Novel boronated chlorin e6-based photosensitizers: Synthesis,binding to albumin and antitumour efficacy |
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Authors: | Valentina A Ol’shevskaya Roza G Nikitina Arina N Savchenko Marina V Malshakova Alexander M Vinogradov Galina V Golovina Dmitry V Belykh Alexander V Kutchin Mikhail A Kaplan Valery N Kalinin Vladimir A Kuzmin Alexander A Shtil |
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Institution: | 1. A.N. Nesmeyanov Institute of Organoelement Compounds, 28 Vavilov Street, 119991 Moscow, Russia;2. Medical Radiological Research Center, 4 Korolev Street, 249020 Obninsk, Russia;3. Institute of Chemistry, 48 Pervomaiskaya Street, 167982 Syktyvkar, Russia;4. N.M. Emanuel Institute of Biochemical Physics, 4 Kosygin Street, 119977 Moscow, Russia;5. N.N. Blokhin Cancer Center, 24 Kashirskoye shosse, 115478 Moscow, Russia |
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Abstract: | Chlorins, a class of plant porphyrins, are perspective as photosensitizing agents due to light absorption in the long wavelength spectral region and deeper photodamage of tissues. Aiming at optimization of antitumour properties of chlorins, we synthesized a series of boronated derivatives of chlorin e6 and their complexes containing Zn(II), Pd(II) or Sn(IV). The compounds were synthesized by alkylation of amino or hydroxy derivatives of chlorin e6 with 1-trifluoromethanesulfonylmethyl-o-carborane. Chlorin e6 13(1)-N-{2-N-(o-carboran-1-yl)methyl]aminoethyl}amide-15(2), 17(3)-dimethyl ester (compound 5) formed complexes with serum albumin, a major porphyrin carrier. The binding constant of these complexes was ~4 times bigger than the respective value for the complexes of albumin with boron-free aminochlorin e6. Compound 5 potently sensitized rat fibroblasts to illumination with monochromatic red light: >98% of cells were necrotic by 24 h post-illumination with 1 μM of 5. This compound demonstrated high efficacy in photodynamic therapy of rat M-1 sarcoma. After PDT with 25 mg/kg of 5 the residual tumours were significantly smaller than in animals subjected to PDT with equal concentration of boron-free aminochlorin e6. No signs of general toxicity were detectable after PDT with 5. Thus, boronation can enhance the potency of chlorins in PDT, in particular, due to an increased binding to albumin. Our data expand the therapeutic applicability of boronated chlorins beyond boron neutron capture therapy; these agents emerge as dual efficacy photoradiosensitizers. |
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