, neutron sources in use or under development for BNCT, clinical dosimetry, treatment planning, and finally a summary of previous and on-going clinical studies for high grade gliomas and recurrent tumors of the head and neck region. Promising results have been obtained with both groups of patients but these outcomes must be more rigorously evaluated in larger, possibly randomized clinical trials. Finally, we will summarize the critical issues that must be addressed if BNCT is to become a more widely established clinical modality for the treatment of those malignancies for which there currently are no good treatment options.

Four phthalocyanine (Pc)-peptide conjugates designed to target the epidermal growth factor receptor (EGFR) were synthesized and evaluated in vitro using four cell lines: human carcinoma A431 and HEp2, human colorectal HT-29, and kidney Vero (negative control) cells. Two peptide ligands for EGFR were investigated: EGFR-L1 and -L2, bearing 6 and 13 amino acid residues, respectively. The peptides and Pc-conjugates were shown to bind to EGFR using both theoretical (Autodock) and experimental (SPR) investigations. The Pc-EGFR-L1 conjugates 5a and 5b efficiently targeted EGFR and were internalized, in part due to their cationic charge, whereas the uncharged Pc-EGFR-L2 conjugates 4b and 6a poorly targeted EGFR maybe due to their low aqueous solubility. All conjugates were nontoxic (IC(50) > 100 μM) to HT-29 cells, both in the dark and upon light activation (1 J/cm(2)). Intravenous (iv) administration of conjugate 5b into nude mice bearing A431 and HT-29 human tumor xenografts resulted in a near-IR fluorescence signal at ca. 700 nm, 24 h after administration. Our studies show that Pc-EGFR-L1 conjugates are promising near-IR fluorescent contrast agents for CRC and potentially other EGFR overexpressing cancers.

A series of new functionalized mono- and dibenzo-appended BODIPY dyes were synthesized from a common tetrahydroisoindole precursor following two different synthetic routes. Route A involved the assembly of the BODIPY core prior to aromatization, while in Route B the aromatization step was performed first. In general, Route A gave higher yields of the target dibenzo-BODIPYs, due to the ease of aromatization of the BODIPYs compared with the corresponding dipyrromethenes, probably due to their higher stability under the oxidative conditions (2,3-dichloro-5,6-dicyano-1,4-benzoquinone in refluxing toluene). However, due to the slow oxidation of highly electron-deficient BODIPY 3 c bearing a meso-C(6)F(5) group, dibenzo-BODIPY 4 c was obtained, in 35 % overall from dipyrromethane, only by Route B. Computational calculations performed at the 6-31G(d,p) level are in agreement with the experimental results, showing similar relative energies for all reaction intermediates in both routes. In addition, BODIPY 3 c had the highest molecular electrostatic potential (MEPN), confirming its high electron deficiency and consequent resistance toward oxidation. X-ray analyses of eight BODIPYs and several intermediates show that benzannulation further enhances the planarity of these systems. The π-extended BODIPYs show strong red-shifted absorptions and emissions, about 50-60 nm per benzoannulated ring, at 589-658 and 596-680 nm, respectively. In particular, db-BODIPY 4 c bearing a meso-C(6)F(5) group showed the longest λ(max) of absorption and emission, along with the lowest fluorescence quantum yield (0.31 in CH(2)Cl(2)); on the other hand monobenzo-BODIPY 8 showed the highest quantum yield (0.99) of this series. Cellular investigations using human carcinoma HEp2 cells revealed high plasma membrane permeability for all dibenzo-BODIPYs, low dark- and photo-cytotoxicities and intracellular localization in the cell endoplasmic reticulum, in addition to other organelles. Our studies indicate that benzo-appended BODIPYs, in particular the highly stable meso-substituted BODIPYs, are promising fluorophores for bioimaging applications., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The aggregation of meso-tetra(4-sulfonatophenyl)porphyrin (H(2)TPPS(4-)) in phosphate solutions was investigated as a function of pH, concentration, time, ionic strength, and solution preparation (either from dilution of a freshly prepared 2 mM stock or by direct preparation of μM solution concentrations) using a combination of complementary analytical techniques. UV-vis and fluorescence spectroscopy indicated the formation of staggered, side-by-side (J-type) assemblies. Their size and self-associative behavior were determined using analytical ultracentrifugation and small-angle X-ray scattering. Our results indicate that in neutral and basic solutions of H(2)TPPS(4-), porphyrin dimers and trimers are formed at micromolar concentrations and in the absence of NaCl to screen any ionic interactions. At these low concentrations and pH 4, the protonated H(4)TPPS(2-) species self-assembles, leading to the formation of particularly stable aggregates bearing 25 ± 3 macrocycles. At higher concentrations, these structures further organize or reorganize into tubular, rod-like shapes of various lengths, which were imaged by cryogenic and freeze-fracture transmission electron microscopy. Micron-scale fibrillar aggregates were obtained even at micromolar concentrations at pH 4 when prepared from dilution of a 2 mM stock solution, upon addition of NaCl, or both.

Di-cationic Zn(II)-phthalocyanines (ZnPcs) are promising photosensitizers for the photodynamic therapy (PDT) of cancers and for photoinactivation of viruses and bacteria. Pegylation of photosensitizers in general enhances their water-solubility and tumor cell accumulation. A series of pegylated di-cationic ZnPcs were synthesized from conjugation of a low molecular weight PEG group to a pre-formed Pc macrocycle, or by mixed condensation involving a pegylated phthalonitrile. All pegylated ZnPcs were highly soluble in polar organic solvents but were insoluble in water; they have intense Q absorptions centered at 680 nm and fluorescence quantum yields of ca. 0.2 in DMF. The non-pegylated di-cationic ZnPc 6a formed large aggregates, which were visualized by atomic force microscopy. The cytotoxicity, cellular uptake and subcellular distribution of all cationic ZnPcs were investigated in human carcinoma HEp2 cells. The most phototoxic compounds were found to be the α-substituted Pcs. Among these, Pcs 4a and 16a were the most effective (IC(50) ca. 10 μM at 1.5 J/cm(2)), in part due to the presence of a PEG group and the two positive charges in close proximity (separated by an ethylene group) in these macrocycles. The β-substituted ZcPcs 6b and 4b accumulated the most within HEp2 cells but had low photocytoxicity (IC(50) > 100 μM at 1.5 J/cm(2)), possibly as a result of their lower electron density of the ring and more extended conformations compared with the α-substituted Pcs. The results show that the charge distribution about the Pc macrocycle and the intracellular localization of the cationic ZnPcs mainly determine their photodynamic activity.

The syntheses, photophysical properties and in vitro biological behavior of a series of nine Zn((II))-phthalocyanines (ZnPcs) bearing one to eight positively-charged trimethylaminophenoxy groups are reported. All ZnPcs are highly soluble in polar organic solvents, and show fluorescence and singlet oxygen quantum yields in the ranges 0.11-0.21 and 0.16-0.47, respectively. The cytotoxicity of the ZnPcs depends on both the number of charges and their site of substitution (α vs. β) on the Pc isoindole units; the most promising for PDT application are the α-substituted di-cationic ZnPcs 6a and 17a.

The syntheses and spectroscopic properties of a series of pegylated zinc(II)-phthalocyanines (Zn-Pcs) containing one, two or eight tri(ethylene glycol) chains are described. The single molecular structure of a phthalonitrile precursor containing one hydroxyl and one PEG group, and its unique intermolecular hydrogen bonding are presented. The pegylated Pcs are highly soluble in polar organic solvents and have fluorescence quantum yields in the range 0.08-0.28.

A series of amino acid conjugates of chlorin e(6), containing lysine or aspartic acid residues in positions 17(3), 15(2), or 13(1) of the macrocycle were synthesized and investigated as photosensitizers for photodynamic therapy of tumors. All three regioisomers were synthesized in good yields and in five steps or less from pheophytin a (1). In vitro investigations using human carcinoma HEp2 cells show that the 15(2)-lysyl regioisomers accumulate the most within cells, and the most phototoxic are the 13(1) regioisomers. The main determinant of biological efficacy appears to be the conjugation site, probably because of molecular conformation. Molecular modeling investigations reveal that the 17(3)-substituted chlorin e(6) conjugates are L-shaped, the 15(2) and 13(1) regioisomers assume extended conformations, and the 13(1) derivatives are nearly linear. It is hypothesized that the 13(1)-aspartylchlorin e(6) conjugate may be a more efficient photosensitizer for PDT than the commercial currently used 15(2) derivative.

b-Bilene hydrochlorides are shown to be improved intermediates for the synthesis of metallo-isoporphyrins in enhanced yields (28% vs. 6%). Several new diamagnetic zinc(II) and a novel paramagnetic copper(II) isoporphyrin salts were also obtained using this approach. Metal-free isoporphyrins were also isolated. In vitro studies using human carcinoma HEp2 cells show that all metallo-isoporphyrins accumulate within cells and localize partially in the mitochondria. The zinc-isoporphyrins were found to be moderately phototoxic while the copper complex showed the lowest phototoxicity, maybe as a result of its paramagnetic nature.

Boron neutron capture therapy (BNCT) is based on the nuclear capture and fission reactions that occur when non-radioactive 10B is irradiated with low energy thermal neutrons to produce α-particles (10B[n,α] Li). Carboranylporphyrins are a class of substituted porphyrins containing multiple carborane clusters. Three of these compounds, designated H2TBP, H2TCP, and H2DCP, have been evaluated in the present study. The goals were two-fold. First, to determine their biodistribution following intracerebral (i.c.) administration by short term (30 min) convection enhanced delivery (CED) or sustained delivery over 24 h by Alzet™ osmotic pumps to F98 glioma bearing rats. Second, to determine the efficacy of H2TCP and H2TBP as boron delivery agents for BNCT in F98 glioma bearing rats. Tumor boron concentrations immediately after i.c. pump delivery were high and they remained so at 24 h. The corresponding normal brain concentrations were low and the blood and liver concentrations were undetectable. Based on these data, therapy studies were initiated at the Massachusetts Institute of Technology (MIT) Research Reactor (MITR) with H2TCP and H2TBP 24 h after CED or pump delivery. Mean survival times (MST) ± standard deviations of animals that had received H2TCP or H2TBP, followed by BNCT, were of 35 ± 4 and 44 ± 10 days, compared to 23 ± 3 and 27 ± 3 days, respectively, for untreated and irradiated controls. However, since the tumor boron concentrations of the carboranylporphyrins were 3-5× higher than intravenous (i.v.) boronophenylalanine (BPA), we had expected that the MSTs would have been greater. Histopathologic examination of brains of BNCT treated rats revealed that there were large numbers of porphyrin-laden macrophages, as well as extracellular accumulations of porphyrins, indicating that the seemingly high tumor boron concentrations did not represent the true tumor cellular uptake. Nevertheless, our data are the first to show that carboranyl porphyrins can be used as delivery agents for BNCT of an experimental brain tumor. Based on these results, we now are in the process of synthesizing and evaluating carboranylporphyrins that could have enhanced cellular uptake and improved therapeutic efficacy.

Two different synthetic routes for the preparation of 5,10,15-triaryl-tetrabenzocorroles have been developed. The first approach is based on the condensation of a tetrahydroisoindole with aryl-aldehydes, and the second pathway involves a cross-coupling reaction between a bromo-substituted corrole and a suitable substrate to form the four β-fused aryl rings. These routes are successful to lead to the target tetrabenzocorroles, obtained in both cases as the corresponding Cu complex and with the highest yield obtained via the one-step cross-coupling methodology. Demetalation of the Cu-tetrabenzocorrole produces the corresponding free base; this macrocycle was further exploited to obtain the Sn and Co complexes in good yields.

A series of low-spin, six-coordinate complexes [Fe(TBzTArP)L(2)]X (1) and [Fe(TBuTArP)L(2)]X (2) (X = Cl(-), BF(4)(-), or Bu(4)N(+)), where the axial ligands (L) are HIm, 1-MeIm, DMAP, 4-MeOPy, 4-MePy, Py, and CN(-), were prepared. The electronic structures of these complexes were examined by (1)H NMR and electron paramagnetic resonance (EPR) spectroscopy as well as density functional theory (DFT) calculations. In spite of the fact that almost all of the bis(HIm), bis(1-MeIm), and bis(DMAP) complexes reported previously (including 2) adopt the (d(xy))(2)(d(xz), d(yz))(3) ground state, the corresponding complexes of 1 show the (d(xz), d(yz))(4)(d(xy))(1) ground state at ambient temperature. At lower temperature, the electronic ground state of the HIm, 1-MeIm, and DMAP complexes of 1 changes to the common (d(xy))(2)(d(xz), d(yz))(3) ground state. All of the other complexes of 1 and 2 carrying 4-MeOPy, 4-MePy, Py, and CN(-) maintain the (d(xz), d(yz))(4)(d(xy))(1) ground state in the NMR temperature range, i.e., 298-173 K. The EPR spectra taken at 4.2 K are fully consistent with the NMR results because the HIm and 1-MeIm complexes of 1 and 2 adopt the (d(xy))(2)(d(xz), d(yz))(3) ground state, as revealed by the rhombic-type spectra. The DMAP complex of 1 exists as a mixture of two electron-configurational isomers. All of the other complexes adopt the (d(xz), d(yz))(4)(d(xy))(1) ground state, as revealed by the axial-type spectra. Among the complexes adopting the (d(xz), d(yz))(4)(d(xy))(1) ground state, the energy gap between the d(xy) and d(π) orbitals in 1 is always larger than that of the corresponding complex of 2. Thus, it is clear that the benzoannelation of the porphyrin ring stabilizes the (d(xz), d(yz))(4)(d(xy))(1) ground state. The DFT calculation of the bis(Py) complex of analogous iron(III) porphyrinate, [Fe(TPTBzP)(Py)(2)](+), suggests that the (d(xz), d(yz))(4)(d(xy))(1) state is more stable than the (d(xy))(2)(d(xz), d(yz))(3) state in both ruffled and saddled conformations. The lowest-energy states in the two conformers are so close in energy that their ordering is reversed depending on the calculation methods applied. On the basis of the spectroscopic and theoretical results, we concluded that 1, having 4-MeOPy, 4-MePy, and Py as axial ligands, exists as an equilibrium mixture of saddled and ruffled isomers both of which adopt the (d(xz), d(yz))(4)(d(xy))(1) ground state. The stability of the (d(xz), d(yz))(4)(d(xy))(1) ground state is ascribed to the strong bonding interaction between the iron d(xy) and porphyrin a(1u) orbitals in the saddled conformer caused by the high energy of the a(1u) highest occupied molecular orbital in TBzTArP. Similarly, a bonding interaction occurs between the d(xy) and a(2u) orbitals in the ruffled conformer. In addition, the bonding interaction of the d(π) orbitals with the low-lying lowest unoccupied molecular orbital, which is an inherent characteristic of TBzTArP, can also contribute to stabilization of the (d(xz), d(yz))(4)(d(xy))(1) ground state.

Several 2-iodopyrroles are used in Pd(0) catalyzed homocoupling reactions at room temperature in the presence of water to efficiently synthesize 2,2'-bipyrroles. These 2,2'-bipyrroles are strongly luminous materials and have high fluorescence quantum yields.

Various dipyrroles possess important motifs for construction of pyrrole-containing pigments. A series of 1,2-dipyrrolylethynes (4a-d) has been efficiently synthesized using an improved one-pot double Sonagashira coupling from trimethylsilylethyne and various 2-iodopyrroles. The resulting 1,2-dipyrrolylethynes were further transformed into novel indolyl-, ethenyl- and carboranyl-dipyrroles (5-7) using the Larock indole synthesis, stereoselective catalytic hydrogenation, or B(10)H(14). Indolyl-dipyrroles were found to selectively bind fluoride ions using one pyrrolic and the indolyl NHs, whereas the carboranyl- and ethenyl-dipyrroles are potentially valuable precursors for the synthesis of porphyrin isomers and expanded pigments.

Five cationic porphyrins bearing one to four -N(CH(3))(3)(+) groups linked to the p-phenyl positions of 5,10,15,20-tetraphenylporphyrin (TPP) were synthesized in order to study the effect of overall charge and its distribution on the cellular uptake, phototoxicity and intracellular localization using human carcinoma HEp2 cells. The di-cationic porphyrins DADP-o and DADP-a accumulated the most within cells and preferentially localize within vesicular compartments and in mitochondria. Of these two only DADP-a was phototoxic to the cells (IC(50)=3 microM at 1 J/cm(2)). The mono-cationic porphyrin MAP was found to be the most phototoxic of the series, and it localized mainly in lipid membranes, including the plasma membrane, ER, mitochondria, and Golgi. Both the tri-cationic porphyrin TRAP and the tetra-cationic porphyrin TEAP localized subcellularly mainly in the mitochondria, but of the two only TEAP showed moderate phototoxicity (IC(50)=8 microM at 1 J/cm(2)). Our results suggest that MAP is the most promising PDT photosensitizer, and that both DADP-o and TRAP might find application as transport vehicles for therapeutics into cells., (Copyright 2010 Elsevier B.V. All rights reserved.)

Amphiphilic and long wavelength red fluorescent dyes (4 and 7) were prepared from the Sonogashira coupling reactions of 3,5-diiodo-BODIPYs (1 and 6). One of these compounds, BODIPY 7, readily accumulated within human carcinoma HEp2 cells and was found to localize mainly within the endoplasmic reticulum (ER).

Porphyrin-peptide conjugates bearing multiple nuclear localization sequences (NLS) could show increased tumor cell uptake and affinity for nuclear receptors, and consequently increased photodynamic activity. Previous studies suggest that an increase number of NLS might enhance the nuclear uptake of proteins and other macromolecules. We report the syntheses and investigation of a series of multimeric porphyrin-NLS conjugates bearing two, three or four peptides with the minimum sequence PKKKRKV, linked via PEG or 5-carbon linkers, and with different distributions at the porphyrin periphery. Our results show that the tumor cell uptake and phototoxicity of these conjugates is mainly determined by their amphiphilic character, and not the number of NLS residues per molecule, contrary to previous studies. The mono- and di-substituted photosensitizers bearing one or two PEG linkers and up to three peptide sequences were found to be the most phototoxic toward human carcinoma HEp2 cells, while the tetra-NLS conjugates symmetrically substituted around the porphyrin ring accumulated the least within cells and were non-phototoxic. All conjugates localized intracellularly within endosomal vesicles and lysosomes, probably as a result of an endocytic mechanism of uptake; as a consequence no nuclear uptake was detected by fluorescence microscopy.

New cobalt(III) bis(dicarbollide) complexes covalently linked to two 2-oligothienyl units have been synthesized and electropolymerized in acetonitrile electrolyte in order to produce the corresponding polythiophene films containing in-chain metallic centers. The polymer films electrogenerated from the bithienyl (4b) and terthienyl (4c) derivatives display redox processes attributed to the Co(III)/Co(II) couple at ca. -1.1 V vs SCE and to the p-doping/undoping of the expected quaterthienyl and sexithienyl segments at ca. 0.8 V vs SCE. In contrast, the anodic oxidation of the thienyl (4a) derivative leads to passivation of the electrode surface. As the length of the oligothiophene substituents increases, the metallic and dicarbollide cage carbon atoms contributions in the HOMO decrease dramatically so that the highest occupied frontier orbitals of 4b and 4c can be considered as almost purely oligothiophene-based. From further UV-vis spectroscopy analysis, it is demonstrated that the polymer incorporating the sexithienyl segments is more conjugated than that with the quaterthienyl segments as the absorption maximum for the interband pi-pi* transition was observed at 410 and 448 nm for poly(4b) and poly(4c) respectively. Furthermore, these polymers display a more extended degree of conjugation than the parent oligothiophenes. Such features indicate a significant electronic delocalization through the cobaltabisdicarbollide moiety. Their conducting probe atomic force microscopy characterization indicates that poly(4b) and poly(4c) behave like heavily doped semiconductors rather than pure semiconductors. Mean conductivity values extracted from the current-voltage profiles are 1.4 x 10(-4) and 7.5 x 10(-4) S cm(-1) for poly(4b) and poly(4c), respectively. Such materials are found to be efficient for the electrocatalytic reduction of protons to dihydrogen, as exemplified for poly(4b). The overpotential for hydrogen evolution is significantly decreased by ca. 230 mV with respect to that obtained with the bare electrode (measured for a current density of 1.4 mA cm(-2) in the presence of 20 mM HBF(4)).

The structure of the ring-opened product from direct oxidation of meso-tetraarylporphyrins has been controversial for three decades. Herein we show that bilitrienones 2 are obtained from oxidation of metal-free dodecasubstituted porphyrins 1 in the presence of sodium nitrite, trifluoroacetic acid and air oxygen. The presence of the para-nonyl groups in 1b stabilized the corresponding bilitrienone 2b, which was characterized by X-ray crystallography. In the absence of the para-nonyl groups bilitrienone 2a undergoes a rapid hydration reaction, giving biladienone 3a as the major isolated product. The molecular structures of 2b and 3a, and. the photochemical isomerization of 3a are discussed.

A water-soluble [meso-tetra(4-nido-carboranylphenyl)porphyrin] (H(2)TCP) bearing 36 boron atoms was studied for its accumulation and its radio/photo-sensitization efficiency towards murine melanotic melanoma cells. The amount of H(2)TCP in the cells increased with the porphyrin dose in the incubation medium up to 100 microM with no significant dark toxicity. Fluorescence microscopy observations showed that the porphyrin was largely localized intracellularly. Based on these "in vitro" results our investigations were pursued using the B16F1 melanotic melanoma subcutaneously transplanted in C57BL6 mice as "in vivo" model. Phormacokinetic studies were performed by injection of H(2)TCP intratumorally (1 mg/kg) and intravenously (10 mg/kg). At 0.5h after i.t. administration or at 24 h after i.v. injection, the amounts of (10)B in the tumour were about 60 ppm and about 6 ppm, respectively. The distribution of H(2)TCP in the tumour after intravenous or intratumoural injection was also assessed by fluorescence microscopy analyses. Under these conditions, preliminary BNCT studies were carried out using a new thermal column called HYTOR (HYbrid Thermal spectrum sHifter TapirO Reactor) inserted in the fast nuclear reactor Tapiro at Enea Casaccia, Italy. The mice were exposed to HYTHOR radiation field for 20 min at a reactor power of 5 kW. In spite of different amounts of (10)B in the tumour at the irradiation time, a similar significant delay in tumour growth (5-6 days) was induced by neutron irradiation in intratoumorally and intravenously injected mice. The response of the melanotic melanoma to H(2)TCP-BNCT was compared with that obtained by irradiation after intraperitoneal injection of boron-phenylalanine.

Syntheses of two new cobaltacarborane-phthalocyanine conjugates, one anionic (Pc 6) and one zwitterionic (Pc 7), were accomplished via cyclotetramerization of the corresponding cobaltacarborane-substituted phthalonitriles (4 or 5) with excess phthalonitrile in quinoline. X-ray structures of two phthalonitrile precursors (2 and 3) were obtained and are discussed, and the absorption and emission properties of the two cobaltacarborane-phthalocyanine conjugates in several solvents were investigated. The anionic conjugate 6 exists mainly as a monomer in polar organic solvents and has fluorescence quantum yields in the region 0.2-0.3. The zwitterionic conjugate 7 aggregates in solution and displays lower quantum yields ~0.1 in organic solvents.