RESUMO
The Pt(IV) prodrug trans, trans, trans-[Pt(pyridine)2(N3)2(OH)2] (Pt1) and its coumarin derivative trans, trans, trans-[Pt(pyridine)2(N3)2(OH)(coumarin-3-carboxylate)] (Pt2) are promising agents for photoactivated chemotherapy. These complexes are inert in the dark but release Pt(II) species and radicals upon visible light irradiation, resulting in photocytotoxicity toward cancer cells. Here, we have used synchrotron techniques to investigate the in-cell behavior of these prodrugs and visualize, for the first time, changes in cellular morphology and Pt localization upon treatment with and without light irradiation. We show that photoactivation of Pt2 induces remarkable cellular damage with extreme alterations to multiple cellular components, including formation of vacuoles, while also significantly increasing the cellular accumulation of Pt species compared to dark conditions. X-ray absorption near-edge structure (XANES) measurements in cells treated with Pt2 indicate only partial reduction of the prodrug upon irradiation, highlighting that phototoxicity in cancer cells may involve not only Pt(II) photoproducts but also photoexcited Pt(IV) species.
Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Pró-Fármacos/farmacologia , Antineoplásicos/química , Antineoplásicos/efeitos da radiação , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/química , Complexos de Coordenação/efeitos da radiação , Humanos , Luz , Células PC-3 , Platina/química , Platina/efeitos da radiação , Pró-Fármacos/química , Pró-Fármacos/efeitos da radiação , Análise de Célula ÚnicaRESUMO
Oxoplatin-B, a platinum(IV) complex [Pt(NH3)2Cl2(L1)(OH)] (1) of 4-methylbenzoic acid (HL1) functionalized with 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) was prepared, characterized and its antitumor activity studied. [Pt(NH3)2Cl2(L2)(OH)] (2) of 4-methylbenzoic acid (HL2) was studied as a control. Complex 1 showed an absorption band at 500 nm (É = 4.34 × 104 M-1 cm-1) and an emission band at 515 nm (λex = 488 nm, ΦF = 0.64) in 1% dimethyl sulfoxide/Dulbecco's Modified Eagle's Medium (pH = 7.2). Visible light-induced (400-700 nm) generation of singlet oxygen was evidenced from 1,3-diphenylisobenzofuran titration study. Complex 1 showed photo-induced cytotoxicity in visible light (400-700 nm, 10 J cm-2) against human breast cancer (MCF-7), cervical cancer (HeLa) and lung cancer (A549) cells (IC50: 1.1-3.8 µM) while being less toxic in normal cells. Confocal imaging showed mitochondrial localization with additional evidence from platinum content from isolated mitochondria and 5,5,6,6'-tetrachloro-1,1',3,3' tetraethylbenzimi-dazoylcarbocyanine iodide (JC-1) assay. Cellular apoptosis was observed from Annexin-V-FITC (fluorescein isothiocyanate)/propidium iodide assay.
Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Mitocôndrias/efeitos dos fármacos , Fármacos Fotossensibilizantes/farmacologia , Pró-Fármacos/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/efeitos da radiação , Apoptose/efeitos dos fármacos , Benzoatos/síntese química , Benzoatos/farmacologia , Benzoatos/efeitos da radiação , Compostos de Boro/síntese química , Compostos de Boro/farmacologia , Compostos de Boro/efeitos da radiação , Bovinos , Linhagem Celular Tumoral , Complexos de Coordenação/síntese química , Complexos de Coordenação/efeitos da radiação , DNA/efeitos dos fármacos , Clivagem do DNA/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Luz , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Fotoquimioterapia , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/efeitos da radiação , Platina/química , Platina/efeitos da radiação , Pró-Fármacos/síntese química , Pró-Fármacos/efeitos da radiação , Oxigênio Singlete/metabolismoRESUMO
The synergistic nanotheranostics of reactive oxygen species (ROS) augment or phototherapy has been a promising method within synergistic oncotherapy. However, it is still hindered by sophisticated design and fabrication, lack of a multimodal synergistic effect, and hypoxia-associated poor photodynamic therapy (PDT) efficacy. Herein, a kind of porous shuttle-shape platinum (IV) methylene blue (Mb) coordination polymer nanotheranostics-loaded 10-hydroxycamptothecin (CPT) is fabricated to address the abovementioned limitations. Our nanoreactors possess spatiotemporally controlled O2 self-supply, self-sufficient singlet oxygen (1O2), and outstanding photothermal effect. Once they are taken up by tumor cells, nanoreactors as a cascade catalyst can efficiently catalyze degradation of the endogenous hydrogen peroxide (H2O2) into O2 to alleviate tumor hypoxia. The production of O2 can ensure enhanced PDT. Subsequently, under both stimuli of external red light irradiation and internal lysosomal acidity, nanoreactors can achieve the on-demand release of CPT to augment in situ mitochondrial ROS and highly efficient tumor ablation via phototherapy. Moreover, under the guidance of near-infrared (NIR) fluorescent imaging, our nanoreactors exhibit strongly synergistic potency for treatment of hypoxic tumors while reducing damages against normal tissues and organs. Collectively, shuttle-shape platinum-coordinated nanoreactors with augmented ROS capacity and enhanced phototherapy efficiency can be regarded as a novel tumor theranostic agent and further promote the research of synergistic oncotherapy.
Assuntos
Antineoplásicos/uso terapêutico , Camptotecina/análogos & derivados , Portadores de Fármacos/química , Nanoestruturas/química , Neoplasias/tratamento farmacológico , Hipóxia Tumoral/efeitos dos fármacos , Animais , Antineoplásicos/química , Camptotecina/química , Camptotecina/uso terapêutico , Catálise/efeitos da radiação , Linhagem Celular Tumoral , Portadores de Fármacos/efeitos da radiação , Liberação Controlada de Fármacos , Feminino , Humanos , Peróxido de Hidrogênio/química , Peróxido de Hidrogênio/metabolismo , Luz , Azul de Metileno/análogos & derivados , Azul de Metileno/efeitos da radiação , Camundongos Endogâmicos BALB C , Nanoestruturas/efeitos da radiação , Neoplasias/metabolismo , Oxigênio/metabolismo , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/uso terapêutico , Terapia Fototérmica , Platina/química , Platina/efeitos da radiação , Polímeros/síntese química , Polímeros/química , Polímeros/efeitos da radiação , Porosidade , Oxigênio Singlete/metabolismo , Nanomedicina TeranósticaRESUMO
We report the first systematic investigation of relativistic effects on the UV-vis spectra of two prototype complexes for so-called photo-activated chemotherapy (PACT), trans-trans-trans-[Pt(N3)2(OH)2(NH3)2] and cis-trans-cis-[Pt(N3)2(OH)2(NH3)2]. In PACT, design of new drugs requires in-depth understanding of the photo-activation mechanisms. A first step is usually to rationalize their UV-vis spectra for which time-dependent density functional theory (TD-DFT) is an indispensable tool. We carried out TD-DFT calculations with a systematic series of non-relativistic (NR), scalar-relativistic (SR), and four-component (4c) Hamiltonians. As expected, large differences are found between spectra calculated within 4c and NR frameworks, while the most intense features (found at higher energies below 300 nm) can be reasonably well reproduced within a SR framework. It is also shown that effective core potentials (ECPs) yield essentially similar results as all-electron SR calculations. Yet the underlying transitions can be strongly influenced by spin-orbit coupling, which is only present in the 4c framework: while this can affect both intense and less intense transitions in the spectra, the effect is most pronounced for weaker transitions at lower energies, above 300 nm. Since the investigated complexes are activated with light of wavelengths above 300 nm, employing a method with explicit inclusion of spin-orbit coupling may be crucial to rationalize the activation mechanism.
Assuntos
Antineoplásicos/química , Complexos de Coordenação/química , Antineoplásicos/efeitos da radiação , Complexos de Coordenação/efeitos da radiação , Teoria da Densidade Funcional , Luz , Modelos Químicos , Platina/química , Platina/efeitos da radiação , Espectrofotometria , EstereoisomerismoRESUMO
Supramolecular coordination is an efficient strategy to construct supramolecular coordination frameworks with predesigned structures, assembled shapes, and specific function. In this work, we report the synthesis, structural characterization, and photophysical property of two tetraphenylethene-based supramolecular coordination frameworks 1a and 1b formed from 1,1,2,2-tetrakis(4-(pyridin-4-yl)phenyl)ethene (2a) or 1,1,2,2-tetrakis(4-((E)-2-(pyridin-4-yl)vinyl)phenyl)ethene (2b) and a linear difunctional platinum(II) ligand (3a) via coordination-driven self-assembly. Controlled by the specific angularity and geometry of tetraphenylethene (with 60° and 120°) and difunctional Pt(II) linker (with 180°), these supramolecular coordination frameworks possess a well-defined and two-dimensional (2D) rhombic network-type topology with good periodicity and porosity. Given the aggregation-induced emission (AIE) property of tetraphenylethene units and the porosity of frameworks, 1a and 1b have been successfully used as fluorescent platforms and energy donors to fabricate efficient artificial light-harvesting materials with two fluorescent acceptors (Nile Red and Sulforhodamine 101) via noncovalent interactions in aqueous solution. Furthermore, these light-harvesting materials have been applied for promoting cancer cell imaging with a full shift of imaging channels from blue/green channels to the red channel. Thus, this study provides an effective approach to fabricate functional frameworks as fluorescent platforms for developing more fluorescent materials.
Assuntos
Compostos de Benzilideno/química , Complexos de Coordenação/química , Corantes Fluorescentes/química , Estruturas Metalorgânicas/química , Compostos de Benzilideno/efeitos da radiação , Complexos de Coordenação/efeitos da radiação , Células HeLa , Humanos , Ligantes , Luz , Estruturas Metalorgânicas/efeitos da radiação , Microscopia Confocal , Microscopia de Fluorescência , Neoplasias/diagnóstico por imagem , Oxazinas/química , Platina/química , Platina/efeitos da radiação , Rodaminas/químicaRESUMO
Liver cancer is a kind of lethal and aggressive malignant neoplasm with a high rate of relapse and metastasis after therapy. An important cause for the relapse and metastasis is the existence of liver cancer stem cells (CSCs), which have high resistance to chemotherapy and high tumorigenic potential. Therefore, it is crucial to develop new methods to eradicate CSCs in tumors. Herein, we develop a photodynamic therapy (PDT) that features bimodal metallacage-loaded nanoparticles (MNPs) for integrated chemotherapy. This platform achieves chemo-photodynamic combinational therapy. Organoplatinum(ii) metallacage-loaded nanoparticles show excellent ability to kill liver CSCs, decreasing their mobility and sphenoid formation ability under near-infrared laser irradiation. Importantly, MNPs can successfully penetrate into 3D tumor spheroids, which display higher drug resistance compared to traditional 2D cultured cells. This destroys CSCs and prevents subsequent tumor formation in vivo. With the excellent combinational therapeutic results in hand, the working mechanisms of MNPs were then studied. MNPs under NIR light irradiation can generate reactive oxygen species (ROS), resulting in damage of mitochondrial membrane and subsequent cell apoptosis with chemotherapeutic platinum. This study proves the great potential of MNPs for combinational cancer therapy, providing a new insight for the next generation of nanomedicines.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Nanopartículas Metálicas/uso terapêutico , Células-Tronco Neoplásicas/efeitos dos fármacos , Fármacos Fotossensibilizantes/uso terapêutico , Animais , Antineoplásicos/química , Antineoplásicos/efeitos da radiação , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Complexos de Coordenação/química , Complexos de Coordenação/efeitos da radiação , Complexos de Coordenação/uso terapêutico , Humanos , Raios Infravermelhos , Fígado/patologia , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Nanopartículas Metálicas/química , Nanopartículas Metálicas/efeitos da radiação , Camundongos Nus , Fotoquimioterapia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/efeitos da radiação , Platina/química , Platina/efeitos da radiação , Porfirinas/química , Porfirinas/efeitos da radiação , Porfirinas/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Esferoides Celulares/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Platinum(ii) complexes, viz. [Pt(L)(cur)] (1), [Pt(L)(py-acac)] (2) and [Pt(L)(an-acac)] (3), where HL is 4,4'-bis-dimethoxyazobenzene, Hcur is curcumin, Hpy-acac and Han-acac are pyrenyl and anthracenyl appended acetylacetone, were prepared, characterized and their anticancer activities were studied. Complex [Pt(L)(acac)] (4) was used as a control. Complex 1 showed an absorption band at 430 nm (ε = 8.8 × 10(4) M(-1) cm(-1)). The anthracenyl and pyrenyl complexes displayed bands near 390 nm (ε = 3.7 × 10(4) for 3 and 4.4 × 10(4) M(-1) cm(-1) for 2). Complex 1 showed an emission band at 525 nm (Φ = 0.017) in 10% DMSO-DPBS (pH, 7.2), while 2 and 3 were blue emissive (λem = 440 and 435, Φ = 0.058 and 0.045). There was an enhancement in emission intensity on glutathione (GSH) addition indicating diketonate release. The platinum(ii) species thus formed acted as a transcription inhibitor. The released ß-diketonate base showed photo-chemotherapeutic activity. The complexes photocleaved plasmid DNA under blue light of 457 nm forming â¼75% nicked circular (NC) DNA with hydroxyl radicals and singlet oxygen as the ROS. Complexes 1-3 were photocytotoxic in skin keratinocyte HaCaT cells giving IC50 of 8-14 µM under visible light (400-700 nm, 10 J cm(-2)), while being non-toxic in the dark (IC50: â¼60 µM). Complex 4 was inactive. Complexes 1-3 generating cellular ROS caused apoptotic cell death under visible light as evidenced from DCFDA and annexin-V/FITC-PI assays. This work presents a novel way to deliver an active platinum(ii) species and a phototoxic ß-diketone species to the cancer cells.
Assuntos
Antineoplásicos/administração & dosagem , Curcumina/administração & dosagem , Platina/administração & dosagem , Antineoplásicos/química , Antineoplásicos/efeitos da radiação , Apoptose/efeitos dos fármacos , Linhagem Celular , Curcumina/química , Curcumina/efeitos da radiação , DNA/efeitos dos fármacos , Clivagem do DNA , Humanos , Luz , Platina/química , Platina/efeitos da radiação , Espécies Reativas de Oxigênio/metabolismoRESUMO
Transition metal compounds are well documented to have diverse applications such as in catalysis, light-emitting materials and therapeutics. In the areas of photocatalysis and photodynamic therapy, metal compounds of heavy transition metals are highly sought after because they can give rise to triplet excited states upon photoexcitation. The long lifetimes (more than 1 µs) of the triplet states of transition metal compounds allow for bimolecular reactions/processes such as energy transfer and/or electron transfer to occur. Reactions of triplet excited states of luminescent metal compounds with oxygen in cells may generate reactive oxygen species and/or induce damage to DNA, leading to cell death. This article recaps the recent findings on photochemical and phototoxic properties of luminescent platinum(II) and gold(III) compounds both from the literature and experimental results from our group.
Assuntos
Dano ao DNA , Ouro/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/fisiopatologia , Fotoquimioterapia/tendências , Fármacos Fotossensibilizantes/uso terapêutico , Platina/uso terapêutico , Catálise/efeitos da radiação , Ouro/química , Ouro/efeitos da radiação , Luz , Platina/química , Platina/efeitos da radiação , Elementos de Transição/química , Elementos de Transição/uso terapêuticoRESUMO
Polypyrrole-encapsulated platinum nanoparticles (PPy/Pt-NPs) prepared by an easy single-step sonochemical synthesis were used as catalysts for the liquid phase hydrogenation of substituted alkenes in methanol or methanol/water mixtures. Polypyrrole (PPy) coatings on the nanoparticles were able to act as nanoscopic filters for substrates molecules, and consequently substrate selectivity could be controlled in the catalytic processes.
Assuntos
Hidrogênio/química , Nanopartículas/química , Nanopartículas/efeitos da radiação , Platina/química , Platina/efeitos da radiação , Polímeros/química , Sonicação/métodos , Hidrogênio/efeitos da radiação , Teste de Materiais , Nanopartículas/ultraestrutura , Polímeros/efeitos da radiaçãoRESUMO
In this work we report on the photo-catalytic performance of phase-pure and iron-doped anatase and rutile nanotubes, produced via a sol-gel process using pristine carbon nanotubes as templates. The encapsulated iron residues can be used to in situ dope the TiO(2) nanotubes without phase separation. The anatase and rutile nanotubes were further impregnated with platinum crystals with a uniform dispersion and an average size of approximately 2 nm. The materials showed dramatically improved activities for the photo-catalytic splitting of water compared to commercial TiO(2) with similar surface area (up to two orders of magnitudes), due to their higher illumination area, extended absorption range and reduced electron-hole recombination rate. The homogeneous dispersion of platinum nanoparticles further increased the hydrogen evolution rate for anatase nanotubes by a factor of seven in comparison to that for the pristine material, thus proving the great potential for commercial applications.
Assuntos
Hidrogênio/química , Ferro/química , Nanotecnologia/métodos , Nanotubos/química , Oxigênio/química , Platina/química , Titânio/química , Água/química , Catálise , Hidrogênio/efeitos da radiação , Luz , Nanotubos/efeitos da radiação , Nanotubos/ultraestrutura , Oxigênio/efeitos da radiação , Fotoquímica/métodos , Platina/efeitos da radiação , Titânio/efeitos da radiação , Raios UltravioletaRESUMO
PURPOSE: In order to study the role of the Linear Energy Transfer (LET) of fast atomic ions in platinum-DNA complexes inducing breaks, DNA Plasmids were irradiated by C(6+) and Fe(26+) ions. MATERIAL AND METHODS: DNA Plasmids (pBR322) loaded with different amounts of platinum contained in a terpyridine-platinum molecule (PtTC) were irradiated by C(6+) ions and Fe(26+) ions. The LET values ranged between 13.4 keV/microm and 550 keV/microm. In some experiments, dimethyl sulfoxide (DMSO) was added. RESULTS: In all experiments, a significant increase in DNA strand breaks was observed when platinum was present. The yield of breaks induced per Gray decreased when the LET increased. The yield of single and double strand breaks per plasmid per track increased with the LET, indicating that the number of DNA breaks per Gray was related to the number of tracks through the medium. CONCLUSIONS: These findings show that more DNA breaks are induced by atomic ions when platinum is present. This effect increases for low LET heavy atoms. As DSB induction may induce cell death, these results could open new perspectives with the association of hadrontherapy and chemotherapy. Thus the therapeutic index might be improved by loading the tumour with platinum salts.
Assuntos
Carbono/química , Adutos de DNA/química , Adutos de DNA/efeitos da radiação , Dano ao DNA/efeitos da radiação , Íons Pesados , Ferro/química , Platina/química , Relação Dose-Resposta à Radiação , Plasmídeos/química , Plasmídeos/efeitos da radiação , Platina/efeitos da radiação , Doses de RadiaçãoRESUMO
Hydrogen production was accomplished under visible-light irradiation by using a system consisting of a biomolecule (chlorophyll a), methylviologen, ethylenediaminetetraacetic acid disodium salt and Pt-loaded poly(l-glutamate) (Poly(Glu)), in aqueous decylammonium chloride (DeAC) solution. Spectroscopic studies revealed that chlorophyll a is solubilized in the hydrophobic clusters of Pt-loaded Poly(Glu)-decylammonium chloride. In the Poly(Glu)-DeAC complex, the electron transfer occurred between chlorophyll a and methylviologen leading to hydrogen production. The most noticeable result is that the rate of hydrogen evolution depends on the change from the random coil to the alpha-helix in conformation of Poly(Glu) induced by the cooperative binding with DeAC.
Assuntos
Hidrogênio/efeitos da radiação , Complexos de Proteínas Captadores de Luz/efeitos da radiação , Luz , Ácido Poliglutâmico/efeitos da radiação , Aminas/química , Dicroísmo Circular , Transporte de Elétrons , Hidrogênio/química , Interações Hidrofóbicas e Hidrofílicas , Complexos de Proteínas Captadores de Luz/química , Fotoquímica , Platina/química , Platina/efeitos da radiação , Ácido Poliglutâmico/química , Estrutura Secundária de Proteína/efeitos da radiação , Sensibilidade e Especificidade , Solubilidade , Soluções/química , Espectrometria de Fluorescência , Fatores de Tempo , Água/químicaRESUMO
This work presents the preparation of radiolabelled cis-dichlorodiammineplatinum (II), CDDP*, sealed in a cadmium capsule. The irradiation of CDDP covered by cadmium, employing exposure times longer than 2 h, demonstrated good chemical purity and high specific activity. This finding allowed a better detection of in vivo CDDP* and suggests that it may be a good tool for studies of long-term biodistribution of pharmaceutical formulations containing this drug.
Assuntos
Antineoplásicos/efeitos da radiação , Cisplatino/efeitos da radiação , Platina/efeitos da radiação , Radioisótopos/química , Animais , Antineoplásicos/farmacocinética , Cádmio/administração & dosagem , Cádmio/química , Cádmio/efeitos da radiação , Carcinoma de Ehrlich/metabolismo , Cisplatino/farmacocinética , Radioisótopos/farmacocinéticaRESUMO
Three photon interaction processes, namely, the photoelectric effect, Compton effect, and pair production, can occur when materials with high atomic numbers are irradiated by the high- and low-energy bremsstrahlung photons from a linear accelerator. A dose enhancement, due to the photoelectric effect and pair production, near targets with platinum implants (with a high atomic number) in radiosurgery cannot be predicted by the XKnife radiosurgery treatment planning system. In the present work, Monte Carlo simulations using PRESTA EGS4 were employed to investigate the resulting dose enhancements from 4, 6, and 10 MV energies commonly used in the stereotactic radiosurgery system. Dose enhancements from 32% to 68% were observed close to the platinum implant for the above energies when using a 12.5 mm collimator. Comparatively higher dose enhancements were observed when using smaller collimators. It was found that this dose enhancement increased with beam energy but decreased as beam size increased.