Novel boronated chlorin e6-based photosensitizers: Synthesis, binding to albumin and antitumour efficacy

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 e(6) 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 similar to 4 times bigger than the respective value for the complexes of albumin with boron-free aminochlorin e(6). Compound 5 potently sensitized rat fibroblasts to illumination with monochromatic red light: > 98% of cells were necrotic by 24 h post-illumination with 1 mu M 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. (c) 2008 Elsevier Ltd. All rights reserved.