boron and phytochlorin

Tumor phototherapy is of great significance for the expansion and advancement of cancer treatment methods. Herein, two-dimensional boron nanosheets (B NSs) with a thickness of 2.4 nm exhibiting an excellent photothermal conversion performance were developed via a simple liquid phase ultrasonic stripping method. Following the loading of the photosensitizer agent chlorin e6 (Ce6) and subsequent modification with poly(allylamine hydrochloride) (PAH) and poly(acrylic acid) (PAA), a B@Ce6-PAH-PAA NS nanomedicine exhibiting dual modal imaging-guided cancer photothermal therapy (PTT) and photodynamic therapy (PDT) properties, as well as outstanding stability was developed. The suitable nano-size (120 nm) of B@Ce6-PAH-PAA NSs can allow drugs to target tumor tissue with an enhanced permeability and retention effect (EPR). The cytotoxicity experiments demonstrated that B@Ce6-PAH-PAA NSs exhibited good biocompatibility even at high concentrations. Furthermore, the in vitro and in vivo experiments showed the excellent synergistic therapeutic effect of this nanomedicine for PTT and PDT.

Topics: Acrylic Resins; Animals; Antineoplastic Agents; Biocompatible Materials; Boron; Cell Proliferation; Cell Survival; Chlorophyllides; Drug Screening Assays, Antitumor; Female; Humans; Mammary Neoplasms, Experimental; MCF-7 Cells; Mice; Mice, Inbred BALB C; Mice, Nude; Nanoparticles; Particle Size; Photochemotherapy; Photosensitizing Agents; Polyamines; Porphyrins; Surface Properties

Further development of boron neutron capture therapy (BNCT) requires new neutronsensitizers with improved ability to deliver (10)B isotopes in cancer cells. Conjugation of boron nanoparticles with porphyrin derivatives is an attractive and recognized strategy to solve this task. We report on breakthroughs in the structural optimization of conjugates of chlorin e6 derivative with cobalt-bis(dicarbollide) nanoparticles resulting in the creation of dimethyl ester 13-carbomoylchlorin e6 [N-hexylamine-N'-ethoxyethoxy]-cobalt-bis(dicarbollide) (conjugate 1). Conjugate 1 is able to accumulate quickly and efficiently (distribution factor of 80) in cancer cells, thus delivering more than 10(9) boron atoms per cell when its extracellular concentration is more than 1 μmol L(-1). Also 1 is an active photosensitizer and is phototoxic towards human lung adenocarcinoma A549 cells at 80 nmol L(-1) (50% cell death). Photoinduced cytotoxicity of 1 is associated with lipid peroxidation, lysosome rupture and protease activity enhancement. Conjugate 1 fluoresces in the red region (670 nm), which is useful to monitor its accumulation and distribution in vivo. It is not toxic to cells without activation by neutrons or photons. Structural features that improve the functional properties of 1 are discussed. The properties of 1 warrant its preclinical evaluation as a multifunctional agent for BNCT, photodynamic therapy and fluorescent tumor diagnosis.

Topics: Biological Transport; Boron; Boron Neutron Capture Therapy; Cell Line, Tumor; Chlorophyllides; Enzyme Activation; Humans; Lipid Peroxidation; Lysosomes; Microscopy, Fluorescence; Nanoparticles; Neutrons; Organometallic Compounds; Peptide Hydrolases; Photons; Photosensitizing Agents; Porphyrins

Photodynamic tumor-destroying activity of the boronated chlorin e6 derivative BACE (chlorin e6 13(1)-N-{2-[N-(1-carba-closo-dodecaboran-1-yl)methyl]aminoethyl}amide-15(2), 17(3)-dimethyl ester), previously described in Moisenovich et al. (2010) PLoS ONE 5(9) e12717, was shown here to be enormously higher than that of unsubstituted chlorin e6, being supported by the data on much higher photocytotoxicity of BACE in M-1 sarcoma cell culture. To validate membrane damaging effect as the basis of the enhanced tumoricidal activity, BACE was compared with unsubstituted chlorin e6 in the potency to photosensitize dye leakage from liposomes, transbilayer lipid flip-flop, inactivation of gramicidin A ionic channels in planar lipid membranes and erythrocyte hemolysis. In all the models comprising artificial and cellular membranes, the photodynamic effect of BACE exceeded that of chlorin e6. BACE substantially differed from chlorin e6 in the affinity to liposomes and erythrocytes, as monitored by fluorescence spectroscopy, flow cytometry and centrifugation. The results support the key role of membrane binding in the photodynamic effect of the boronated chlorin e6 amide.

Topics: Amides; Animals; Boron; Cell Membrane; Cells, Cultured; Chlorophyllides; Erythrocytes; Female; Flow Cytometry; Hemolysis; Humans; Light; Lipid Bilayers; Liposomes; Membranes, Artificial; Photosensitizing Agents; Porphyrins; Rats; Sarcoma

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 e(6) with 1-trifluoromethanesulfonylmethyl-o-carborane. Chlorin e(6) 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 approximately 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 24h post-illumination with 1 microM of 5. This compound demonstrated high efficacy in photodynamic therapy of rat M-1 sarcoma. After PDT with 25mg/kg of 5 the residual tumours were significantly smaller than in animals subjected to PDT with equal concentration of boron-free aminochlorin e(6). 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.

Topics: Albumins; Animals; Antineoplastic Agents; Boron; Cell Line; Chlorophyllides; Humans; Photosensitizing Agents; Porphyrins; Rats; Triazenes