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Chlorin e6 fused with a cobalt-bis(dicarbollide) nanoparticle provides efficient boron delivery and photoinduced cytotoxicity in cancer cells

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Abstract

Further development of boron neutron capture therapy (BNCT) requires new neutronsensitizers with improved ability to deliver 10B 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 109 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.

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Abbreviations

ACC:

Average cytoplasmic concentration

ATP:

Adenosine triphosphate

BC11:

Lipid peroxidation sensor BODIPY® 581/591 C11

BNCT:

Boron-neutron capture therapy

DNA:

Deoxyribonucleic acid

FWHM:

A full width at the half of maximum of the fluorescence spectrum

PDT:

Photodynamic therapy

RNA:

Ribonucleic acid

TOG:

Transferrin conjugated with Oregon Green 488

Cex:

Concentration of conjugate in cellular extract

CACC:

Average cytoplasmic concentration of conjugate

K:

Maximal ratio of CACC to extracellular concentration of conjugate

LD90:

Conjugate concentration that provides 90% photoinduced cell death

LD50:

Conjugate concentration that provides 50% photoinduced cell death

Nc:

Number of cells

Tup:

Time for 50% uptake of a conjugate in cells

Tef:

Time for 50% efflux of a conjugate from cells

R:

Ratio of the integrated fluorescence intensity of the studied conjugate in the examined solution to the intensity of this conjugate in 1% Cremophor solution

Vex:

Extract volume

Vcyt:

Cytoplasm volume of a cell

Φ(1O2):

Quantum yield of singlet oxygen generation

λf:

Maximum of fluorescence emission

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Authors and Affiliations

  1. Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya, 16/10, 117997, Moscow, Russia

    Anastasija V. Efremenko, Anastasija A. Ignatova & Alexey V. Feofanov

  2. Biological Faculty, Lomonosov Moscow State University, Vorobyevi Gori 1, Moscow, 119992, Russia

    Anastasija V. Efremenko, Anastasija A. Ignatova & Alexey V. Feofanov

  3. M.V. Lomonosov Moscow State Academy of Fine Chemical Technology, Vernadskii Prosp. 86, 119571, Moscow, Russia

    Mikhail A. Grin & Andrey F. Mironov

  4. A.N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Vavilov Str. 28, 119991, Moscow, Russia

    Igor B. Sivaev & Vladimir I. Bregadze

Authors
  1. Anastasija V. Efremenko
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  2. Anastasija A. Ignatova
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  3. Mikhail A. Grin
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  4. Igor B. Sivaev
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  5. Andrey F. Mironov
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  6. Vladimir I. Bregadze
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  7. Alexey V. Feofanov
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Correspondence to Alexey V. Feofanov.

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Efremenko, A.V., Ignatova, A.A., Grin, M.A. et al. Chlorin e6 fused with a cobalt-bis(dicarbollide) nanoparticle provides efficient boron delivery and photoinduced cytotoxicity in cancer cells. Photochem Photobiol Sci 13, 92–102 (2014). https://doi.org/10.1039/c3pp50226k

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