RESUMO
BACKGROUND: Proper catheter placement for convection-enhanced delivery (CED) is required to maximize tumor coverage and minimize exposure to healthy tissue. We developed an image-based model to patient-specifically optimize the catheter placement for rhenium-186 (186Re)-nanoliposomes (RNL) delivery to treat recurrent glioblastoma (rGBM). METHODS: The model consists of the 1) fluid fields generated via catheter infusion, 2) dynamic transport of RNL, and 3) transforming RNL concentration to the SPECT signal. Patient-specific tissue geometries were assigned from pre-delivery MRIs. Model parameters were personalized with either 1) individual-based calibration with longitudinal SPECT images, or 2) population-based assignment via leave-one-out cross-validation. The concordance correlation coefficient (CCC) was used to quantify the agreement between the predicted and measured SPECT signals. The model was then used to simulate RNL distributions from a range of catheter placements, resulting in a ratio of the cumulative RNL dose outside versus inside the tumor, the "off-target ratio" (OTR). Optimal catheter placement) was identified by minimizing OTR. RESULTS: Fifteen patients with rGBM from a Phase I/II clinical trial (NCT01906385) were recruited to the study. Our model, with either individual-calibrated or population-assigned parameters, achieved high accuracy (CCC > 0.80) for predicting RNL distributions up to 24 h after delivery. The optimal catheter placements identified using this model achieved a median (range) of 34.56 % (14.70 %-61.12 %) reduction on OTR at the 24 h post-delivery in comparison to the original placements. CONCLUSIONS: Our image-guided model achieved high accuracy for predicting patient-specific RNL distributions and indicates value for optimizing catheter placement for CED of radiolabeled liposomes.
Assuntos
Glioblastoma , Rênio , Humanos , Glioblastoma/diagnóstico por imagem , Rênio/uso terapêutico , Neoplasias Encefálicas/diagnóstico por imagem , Nanopartículas/química , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Catéteres , Convecção , Imageamento por Ressonância Magnética/métodos , Masculino , Feminino , Recidiva Local de Neoplasia/diagnóstico por imagem , Pessoa de Meia-Idade , Sistemas de Liberação de Medicamentos/métodos , Lipossomos/químicaRESUMO
Here, we have synthesized and characterized three visible light responsive terpyridine based-Re(I)-tricarbonyl complexes; [Re(CO)3(ph-tpy)Cl] (Retp1), [Re(CO)3(an-tpy)Cl] (Retp2), and [Re(CO)3(py-tpy)Cl] (Retp3) where ph-tpy = 4'-phenyl-2,2':6',2â³-terpyridine; an-tpy = 4'-anthracenyl-2,2':6',2â³-terpyridine, py-tpy = 4'-pyrenyl-2,2':6',2â³-terpyridine. The structures of Retp1 and Retp2 were confirmed from the SC-XRD data, indicating distorted octahedral structures. Unlike traditional PDT agents, these complexes generated reactive oxygen species (ROS) via type I and type II pathways and oxidized redox crucial NADH (reduced nicotinamide adenine dinucleotide) upon visible light exposure. Retp3 showed significant mitochondrial localization and demonstrated photoactivated anticancer activity (IC50 â¼ 2 µM) by inducing ROS-mediated cell death in cancer cells selectively (photocytotoxicity Index, PI > 28) upon compromising mitochondrial function in A549 cells. Their diagnostic capabilities were ultimately assessed using clinically relevant 3D multicellular tumor spheroids (MCTs).
Assuntos
Antineoplásicos , Complexos de Coordenação , NAD , Oxirredução , Piridinas , Espécies Reativas de Oxigênio , Rênio , Humanos , Espécies Reativas de Oxigênio/metabolismo , NAD/química , NAD/metabolismo , Piridinas/química , Piridinas/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Rênio/química , Rênio/farmacologia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/síntese química , Luz , Ensaios de Seleção de Medicamentos Antitumorais , Fotoquimioterapia , Estrutura Molecular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células A549 , Linhagem Celular TumoralRESUMO
Pertechnetate (99TcO4-), a physiologically toxic radioactive anion, is of great concern due to its high mobility in environmental contamination remediation. Although the soluble oxyanion can be photoreduced to sparingly soluble TcO2·nH2O, its effective removal from a strongly acidic aqueous solution remains a challenge. Here, we found that low-crystalline nitrogen-doped titanium oxide (N-TiO2, 0.6 g L-1) could effectively uptake perrhenate (ReO4-, 10 mg L-1, a nonradioactive surrogate for TcO4-) with 50.8% during 360 min under simulated sunlight irradiation at pH 1.0, but P25 and anatase could not. The nitrogen active center formed by trace nitrogen doping in N-TiO2 can promote the separation and transfer of photogenerated carriers. The positive valence band value of N-TiO2 is slightly higher than those of P25 and anatase, which means that the photogenerated holes have a stronger oxidizability. These holes are involved in the formation of strong reducing â¢CO2- radicals from formic acid oxidation. The active radicals convert ReO4- to Re(VI), which is subsequently disproportionated to Re(IV) and Re(VII). Effective photocatalytic reduction/removal of Re(VII)/Tc(VII) is performed on the material, which may be considered a potential and convenient strategy for technetium decontamination and extraction in a strongly acidic aqueous solution.
Assuntos
Titânio , Catálise , Titânio/química , Oxirredução , Rênio/química , Água/química , Concentração de Íons de Hidrogênio , SoluçõesRESUMO
The Re(I) organometallic compounds [(Re(CO)3L1-6 )Cl], where Ligand(L) = Tryptanthrin derivatives were prepared and characterized by various spectroscopic techniques. To assess the binding capacities and binding manner, tests of Calf thymus DNA under the impact of organometallic complexes were conducted using absorption titration and viscosity measuring techniques. Data from the research mentioned above point to an intercalation type of binding, which was verified by the docking study. Swiss ADME tools carried out an ADME study. The work focuses on computing the molecular orbital energies for the synthesized compounds using the density functional theory (DFT). The compounds were tested against the MCF-7 cell line to determine their anticancer effects. It was observed that their IC50 values were equivalent to those of the standard medication, indicating that they had a similar antiproliferative impact.
Assuntos
Antineoplásicos , Rênio , Rênio/química , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Células MCF-7 , Proliferação de Células/efeitos dos fármacos , Compostos Organometálicos/farmacologia , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Simulação de Acoplamento Molecular , DNA/metabolismo , Complexos de Coordenação/farmacologia , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Ensaios de Seleção de Medicamentos Antitumorais , Teoria da Densidade Funcional , Bovinos , Quinazolinonas/síntese química , Quinazolinonas/farmacologia , Quinazolinonas/química , Estrutura Molecular , Animais , Indóis/farmacologia , Indóis/química , Indóis/síntese químicaRESUMO
Benchtop 99Mo/99mTc and 188W/188Re generators enable economical production of molecular theranostic 99mTc and 188Re radiopharmaceuticals, provided that simple, kit-based chemistry exists to radiolabel targeting vectors with these radionuclides. We have previously described a diphosphine platform that efficiently incorporates 99mTc into receptor-targeted peptides. Here, we report its application to label a prostate-specific membrane antigen (PSMA)-targeted peptide with 99mTc and 188Re for diagnostic imaging and systemic radiotherapy of prostate cancer. Methods: Two diphosphine-dipeptide bioconjugates, DP1-PSMAt and DP2-PSMAt, were formulated into kits for radiolabeling with 99mTc and 188Re. The resulting radiotracers were studied in vitro, in prostate cancer cells, and in vivo in mouse xenograft models, to assess similarity of uptake and biodistribution for each 99mTc/188Re pair of agents. Results: Both DP1-PSMAt and DP2-PSMAt could be efficiently radiolabeled with 99mTc and 188Re using kit-based methods to furnish the isostructural compounds M-DP1-PSMAt and M-DP2-PSMAt (M = [99mTc]Tc, [188Re]Re). All 99mTc/188Re radiotracers demonstrated specific uptake in PSMA-expressing prostate cancer cells, with negligible uptake in prostate cancer cells that did not express PSMA or in which PSMA uptake was blocked. M-DP1-PSMAt and M-DP2-PSMAt also exhibited high tumor uptake (18-30 percentage injected dose per gram at 2 h after injection), low retention in nontarget organs, fast blood clearance, and excretion predominantly via a renal pathway. Importantly, each pair of 99mTc/188Re radiotracers showed near-identical biologic behavior in these experiments. Conclusion: We have prepared and developed novel pairs of isostructural PSMA-targeting 99mTc/188Re theranostic agents. These generator-based theranostic agents have potential to provide access to the benefits of PSMA-targeted diagnostic imaging and systemic radiotherapy in health care settings that do not routinely have access to either reactor-produced 177Lu radiopharmaceuticals or PET/CT infrastructure.
Assuntos
Neoplasias da Próstata , Radioisótopos , Rênio , Tecnécio , Masculino , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/radioterapia , Neoplasias da Próstata/metabolismo , Camundongos , Rênio/química , Animais , Humanos , Tecnécio/química , Radioisótopos/química , Linhagem Celular Tumoral , Distribuição Tecidual , Glutamato Carboxipeptidase II/metabolismo , Antígenos de Superfície/metabolismo , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacocinética , Nanomedicina Teranóstica , Peptídeos/química , Medicina de PrecisãoRESUMO
The toxicity profile of fac-[Re(CO)3(N-N)L]+ complexes against microbial and tumoral cells has been extensively studied, primarily focusing on modifications to the bidentate diimine (N-N) ligand. However, less attention has been paid to modifications of the axial ligand L, which is perpendicular to the Re-N-N plane. This study reveals that the high toxicity of the fac-[Re(CO)3(bpy)(Ctz)]+ complex may be attributed to the structural effect of the trityl (CPh3) group present in clotrimazole, as removal of phenyl rings causes a significant decrease in the activity against Staphylococcus aureus (S. aureus). Moreover, substitution of the 1-tritylimidazole ligand by the structurally related ligands PPh3 and PCy3 maintains similarly high activity levels. These findings contribute to understanding the interactions of toxic complexes with bacterial membranes, suggesting that the ligand structures play a crucial role in inhibiting cell wall synthesis processes, potentially including Lipid II synthesis. Compounds with Ph3E (E = C-imidazole; P) groups also showed to be 10 times more toxic than cisplatin against three mammalian cell lines (IC50: 2-4 µM). In contrast, the analogue 1-benzylimidazole and 1-tert-butylimidazole derivatives were as toxic as cisplatin. We observed that the decomposition of the [Re(I)(CO)3] fragment inside mammalian cell lines liberates CO, which is expected to exert biological effects. Therefore, compounds of this family possessing the structural motif Ph3E seem to combine high antimicrobial and antitumoral activities, the latter being much higher than that of cisplatin.
Assuntos
Antineoplásicos , Monóxido de Carbono , Complexos de Coordenação , Testes de Sensibilidade Microbiana , Rênio , Staphylococcus aureus , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Staphylococcus aureus/efeitos dos fármacos , Monóxido de Carbono/química , Monóxido de Carbono/farmacologia , Rênio/química , Rênio/farmacologia , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Linhagem Celular Tumoral , Estrutura Molecular , Ligantes , Ensaios de Seleção de Medicamentos Antitumorais , Sobrevivência Celular/efeitos dos fármacos , Relação Estrutura-Atividade , Proliferação de Células/efeitos dos fármacosRESUMO
A stimuli-responsive drug delivery nanocarrier with a core-shell structure combining photothermal therapy and chemotherapy for killing cancer cells was constructed in this study. The multifunctional nanocarrier ReS2@mSiO2-RhB entails an ReS2 hierarchical nanosphere coated with a fluorescent mesoporous silica shell. The three-dimensional hierarchical ReS2 nanostructure is capable of effectively absorbing near-infrared (NIR) light and converting it into heat. These ReS2 nanospheres were generated by a hydrothermal synthesis process leading to the self-assembly of few-layered ReS2 nanosheets. The mesoporous silica shell was further coated on the surface of the ReS2 nanospheres through a surfactant-templating sol-gel approach to provide accessible mesopores for drug uploading. A fluorescent dye (Rhodamine B) was covalently attached to silica precursors and incorporated during synthesis in the mesoporous silica walls toward conferring imaging capability to the nanocarrier. Doxorubicin (DOX), a known cancer drug, was used in a proof-of-concept study to assess the material's ability to function as a drug delivery carrier. While the silica pores are not capped, the drug molecule loading and release take advantage of the pH-governed electrostatic interactions between the drug and silica wall. The ReS2@mSiO2-RhB enabled a drug loading content as high as 19.83 mg/g doxorubicin. The ReS2@mSiO2-RhB-DOX nanocarrier's cumulative drug release rate at pH values that simulate physiological conditions showed significant pH responsiveness, reaching 59.8% at pH 6.8 and 98.5% and pH 5.5. The in vitro testing using HeLa cervical cancer cells proved that ReS2@mSiO2-RhB-DOX has a strong cancer eradication ability upon irradiation with an NIR laser owing to the combined drug delivery and photothermal effect. The results highlight the potential of ReS2@mSiO2-RhB nanoparticles for combined cancer therapy in the future.
Assuntos
Doxorrubicina , Liberação Controlada de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Teste de Materiais , Nanopartículas , Tamanho da Partícula , Terapia Fototérmica , Rênio , Dióxido de Silício , Dióxido de Silício/química , Humanos , Doxorrubicina/farmacologia , Doxorrubicina/química , Concentração de Íons de Hidrogênio , Nanopartículas/química , Rênio/química , Rênio/farmacologia , Dissulfetos/química , Porosidade , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Materiais Biocompatíveis/síntese química , Sobrevivência Celular/efeitos dos fármacos , Antineoplásicos/química , Antineoplásicos/farmacologia , Portadores de Fármacos/química , Células HeLaRESUMO
Rhenium complexes show great promise as anticancer drug candidates. Specifically, compounds with a Re(CO)3(NN)(py)+ core in their architecture have shown cytotoxicity equal to or greater than that of well-established anticancer drugs based on platinum or organic molecules. This study aimed to evaluate how the strength of the interaction between rhenium(I) tricarbonyl complexes fac-[Re(CO)3(NN)(py)]+, NN = 1,10-phenanthroline (phen), dipyrido[3,2-f:2',3'-h]quinoxaline (dpq) or dipyrido[3,2-a:2'3'-c]phenazine (dppz) and biomolecules (protein, lipid and DNA) impacted the corresponding cytotoxic effect in cells. Results showed that fac-[Re(CO)3(dppz)(py)]+ has higher Log Po/w and binding constant (Kb) with biomolecules (protein, lipid and DNA) compared to complexes of fac-[Re(CO)3(phen)(py)]+ and fac-[Re(CO)3(dpq)(py)]+. As consequence, fac-[Re(CO)3(dppz)(py)]+ exhibited the highest cytotoxicity (IC50 = 8.5 µM for HeLa cells) for fac-[Re(CO)3(dppz)(py)]+ among the studied compounds (IC50 > 15 µM). This highest cytotoxicity of fac-[Re(CO)3(dppz)(py)]+ are probably related to its lipophilicity, higher permeation of the lipid bilayers of cells, and a more potent interaction of the dppz ligand with biomolecules (protein and DNA). Our findings open novel avenues for rational drug design and highlight the importance of considering the chemical structures of rhenium complexes that strongly interact with biomolecules (proteins, lipids, and DNA).
Assuntos
Antineoplásicos , Complexos de Coordenação , DNA , Rênio , Rênio/química , Humanos , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/química , DNA/química , DNA/metabolismo , Fenantrolinas/química , Fenantrolinas/farmacologia , Quinoxalinas/química , Quinoxalinas/farmacologia , Fenazinas/química , Fenazinas/farmacologia , Linhagem Celular Tumoral , Células HeLaRESUMO
The hypoxic microenvironment of solid tumors severely lowers the efficacy of oxygen-dependent photodynamic therapy (PDT). The development of hypoxia-tolerant photosensitizers for PDT is an urgent requirement. In this study, a novel rhenium complex (Re-TTPY) to develop a "closed-loop" therapy based on PDT-induced ferroptosis and immune therapy is reported. Due to its electron donor-acceptor (D-A) structure, Re-TTPY undergoes energy transfer and electron transfer processes under 550 nm light irradiation and displays hypoxia-tolerant type I/II combined PDT capability, which can generate 1O2, O2 -, and ·OH simultaneously. Further, the reactive oxygen species (ROSs) leads to the depletion of 1,4-dihydronicotinamide adenine dinucleotide (NADH), glutathione peroxidase 4 (GPX4), and glutathione (GSH). As a result, ferroptosis occurs in cells, simultaneously triggers immunogenic cell death (ICD), and promotes the maturation of dendritic cells (DCs) and infiltration of T cells. The release of interferon-γ (IFN-γ) by CD8+ T cells downregulates the expression of GPX4, further enhancing the occurrence of ferroptosis, and thereby, forming a mutually reinforcing "closed-loop" therapeutic approach.
Assuntos
Ferroptose , Imunoterapia , Fotoquimioterapia , Fármacos Fotossensibilizantes , Rênio , Ferroptose/efeitos dos fármacos , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Animais , Camundongos , Humanos , Imunoterapia/métodos , Fotoquimioterapia/métodos , Rênio/química , Rênio/farmacologia , Linhagem Celular Tumoral , Espécies Reativas de Oxigênio/metabolismo , Células Dendríticas/metabolismo , Células Dendríticas/efeitos dos fármacos , Feminino , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Camundongos Endogâmicos C57BLRESUMO
Metal-based complexes with their unique chemical properties, including multiple oxidation states, radio-nuclear capabilities and various coordination geometries yield value as potential pharmaceuticals. Understanding the interactions between metals and biological systems will prove key for site-specific coordination of new metal-based lead compounds. This study merges the concepts of target coordination with fragment-based drug methodologies, supported by varying the anomalous scattering of rhenium along with infrared spectroscopy, and has identified rhenium metal sites bound covalently with two amino acid types within the model protein. A time-based series of lysozyme-rhenium-imidazole (HEWL-Re-Imi) crystals was analysed systematically over a span of 38 weeks. The main rhenium covalent coordination is observed at His15, Asp101 and Asp119. Weak (i.e. noncovalent) interactions are observed at other aspartic, asparagine, proline, tyrosine and tryptophan side chains. Detailed bond distance comparisons, including precision estimates, are reported, utilizing the diffraction precision index supplemented with small-molecule data from the Cambridge Structural Database. Key findings include changes in the protein structure induced at the rhenium metal binding site, not observed in similar metal-free structures. The binding sites are typically found along the solvent-channel-accessible protein surface. The three primary covalent metal binding sites are consistent throughout the time series, whereas binding to neighbouring amino acid residues changes through the time series. Co-crystallization was used, consistently yielding crystals four days after setup. After crystal formation, soaking of the compound into the crystal over 38 weeks is continued and explains these structural adjustments. It is the covalent bond stability at the three sites, their proximity to the solvent channel and the movement of residues to accommodate the metal that are important, and may prove useful for future radiopharmaceutical development including target modification.
Assuntos
Muramidase , Compostos Organometálicos , Rênio , Rênio/química , Muramidase/química , Muramidase/metabolismo , Compostos Organometálicos/química , Compostos Organometálicos/metabolismo , Desenvolvimento de Medicamentos/métodos , Cristalografia por Raios X , Sítios de Ligação , Complexos de Coordenação/química , Imidazóis/química , Imidazóis/metabolismo , Modelos MolecularesRESUMO
Rhenium(I) tricarbonyl complexes are widely studied for their cell imaging properties and anti-cancer and anti-microbial activities, but the complexes with S-donor ligands remain relatively unexplored. A series of six fac-[Re(NN)(CO)3(SR)] complexes, where (NN) is 2,2'-bipyridyl (bipy) or 1,10-phenanthroline (phen), and RSH is a series of thiocarboxylic acid methyl esters, have been synthesized and characterized. Cellular uptake and anti-proliferative activities of these complexes in human breast cancer cell lines (MDA-MB-231 and MCF-7) were generally lower than those of the previously described fac-[Re(NN)(CO)3(OH2)]+ complexes; however, one of the complexes, fac-[Re(CO)3(phen)(SC(Ph)CH2C(O)OMe)] (3b), was active (IC50 â¼ 10 µM at 72 h treatment) in thiol-depleted MDA-MB-231 cells. Moreover, unlike fac-[Re(CO)3(phen)(OH2)]+, this complex did not lose activity in the presence of extracellular glutathione. Taken together these properties show promise for further development of 3b and its analogues as potential anti-cancer drugs for co-treatment with thiol-depleting agents. Conversely, the stable and non-toxic complex, fac-[Re(bipy)(CO)3(SC(Me)C(O)OMe)] (1a), predominantly localized in the lysosomes of MDA-MB-231 cells, as shown by live cell confocal microscopy (λex = 405 nm, λem = 470-570 nm). It is strongly localized in a subset of lysosomes (25 µM Re, 4 h treatment), as shown by co-localization with a Lysotracker dye. Longer treatment times with 1a (25 µM Re for 48 h) resulted in partial migration of the probe into the mitochondria, as shown by co-localization with a Mitotracker dye. These properties make complex 1a an attractive target for further development as an organelle probe for multimodal imaging, including phosphorescence, carbonyl tag for vibrational spectroscopy, and Re tag for X-ray fluorescence microscopy.
Assuntos
Antineoplásicos , Proliferação de Células , Complexos de Coordenação , Rênio , Enxofre , Humanos , Rênio/química , Rênio/farmacologia , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Ligantes , Enxofre/química , Enxofre/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Estrutura MolecularRESUMO
Analogous to thermal ablation techniques in clinical settings, cell necrosis induced during tumor photothermal therapy (PTT) can provoke an inflammatory response that is detrimental to the treatment of tumors. In this study, we employed a straightforward one-step liquid-phase reduction process to synthesize uniform RhRe nanozymes with an average hydrodynamic size of 41.7 nm for non-inflammatory photothermal therapy. The obtained RhRe nanozymes showed efficient near-infrared (NIR) light absorption for effective PTT, coupled with a remarkable capability to scavenge reactive oxygen species (ROS) for anti-inflammatory treatment. After laser irradiation, the 4T1 tumors were effectively ablated without obvious tumor recurrence within 14 days, along with no obvious increase in pro-inflammatory cytokine levels. Notably, these RhRe nanozymes demonstrated high biocompatibility with normal cells and tissues, both in vitro and in vivo, as evidenced by the lack of significant toxicity in female BALB/c mice treated with 10 mg/kg of RhRe nanozymes over a 14 day period. This research highlights RhRe alloy nanoparticles as bioactive nanozymes for non-inflammatory PTT in tumor therapy.
Assuntos
Ligas , Camundongos Endogâmicos BALB C , Terapia Fototérmica , Rênio , Ródio , Animais , Ródio/química , Ródio/farmacologia , Camundongos , Ligas/química , Ligas/farmacologia , Feminino , Rênio/química , Rênio/farmacologia , Linhagem Celular Tumoral , Humanos , Espécies Reativas de Oxigênio/metabolismoRESUMO
Cancer is one of the deadliest diseases worldwide. Chemotherapy remains one of the most dominant forms for anticancer treatment. Despite their clinical success, the used chemotherapeutic agents are associated with severe side effect and pharmacological limitations. To overcome these drawbacks there is a need for the development of new types of chemotherapeutic agents. Herein, the chemical synthesis and biological evaluation of dinuclear rhenium(I) complexes as potential chemotherapeutic drug candidates are proposed. The metal complexes were found to be internalized by an energy dependent endocytosis pathway, primary accumulating in the mitochondria. The rhenium(I) complexes demonstrated to induce cell death against a variety of cancer cells in the micromolar range through apoptosis. The lead compound showed to eradicate a pancreatic carcinoma multicellular tumor spheroid at micromolar concentrations.
Assuntos
Antineoplásicos , Apoptose , Complexos de Coordenação , Rênio , Rênio/química , Humanos , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Proliferação de Células/efeitos dos fármacosRESUMO
Herein, we have compared the effectivity of light-based photoactivated cancer therapy and ultrasound-based sonodynamic therapy with Re(I)-tricarbonyl complexes (Re1-Re3) against cancer cells. The observed photophysical and TD-DFT calculations indicated the potential of Re1-Re3 to act as good anticancer agents under visible light/ultrasound exposure. Re1 did not display any dark- or light- or ultrasound-triggered anticancer activity. However, Re2 and Re3 displayed concentration-dependent anticancer activity upon light and ultrasound exposure. Interestingly, Re3 produced 1O2 and OH⢠on light/ultrasound exposure. Moreover, Re3 induced NADH photo-oxidation in PBS and produced H2O2. To the best of our knowledge, NADH photo-oxidation has been achieved here with the Re(I) complex for the first time in PBS. Additionally, Re3 released CO upon light/ultrasound exposure. The cell death mechanism revealed that Re3 produced an apoptotic cell death response in HeLa cells via ROS generation. Interestingly, Re3 showed slightly better anticancer activity under light exposure compared to ultrasound exposure.
Assuntos
Antineoplásicos , Fenantrolinas , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Ligantes , Células HeLa , Fenantrolinas/química , Fenantrolinas/farmacologia , Rênio/química , Rênio/farmacologia , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Complexos de Coordenação/efeitos da radiação , Apoptose/efeitos dos fármacos , Luz , Espécies Reativas de Oxigênio/metabolismo , Terapia por Ultrassom , Fotoquimioterapia , Ensaios de Seleção de Medicamentos Antitumorais , Neoplasias/tratamento farmacológicoRESUMO
A series of rhenium(I) complexes of the type fac-[Re(CO)3(N^N)L]0/+, Re1-Re9, was synthesized, where N^N = benzimidazole-derived bidentate ligand with an ester functionality and L = chloride or pyridine-type ligand. The new compounds demonstrated potent activity toward ovarian A2780 cancer cells. The most active complexes, Re7-Re9, incorporating 4-NMe2py, exhibited remarkable activity in 3D HeLa spheroids. The emission in the red region of Re9, which contains an electron-deficient benzothiazole moiety, allowed its operability as a bioimaging tool for in vitro and in vivo visualization. Re9 effectivity was tested in two different C. elegans tumoral strains, JK1466 and MT2124, to broaden the oncogenic pathways studied. The results showed that Re9 was able to reduce the tumor growth in both strains by increasing the ROS production inside the cells. Moreover, the selectivity of the compound toward cancerous cells was remarkable as it did not affect neither the development nor the progeny of the nematodes.
Assuntos
Antineoplásicos , Caenorhabditis elegans , Complexos de Coordenação , Rênio , Animais , Caenorhabditis elegans/efeitos dos fármacos , Rênio/química , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Antineoplásicos/uso terapêutico , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Complexos de Coordenação/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Linhagem Celular Tumoral , Nanomedicina Teranóstica , Ensaios de Seleção de Medicamentos Antitumorais , Proliferação de Células/efeitos dos fármacosRESUMO
The use of radiopharmaceuticals has gained a special place in the diagnosis and treatment of cancers and evaluation of the function of different organs of the body. In this study, the absorbed dose distribution of organs after injection of 188Re-Mu-9 has been investigated using MIRD method and MCNP-4C simulation code. The 188Re-Mu-9 labeled was injected the mouse body and the amount of 188Re-labeled accumulation was evaluated after 1, 4 and 2 4 h. Having a map of the distribution of radiopharmaceutical activity in the animal body, it is possible to convert it into a human model to obtain the internal dose received by 188Re-Mu-9 injection using the MIRD calculation method and the MCNP simulation code. According to the results of the study, the animal/human model can be acceptable method for dose estimation of antibody-based radiopharmaceuticals.
Assuntos
Compostos Radiofarmacêuticos , Rênio , Humanos , Camundongos , Animais , Compostos Radiofarmacêuticos/uso terapêutico , Radioisótopos , Rênio/uso terapêutico , Radiometria/métodosRESUMO
BACKGROUND/AIM: Rhenium(I)-diselenoether (Re-diSe) is a promising anticancer agent composed of one rhenium and two selenium atoms. Its effectiveness was established in inhibiting cancer cells while maintaining low toxicity toward normal cells at a 5 µM dose for 120 hours in MDA-MB-231 cells. In MDA-MB-231 breast tumor-bearing mice, anti-tumor and anti-metastatic effects were observed at a 10 mg/kg dose. However, contradictory results were observed in the 4T1 breast cancer model, where a dose of 60 mg/kg had a pro-tumor effect. To address these discrepancies, the efficacy of Re-diSe at the effective 10 mg/kg dose was validated in a transplanted MDA-MB-231 breast tumor model using the chicken chorioallantoic membrane assay. MATERIALS AND METHODS: MDA-MB-231 cancer cells were xenografted onto the chicken chorioallantoic membrane (CAM), and daily drug administration was carried out for nine days at doses of 0.1, 1, and 10 mg/kg. At the study's conclusion, a standard histological analysis was conducted. RESULTS: The low dose of 0.1 mg/kg showed a significant reduction in tumor weights compared to controls. The 1 mg/kg dose resulted in an increased inflammation score but did not induce a significant difference in tumor weights compared to the 0.1 mg/kg dose. Notably, at the 10 mg/kg dose, six out of 11 treated embryos displayed no visible signs of tumors. These tumors exhibited extensive tumor necrosis and significant infiltration by inflammatory cells. CONCLUSION: In this particular model, the anticancer efficacy of Re-diSe was achieved at the low dose of 0.1 mg/kg. The higher dose of 10 mg/kg, while eliminating visible tumors, might have immune-mediated effects, as indicated by substantial tumor necrosis and infiltration by inflammatory cells. Overall, this study successfully demonstrated the effectiveness of Re-diSe as an anticancer agent.
Assuntos
Antineoplásicos , Neoplasias da Mama , Neoplasias Mamárias Animais , Rênio , Neoplasias de Mama Triplo Negativas , Humanos , Embrião de Galinha , Animais , Camundongos , Feminino , Galinhas , Rênio/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias Mamárias Animais/tratamento farmacológico , Necrose , Linhagem Celular Tumoral , Neoplasias da Mama/tratamento farmacológico , Proliferação de CélulasRESUMO
The main goal of this work was to elucidate the potential relevance of (radio)metal chelates of 99mTc and Re targeting G-quadruplex structures for the design of new tools for cancer theranostics. 99mTc provides the complexes with the ability to perform single-photon-emission computed tomography imaging studies, while the Re complexes should act as anticancer agents upon interaction with specific G4 DNA or RNA structures present in tumor tissues. Towards this goal, we have developed isostructural 99mTc(I) and Re(I) tricarbonyl complexes anchored by a pyrazolyl-diamine (Pz) chelator carrying a pendant pyridostatin (PDS) fragment as the G4-binding motif. The interaction of the PDF-Pz-Re (8) complex with different G4-forming oligonucleotides was studied by circular dichroism, fluorescence spectroscopy and FRET-melting assays. The results showed that the Re complex retained the ability to bind and stabilize G4-structures from different DNA or RNA sequences, namely those present on the SRC proto-oncogene and telomeric RNA (TERRA sequence). PDF-Pz-Re (8) showed low to moderate cytotoxicity in PC3 and MCF-7 cancer cell lines, as typically observed for G4-binders. Biodistribution studies of the congener PDF-Pz-99mTc (12) in normal mice showed that the complex undergoes a fast blood clearance with a predominant hepatobiliary excretion, pointing also for a high inâ vitro stability.
Assuntos
Aminoquinolinas , Quadruplex G , Neoplasias , Ácidos Picolínicos , Rênio , Camundongos , Animais , Tecnécio/química , Distribuição Tecidual , DNA/química , Quelantes/química , Tomografia Computadorizada de Emissão de Fóton Único , RNA , Rênio/química , Compostos Radiofarmacêuticos/químicaRESUMO
In an effort to develop new potent anticancer agents, two Schiff base rhenium(I) tricarbonyl complexes, containing the ubiquitous aminoquinoline scaffold, were synthesized. Both aminoquinoline ligands and Re(I) complexes showed adequate stability over a 48-h incubation period. Furthermore, the cytotoxic activity of the precursor ligands and rhenium(I) complexes were evaluated against the hormone-dependent MCF-7 and hormone-independent triple negative MDA-MB-231 breast cancer cell lines. Inclusion of the [Re(CO)3Cl]+ entity significantly enhanced the cytotoxicity of the aminoquinoline Schiff base ligands against the tested cancer cell lines. Remarkably, the incorporation of the Schiff-base iminoquinolyl entity notably enhanced the cytotoxic activity of the Re(I) complexes, in comparison with the iminopyridyl entity. Notably, the quinolyl-substituted complex showed up to three-fold higher activity than cisplatin against breast cancer cell lines, underpinning the significance of the quinoline pharmacophore in rational drug design. In addition, the most active Re(I) complex showed better selectivity towards the breast cancer cells over non-tumorigenic FG-0 cells. Western blotting revealed that the complexes increased levels of γH2AX, a key DNA damage response protein. Moreover, apoptosis was confirmed in both cell lines due to the detection of cleaved PARP. The complexes show favourable binding affinities towards both calf thymus DNA (CT-DNA), and bovine serum albumin (BSA), and the order of their interactions align with their cytotoxic effects. The in silico molecular simulations of the complexes were also performed with CT-DNA and BSA targets.