RESUMO
Most photosensitizers of interest for photodynamic therapy-especially porphyrinoids and chlorins-are hydrophobic. To circumvent this difficulty, the use of nanocarriers is an attractive strategy. In this perspective, we have developed highly water-soluble and biocompatible fluorescent organic nanoparticles (FONPs) made from citric acid and diethyltriamine which are then activated by ethlynene diamine as nanoplatforms for efficient photosensitizers (PSs). Purpurin 18 (Pp18) was selected as a biosourced chlorin photosensitizer combining the efficient single oxygen generation ability and suitable absorption in the biological spectral window. The simple reaction of activated FONPs with Pp18, which contains a reactive anhydride ring, yielded nanoparticles containing both Pp18 and Cp6 derivatives. These functionalized nanoparticles combine solubility in water, high singlet oxygen generation quantum yield in aqueous media (0.72) and absorption both in the near UV region (FONPS) and in the visible region (Soret band approximately 420 nm as well as Q bands at 500 nm, 560 nm, 660 nm and 710 nm). The functionalized nanoparticles retain the blue fluorescence of FONPs when excited in the near UV region but also show deep-red or NIR fluorescence when excited in the visible absorption bands of the PSs (typically at 520 nm, 660 nm or 710 nm). Moreover, these nanoparticles behave as efficient photosensitizers inducing colorectal cancer cell (HCT116 and HT-29 cell lines) death upon illumination at 650 nm. Half maximal inhibitory concentration (IC50) values down to, respectively, 0.04 and 0.13 nmol/mL were observed showing the potential of FONPs[Cp6] for the PDT treatment of cancer. In conclusion, we have shown that these novel biocompatible nanoparticles, which can be elaborated from biosourced components, both show deep-red emission upon excitation in the red region and are able to produce singlet oxygen with high efficiency in aqueous environments. Moreover, they show high PDT efficiency on colorectal cancer cells upon excitation in the deep red region. As such, these functional organic nanoparticles hold promise both for PDT treatment and theranostics.
RESUMO
Tailor-made NIR emitting dyes were designed as multimodal optical probes. These asymmetric amphiphilic compounds show combined intense absorption in the visible region, NIR fluorescence emission, high two-photon absorption in the NIR (with the maximum located around 1000 nm) as well as large Stokes' shift values and second-harmonic generation ability. Thanks to their structure, high loading into nanoemulsions (NEs) could be achieved leading to very high one- and two-photon brightness. These dyes were demonstrated to act as multimodal contrast agents able to generate different optical modalities of interest for bioimaging. Indeed, the uptake and carrier behaviour of the dye-loaded NEs into cancer cells could be monitored by simultaneous two-photon fluorescence and second-harmonic generation optical imaging. Multimodal imaging provided deep insight into the mechanism and kinetics of dye internalisation. Quite interestingly, the nature of the dyes was also found to influence both the kinetics of endocytosis and the internalisation pathways in glioblastoma cancer cells. By modulating the charge distribution within the dyes, the NEs can be tuned to escape lysosomes and enter the mitochondria. Moreover, surface functionalization with PEG macromolecules was realized to yield stealth NIRF-NEs which could be used for in vivo NIRF imaging of subcutaneous tumours in mice.
RESUMO
cis- and trans-(Cl,Cl)-[RuII(FT)Cl2(NO)](PF6) complexes show efficient NO photodelivery upon two-photon excitation in the NIR region. Moreover, cytotoxicity and phototoxicity studies provide evidence that these complexes are promising candidates as photoactivatable molecular tools for resection of malignancies.
Assuntos
Antineoplásicos/química , Raios Infravermelhos , Óxido Nítrico/metabolismo , FototerapiaRESUMO
Quaterpyridines have been demonstrated to be useful building blocks in metallo-supramolecular chemistry; however, their synthesis requires the preparation of sensitive building blocks. We present here three examples of nonsymmetric quaterpyridines that were easily obtained in yields of 70-85% by condensation of commercially available enones with 6-acetyl-2,2':6',2''-terpyridine through a Kröhnke pyridine synthesis. Easy access to 6-acetyl-2,2':6',2''-terpyridine starting from 2,6-diacetylpyridine and 2-acetylpyridine is described. The X-ray analysis of a chiral quaterpyridine and its Pt(II) complex is presented.
RESUMO
The 4'-(2-fluorenyl)-2,2':6',2''-terpyridine (FT) ligand and its cis(Cl,Cl)- and trans(Cl,Cl)-[Ru(II)(FT)Cl2(NO)](PF6) complexes have been synthesized. Both isomers were separated by HPLC and fully characterized by (1)H and (13)C NMR. The X-ray diffraction crystal structures were solved for FT (Pna21 space group, a = 34.960(4), b = 5.9306(7), c = 9.5911(10) Å), and trans(Cl,Cl)-[Ru(II)(FT)Cl2(NO)](PF6)·MeOH (P1[combining macron] space group, a = 10.3340(5), b = 13.0961(6), c = 13.2279(6) Å, α = 72.680(2), ß = 70.488(2), γ = 67.090(2)°). Photo-release of NOË radicals occurs under irradiation at 405 nm, with a quantum yield of 0.31 and 0.10 for cis(Cl,Cl)-[Ru(II)(FT)Cl2(NO)](PF6) and trans(Cl,Cl)-[Ru(II)(FT)Cl2(NO)](PF6), respectively. This significant difference is likely due to the trans effect of Cl(-), which favors the photo-release. UV-visible spectroscopy and cyclic voltammetry indicate the formation of ruthenium(iii) species as photoproducts. A density functional theory (DFT) analysis provides a rationale for the understanding of the photo-physical properties, and allows relating the weakening of the Ru-NO bond, and finally the photo-dissociation, to HOMO â LUMO excitations.
Assuntos
Óxido Nítrico/análise , Processos Fotoquímicos , Piridinas/análise , Rutênio/análise , Cristalografia por Raios X , Espectroscopia Fotoeletrônica/métodos , Piridinas/química , Rutênio/química , Difração de Raios XRESUMO
Five Pt(II) complexes were tested for their ability to interfere in Cu(II) or Zn(II) coordination to the Aß peptide. Two of them induce modifications of the Cu(II) sphere but not the associated Cu(Aß) ROS production. In contrast, they do completely preclude Zn induced Aß aggregation.
Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Complexos de Coordenação/metabolismo , Cobre/química , Platina/química , Zinco/química , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Sequência de Aminoácidos , Peptídeos beta-Amiloides/química , Benzotiazóis , Complexos de Coordenação/química , Complexos de Coordenação/uso terapêutico , Humanos , Concentração de Íons de Hidrogênio , Dados de Sequência Molecular , Espectrometria de Fluorescência , Tiazóis/químicaRESUMO
Combined coordination of Zn(II) and Cu(I) or Cu(II) to the amyloid-ß peptide has been investigated using XANES, EPR and NMR spectroscopies. While Zn(II) does alter Cu(II) binding to Aß, this has no effect on (Aß)Cu induced ROS production and associated cell toxicity.
Assuntos
Peptídeos beta-Amiloides/química , Cobre/química , Fragmentos de Peptídeos/química , Zinco/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/química , Complexos de Coordenação/toxicidade , Humanos , Ligação Proteica , Espécies Reativas de Oxigênio/metabolismoRESUMO
Breaking the mold: Inhibition of toxic amyloid-ß (Aß) aggregates and disruption of Cu-Aß with subsequent redox-silencing of Cu have been considered promising strategies against Alzheimer's disease. The design and proof of concept of simple peptides containing a Cu-chelating/redox-silencing unit and an Aß-aggregation inhibition unit (ß-sheet breaker) is described (see scheme).
Assuntos
Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/química , Amiloide/antagonistas & inibidores , Amiloide/química , Quelantes/química , Cobre/química , Sequência de Aminoácidos , Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Quelantes/farmacologia , Cobre/farmacologia , Modelos Moleculares , Dados de Sequência Molecular , Oxirredução , Fragmentos de Peptídeos/metabolismo , Ligação Proteica , Estrutura Secundária de ProteínaRESUMO
Coordination of a cyclometallated Pt(II) complex (1) to an amyloid-ß peptide was probed by NMR and ESI-MS. Furthermore, EPR showed that binding of 1 to the Cu(II)-amyloid-ß species resulted in a reshuffling of the Cu(II) coordination sphere, which was absent or lower for the sister non cyclometallated Pt(II) complexes.
Assuntos
Peptídeos beta-Amiloides/metabolismo , Cobre/metabolismo , Compostos Organoplatínicos/metabolismo , Fragmentos de Peptídeos/metabolismo , Peptídeos beta-Amiloides/química , Cobre/química , Cristalografia por Raios X , Espectroscopia de Ressonância de Spin Eletrônica , Compostos Organoplatínicos/química , Fragmentos de Peptídeos/química , Ligação ProteicaAssuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/química , Metais/química , Doença de Alzheimer/etiologia , Doença de Alzheimer/terapia , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Quelantes/química , Quelantes/farmacologia , Estresse OxidativoRESUMO
Photophysical and photochemical properties of a series of mononuclear and binuclear ruthenium(II) complexes of phen (phen=1,10-phenanthroline), in the absence or in the presence of calf-thymus DNA have been investigated by steady-state as well as time-resolved methods. The complexes of this series are [Ru(x)(phen)(2x)(L)](2x+) (x=1 or 2) type, where L is a bpy (4,4'-dimethyl-2,2'-bypiridine, with x=1) or a bis-bpy covalently linked by flexible chains including either polymethylene groups or polyamine functions (with x=2). Upon addition of DNA, the most important increasing luminescence and change of emission maxima wavelength are observed for the bimetallic compounds having amine functions in their spacer. A biexponential decay in luminescence is found with emission lifetimes of the complexes upon binding to DNA. Moreover, these complexes induce efficient photocleavage of DNA by irradiation at 450 nm. This efficiency is particularly important when the binuclear complexes include amino groups. Topoisomerization experiments have pointed out a similarity between the DNA cleaving ability of these complexes and their intercalation into DNA. Scavenging experiments have shown that the oxidative species involved in DNA cleavage was mainly (1)O(2), via a type II mechanism.
Assuntos
2,2'-Dipiridil/análogos & derivados , DNA/metabolismo , Compostos Organometálicos/química , Fenantrolinas/química , Rutênio/química , DNA/efeitos da radiação , DNA Topoisomerases/química , DNA Topoisomerases/metabolismo , Transferência de Energia , Sequestradores de Radicais Livres/análise , Ligantes , Medições Luminescentes , Fotoquímica , Poliaminas/química , Espécies Reativas de Oxigênio/metabolismo , Sais/farmacologia , Espectrofotometria/métodosRESUMO
The ruthenium bis(bipyridine) sulfoxide complexes Ru-1 and Ru-2 exhibit high catalytic activity for epoxidation of unfunctionalized olefins in the presence of [bis(acetoxy)iodo]benzene; with the chiral catalyst, Ru-2, asymmetric induction up to 94% was observed for beta-methylstyrene.