Daniela Pietrangeli

Carborane derivatives loaded into liposomes as efficient delivery systems for boron neutron capture therapy.

Boron neutron capture therapy (BNCT) is an anticancer therapy based on the incorporation of (10)B in tumors, followed by neutron irradiation. Recently, the synthesis and delivery of new boronated compounds have been recognized as some of the main challenges in BNCT application. Here, we report on the use of liposomes as carriers for BNCT active compounds. Two carborane derivatives, i.e., o-closocarboranyl beta-lactoside (LCOB) and 1-methyl-o-closocarboranyl-2-hexylthioporphyrazine (H(2)PzCOB), were loaded into liposomes bearing different surface charges. The efficacy of these formulations was tested on model cell cultures, that is, DHD/K12/TRb rat colon carcinoma and B16-F10 murine melanoma. These induce liver and lung metastases, respectively, and are used to study the uptake of standard BNCT drugs, including borophenylalanine (BPA). Boron concentration in treated cells was measured by alpha spectrometry at the TRIGA mark II reactor (University of Pavia). Results showed high performance of the proposed formulations. In particular, the use of cationic liposomes increased the cellular concentration of (10)B by at least 30 times more than that achieved by BPA.

Symmetrically substituted nido-carboranylphthalocyanines: facile synthesis, characterization, and solution properties. Evidence for intra- and intermolecular H+/K+ exchange.

The direct, non ex post synthesis of a novel phthalocyanine decorated with eight thiohexyl-nido-carborane functions, nido-[H(2)MCHESPc]K(8), where the anionic polyhedra are in the form of K(+) salt, is reported and discussed. The solution properties of this compound, including the unprecedented exchange between the pyrrolic protons and the peripheral alkali-metal ions, are also analyzed.

Water-soluble carboranyl-phthalocyanines for BNCT. Synthesis, characterization, and in vitro tests of the Zn(ii)-nido-carboranyl-hexylthiophthalocyanine

The zinc(II) complex of the octa-anionic 2,3,9,10,16,17,23,24-octakis-(7-methyl-7,8-dicarba-nido-undeca-boran-8-yl)hexyl-thio-6,13,20,27-phthalocyanine (nido-[ZnMCHESPc]Cs8, 7) has been obtained in the form of caesium salt through mild deboronation of the neutral precursor, the closo-[ZnMCHESPc] complex, 6, with CsF. 6 has been synthesized, in turn, by heating a finely ground mixture of the appropriate phthalonitrile and zinc(II) acetate at 180.0 °C. The complexes have been characterized by elemental analyses, FT-IR, UV-visible absorption and fluorescence emission spectroscopy, and their structures were assessed by (1)H, (13)C, (11)B, and two-dimensional homo- and hetero-correlated NMR spectroscopy experiments. 7 showed appreciable solubility in water solution, together with a marked tendency to aggregate. Aggregation of 7 in the hydrotropic medium resulted in significant fluorescence quenching. Instead, fluorescence quantum yields (Φ(F)) of 0.14 and 0.08, and singlet oxygen quantum yields (Φ(Δ)) of 0.63 and 0.24 were obtained for 6 and 7, respectively, in a DMF solution. In vitro boron neutron capture therapy (BNCT) experiments, employing boron imaging techniques as implemented in qualitative and quantitative neutron autoradiography methods, showed that 7 is capable of increasing the boron concentration of two selected cancerous cell lines, the DHD/K12/TRb of rat colon adenocarcinoma and UMR-106 of rat osteosarcoma, with the large-size Cs(+) counter-ions used to neutralize the negatively charged carborane polyhedra not presenting a significant obstacle to the process. Taken together, BNCT and photophysical measurement results indicated that 7 is potentially suitable for bimodal or multimodal anticancer therapy.

Electrochemical and Spectroscopic Behavior of Iron(III) Porphyrazines in Langmuir−Schäfer Films

Thin films of a newly synthesized iron(III) porphyrazine, LFeOESPz ( L = ClEtO, OESPz = ethylsulfanylporphyrazine), have been deposited by the Langmuir-Schafer (LS) technique (horizontal lifting) on ITO or gold substrates. Before deposition, the floating films have been investigated at the air-water interface by pressure/area per molecule (pi/ A) experiments, Brewster angle microscopy (BAM) and UV-vis reflection spectroscopy (RefSpec). The complex reacts with water subphase (pH 6.2) forming the mu-oxo dimer, which becomes the predominant component of the LS films ( LS-Fe) as indicated by optical, IR, XPS, and electrochemical data. LS-Fe multilayers exhibit, between open circuit potential (OCP) and +0.90 V (vs SCE), two independent peak pairs with formal potentials, E surf (I) and E surf(II) of +0.56 V and +0.78 V, respectively. According to dynamic voltammetric and coulometric experiments the peak pair at +0.56 V is attributed to one-electron process at the iron(III) centers on the monomer, while the peak pair at +0.78 V is associated to a four-electron process involving mu-oxo-dimer oligomers. LS-Fe films prove to be quite stable electrochemically between OCP and +0.90 V. The electrochemical stability decreases, however, when the potential range is extended both anodically and cathodically outside these limits, due to formation of new species. Upon incubation with TCA solutions, LS-Fe films show remarkable changes in the UV-vis spectra, which are consistent with a significant mu-oxo dimer --> monomer conversion. Addition of TCA to the electrochemical cell using a LS-Fe film as working electrode, results in a linear increase of a cathodic current peak near -0.40 V as the TCA concentration varies in the 0.1-2.0 mM range. This behavior is interpreted in terms of TCA inducing a progressive change in the composition of the LS-Fe films in favor of the monomeric iron(III) porphyrazine, which is responsible for the observed increase in the cathodic current near -0.40 V.

Carboranylporphyrazines for anti-cancer therapies: synthesis and physicochemical properties

The synthesis, the salient physicochemical properties, and liposome insertion of carboranyl-alkylthio-porphyrazines, a new family of potential BNCT agents, are here reviewed together with recent progresses in their metalation and conversion in the water-soluble counterparts.

Mass spectrometric evidence for collisionally induced removal of H2 from monoanions of 10B nido-carborane derivatives investigated by electrospray ionization quadrupole linear ion trap and Fourier transform ion cyclotron resonance mass spectrometry

Some newly synthesized (10)B nido-carborane derivatives, i.e., 7,8-dicarba-nido-undecaborane monoanions ([7-Me-8-R-C(2)B(9)H(10)](-)K(+), R = H, butyl, hexyl, octyl and decyl), have been fully characterised and examined by electrospray ionization and Fourier transform ion cyclotron resonance mass spectrometry with liquid chromatographic separation (LC/ESI-FTICR-MS). These boron-containing compounds exhibit abundant molecular ions ([M](-)) at m/z 140.22631 [C(3) (10)B(9)H(14)](-), m/z 196.28883 [C(7) (10)B(9)H(22)](-), m/z 224.32032 [C(9) (10)B(9)H(26)](-), m/z 252.35133 [C(11) (10)B(9)H(30)](-) and m/z 280.38354 [C(13) (10)B(9)H(34)](-) at the normal tube lens voltage setting of -90 V, which was an instrumental parameter value selected in the tuning operation. Additional [M-nH(2)](-) (n = 1-4) ions were observed in the mass spectra when higher tube lens voltages were applied, i.e., -140 V. High-resolution FTICR-MS data revealed the accurate masses of fragment ions, bearing either an even or an odd number of electrons. Collision-induced dissociation of the [M-nH(2)](-) ions (n = 0-4) in the quadrupole linear ion trap (LTQ) analyzer confirmed the loss of hydrogen molecules from the molecular ions. It is suggested that the loss of H(2) molecules from the alkyl chain is a consequence of the stabilization effect of the nido-carborane charged polyhedral skeleton.

On the flexibility of carboranylalkylthio substituents in porphyrazines and its relevance to the photophysical properties

Ultrafast transient absorption spectrometry and DFT/TDDFT calculations reveal that following photoexcitation, carboranyl- and carboranyl-free alkylthioporphyrazines deactivate by the pathway S1(π,π*)→Sn(Cβ-2pz/Sl.p.,π*)→ground state. The presence of quenching singlet excited states with predominantly Cβ-2pz/Sl.p.,π* character immediately below the primarily photogenerated S1(π,π*) state is a consequence of the electronic structure changes induced by the inherent flexibility of the alkylthio chains.

Synthesis and characterization of nanosized polycarboranyl-porphyrazine conjugates

The synthesis and characterization of a highly boronated porphyrazine, 2,3,7,8,12,13,17,18-octakis-[6-(2-(1′-methyl-1′,2′-dicarba-closo-dodecaboran-2′ -yl)hexyl)-1,2-dicarba-closo-dodecaboran-1-yl)hexylthio] 5,10,15,20 (21H, 23H) porphyrazine (H2(MCHE)CHESPz), is reported. This nanosized molecule bears eight dicarboranyl-substituted carborarod-like alkyl pendants and, as such, represents a rare example, if any, of a tetrapyrolic system bearing 160 boron atoms per molecule, corresponding to 40% boron content by weight.

Synthesis, coordination chemistry, and physico-chemical properties of the 2-chloroethoxy-iron(III)(ethylthio) porphyrazine

Reaction of octakis(ethylthio)porphyrazine (H2OESPz) with FeBr2 in ClCH2CH2OH at 135 °C affords the 2-chloroethoxy-iron(III)-(ethylthio)porphyrazine, (ClCH2CH2O)FeIIIOESPz, (LFeIIIOESPz) in good yield. The spectroscopic, redox, and coordination properties of the complex and its μ-oxo dimer derivative, [FeIIIOESPz]2O, are investigated and compared to those of the iron(III)porphyrin analogs.