Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 140
Filtrar
1.
Dalton Trans ; 50(44): 16254-16264, 2021 Nov 16.
Artículo en Inglés | MEDLINE | ID: mdl-34730147

RESUMEN

This study reports the synthesis, structural characterization and cytotoxic activity of four new palladium/pyridylporphyrin complexes, with the general formula {TPyP[PdCl(P-P)]4}(PF6)4, where P-P is 1,2-bis(diphenylphosphino)ethane (dppe), 1,3-bis(diphenylphosphino)propane (dppp), 1,2-bis(diphenylphosphino)butane (dppb) or 1,1'-bis(diphenylphosphino)ferrocene (dppf). The complexes were characterized by elemental analysis, and by FT-IR, UV/Vis, 1H and 31P{1H} NMR (1D/2D) spectroscopy. The slow evaporation of a methanolic solution of {TPyP[PdCl(dppb)]4}(PF6)4 (in an excess of NaBF4 salt) resulted in single crystals suitable for X ray diffraction, allowing the determination of the tridimensional structure of this complex, which crystallized in the P21/a space group. The cytotoxicity of the complexes against MDA-MB-231 (breast cancer cells) and MCF-10A (non-tumor breast cancer cells), was determined by the colorimetric MTT method, which revealed that all four complexes show selective indexes close to 1.2, lower than that of cisplatin for the same cells (12.12). The interaction of the complexes with CT-DNA was evaluated by UV-visible and viscosity measurements and it was determined that the complexes interact moderately with CT-DNA, probably by H-bonding/π-π stacking and electrostatic interactions.


Asunto(s)
Antineoplásicos , Complejos de Coordinación , Paladio , Porfirinas , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Línea Celular , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Complejos de Coordinación/administración & dosificación , Complejos de Coordinación/química , ADN/química , Humanos , Paladio/administración & dosificación , Paladio/química , Porfirinas/administración & dosificación , Porfirinas/química , Viscosidad
2.
Dalton Trans ; 50(44): 16273-16280, 2021 Nov 16.
Artículo en Inglés | MEDLINE | ID: mdl-34730150

RESUMEN

With the aim of gaining new insight into the underlying apoptosis mechanisms and in vivo efficacy of cyclometalated Ir(III) complexes as metalodrugs, six new cyclometalated Ir(III)-quinoline complexes, [Ir(1a)(2pq)2] (2a), [Ir(1b)(2pq)2] (2b), [Ir(1c)(2pq)2] (2c), [Ir(1d)(2pq)2] (2d), [Ir(1e)(2pq)2] (2e), and [Ir(1f)(2pq)2] (2f) (2pq = 2-phenylisoquinoline), have been synthesized using 5,7-dihalo-8-hydroxylquinoline ligands (1a-1f) and [Ir(2pq)2Cl]2 precursors and characterized. Complexes 2a-2f have shown potent anticancer activity against cisplatin-resistant SK-OV-3/DDP and A549/DDP cells (IC50 = 0.11-1.83 µM), following the order 2e > 2f > 2b > 2c > 2d > 2a. Confocal microscopy images suggest that 2e and 2b could act as red-color probes for specific cell imaging and efficiently initiate apoptosis and autophagy in the mitochondria, cell cytosol, and nucleus. Overexpression of beclin1, caspase-9, cytochrome c, LC3II, and apaf-1; inhibition of p62, cyclin D1, cyclin A2, and CDK2; and a substantial rapid accumulation suggest a paraptotic mode of cell death induced by autophagy, DNA damage, and mitochondrial stress. In addition, the inhibitory rate of 2e on A549/DDP tumor growth was 64.1% at a concentration of 10.0 mg kg-1, which is clearly higher than that of cisplatin. According to the biological assay, the cyclometalated Ir(III)-quinoline complex 2e exhibited a higher anticancer effect than 2b, which may be associated with the electronic effect of the methyl group of the 1e ligand of 2e playing a key role in the mechanism.


Asunto(s)
Antineoplásicos , Complejos de Coordinación , Iridio , Quinolinas , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Calcio/metabolismo , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Complejos de Coordinación/administración & dosificación , Complejos de Coordinación/química , Daño del ADN , Iridio/administración & dosificación , Iridio/química , Ligandos , Ratones Desnudos , Mitocondrias/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , Quinolinas/administración & dosificación , Quinolinas/química , Especies Reactivas de Oxígeno/metabolismo
3.
Dalton Trans ; 50(44): 16311-16325, 2021 Nov 16.
Artículo en Inglés | MEDLINE | ID: mdl-34730582

RESUMEN

Six different acylthiourea ligands (L1-L6) and their corresponding Ru(II)-p-cymene complexes (P1-P6) were designed to explore the structure-activity relationship of the complexes upon aliphatic chain and aromatic conjugation on the C- and N-terminals, respectively. The compounds were synthesized and adequately characterized using various analytical and spectroscopic techniques. The structures of P2-P6, solved using single crystal X-ray diffraction (XRD), confirmed the neutral monodentate coordination of the S atoms of the acylthiourea ligands to Ru(II) ions. In silico studies showed an increase of lipophilicity for the ligands with an increase in alkyl chain length or aromatic conjugation at the C- or N-terminal, respectively. Subsequently, mitogen-activated protein kinases (MAPK) were predicted as one of the primary targets for the complexes, which showed good binding affinity towards extracellular signal-regulated kinases (ERK1, ERK2 and ERK5), c-Jun N-terminal kinase (JNK) and p38 of the MAPK pathway. Henceforth, the complexes were tested for their anticancer activity in lung carcinoma (A549) and cisplatin-resistant lung carcinoma (cisA549R) cells and human umbilical vein epithelial normal cells (HUVEC). Interestingly, an increase in chain length or aromatic conjugation led to an increase in the activity of the complexes, with P5 (7.73 and 13.04 µM) and P6 (6.52 and 14.45 µM) showing the highest activity in A549 and cisA549R cells, which is better than the positive control, cisplatin (8.72 and 44.28 µM). Remarkably, we report the highest activity yet observed for complexes of the type [(η6-p-cymene)RuIICl2(S-acylthiourea)] in the tested cell lines. Aqueous solution studies showed that complexes P5 and P6 are rapidly hydrolyzed to produce solely aquated species that remained stable for 24 h. Staining assays and flow cytometric analyses of P5 and P6 in A549 cells revealed that the complexes induced apoptosis and arrested the cell cycle predominantly in the S phase. In vivo studies demonstrated the higher toxicity of cisplatin and a comparatively higher survival rate of mice injected with the most active complex P6. Histological analyses revealed that treatment with P6 at high doses of up to 8 mg kg-1 did not cause any palpable damage to the tested organs.


Asunto(s)
Antineoplásicos , Complejos de Coordinación , Cimenos , Rutenio , Tioamidas , Tiourea , Células A549 , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Antineoplásicos/farmacocinética , Apoptosis/efectos de los fármacos , Disponibilidad Biológica , Supervivencia Celular/efectos de los fármacos , Complejos de Coordinación/administración & dosificación , Complejos de Coordinación/química , Complejos de Coordinación/farmacocinética , Cimenos/administración & dosificación , Cimenos/química , Cimenos/farmacocinética , Femenino , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Humanos , Absorción Intestinal , Ligandos , Masculino , Ratones Endogámicos ICR , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Simulación del Acoplamiento Molecular , Rutenio/administración & dosificación , Rutenio/química , Rutenio/farmacocinética , Tioamidas/administración & dosificación , Tioamidas/química , Tioamidas/farmacocinética , Tiourea/administración & dosificación , Tiourea/química , Tiourea/farmacocinética
4.
Dalton Trans ; 50(44): 16053-16066, 2021 Nov 16.
Artículo en Inglés | MEDLINE | ID: mdl-34617075

RESUMEN

α-N-Heterocyclic thiosemicarbazones such as triapine and COTI-2 are currently investigated as anticancer therapeutics in clinical trials. However, triapine was widely inactive against solid tumor types. A likely explanation is the short plasma half-life time and fast metabolism. One promising approach to overcome these drawbacks is the encapsulation of the drug into nanoparticles (passive drug-targeting). In a previous work we showed that it was not possible to stably encapsulate free triapine into liposomes. Hence, in this manuscript we present the successful preparation of liposomal formulations of the copper(II) complexes of triapine and COTI-2. To this end, various drug-loading strategies were examined and the resulting liposomes were physico-chemically characterized. Especially for liposomal Cu-triapine, a decent encapsulation efficacy and a slow drug release behavior could be observed. In contrast, for COTI-2 and its copper(II) complex no stable loading could be achieved. Subsequent in vitro studies in different cell lines with liposomal Cu-triapine showed the expected strongly reduced cytotoxicity and DNA damage induction. Also in vivo distinctly higher copper plasma levels and a continuous release could be observed for the liposomal formulation compared to free Cu-triapine. Taken together, the here presented nanoformulation of Cu-triapine is an important step further to increase the plasma half-life time and tumor targeting properties of anticancer thiosemicarbazones.


Asunto(s)
Antineoplásicos , Complejos de Coordinación , Cobre , Tiosemicarbazonas , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Complejos de Coordinación/administración & dosificación , Complejos de Coordinación/química , Complejos de Coordinación/farmacocinética , Cobre/administración & dosificación , Cobre/química , Cobre/farmacocinética , Liberación de Fármacos , Femenino , Humanos , Liposomas , Metahemoglobina/metabolismo , Ratones Endogámicos BALB C , Tiosemicarbazonas/administración & dosificación , Tiosemicarbazonas/química , Tiosemicarbazonas/farmacocinética
5.
Chemotherapy ; 66(4): 113-123, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34515066

RESUMEN

BACKGROUND: Whether topotecan plus platinum-based chemotherapy (TP) can achieve better results than etoposide plus platinum-based chemotherapy (EP) for small-cell lung cancer (SCLC) treatment is still controversial in clinical applications. We compared the effectiveness and toxicity of TP versus EP in this meta-analysis. METHODS: We searched PubMed, ScienceDirect, Cochrane Library, Scopus, Ovid MEDLINE, Embase, Web of Science, and Google Scholar databases for completeness one by one to find articles that met the conditions. Overall survival (OS) and progression-free survival (PFS) were analyzed as primary endpoints, and the objective response rate (ORR), disease control rate (DCR), and adverse events (AEs) were analyzed as secondary endpoints. RESULTS: In total, 2,480 articles were retrieved, and 6 randomized controlled trials (RCTs) contained results based on 1,924 patients. EP suggested conspicuously better OS (hazard ratio [HR]: 1.24 [1.02, 1.50], p = 0.03) and PFS (HR: 1.39 [1.17, 1.64], p = 0.0001) in SCLC treatment than TP, and ORR (54.1% vs. 60.2%, risk ratio [RR]: 0.77 [0.57, 1.06], p = 0.11), and DCR (74.9% vs. 84.4%, RR: 0.89 [0.79, 1.00], p = 0.06) tended to favor EP. Subgroup analysis of subsistence showed that EP had prominent benefit in the following subgroups: Asian, median age > 60, first-line treatment, ECOG 0-2, intravenous topotecan, and cisplatin. AEs illustrated that EP had conspicuously more anemia and alopecia than TP. CONCLUSIONS: Compared with TP, EP was noticeably better in OS and PFS, but EP was toxic in terms of anemia and alopecia. More multicenter, better planned RCTs are needed.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Etopósido/administración & dosificación , Neoplasias Pulmonares/tratamiento farmacológico , Platino (Metal)/química , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Topotecan/administración & dosificación , Complejos de Coordinación/administración & dosificación , Humanos , Neoplasias Pulmonares/mortalidad , Ensayos Clínicos Controlados Aleatorios como Asunto , Carcinoma Pulmonar de Células Pequeñas/mortalidad , Resultado del Tratamiento
6.
Molecules ; 26(11)2021 May 25.
Artículo en Inglés | MEDLINE | ID: mdl-34070457

RESUMEN

Cisplatin and derivatives are highly effective in the treatment of a wide range of cancer types; however, these metallodrugs display low selectivity, leading to severe side effects. Additionally, their administration often results in the development of chemoresistance, which ultimately results in therapeutic failure. This scenario triggered the study of other transition metals with innovative pharmacological profiles as alternatives to platinum, ruthenium- (e.g., KP1339 and NAMI-A) and gold-based (e.g., Auranofin) complexes being among the most advanced in terms of clinical evaluation. Concerning the importance of improving the in vivo selectivity of metal complexes and the current relevance of ruthenium and gold metals, this review article aims to survey the main research efforts made in the past few years toward the design and biological evaluation of target-specific ruthenium and gold complexes. Herein, we give an overview of the inorganic and organometallic molecules conjugated to different biomolecules for targeting membrane proteins, namely cell adhesion molecules, G-protein coupled receptors, and growth factor receptors. Complexes that recognize the progesterone receptors or other targets involved in metabolic pathways such as glucose transporters are discussed as well. Finally, we describe some complexes aimed at recognizing cell organelles or compartments, mitochondria being the most explored. The few complexes addressing targeted gene therapy are also presented and discussed.


Asunto(s)
Antineoplásicos/farmacología , Complejos de Coordinación/farmacología , Compuestos de Oro/farmacología , Compuestos de Rutenio/farmacología , Antineoplásicos/administración & dosificación , Moléculas de Adhesión Celular/efectos de los fármacos , Línea Celular Tumoral , Complejos de Coordinación/administración & dosificación , Compuestos de Oro/administración & dosificación , Humanos , Receptores Acoplados a Proteínas G/efectos de los fármacos , Receptores de Factores de Crecimiento/efectos de los fármacos , Compuestos de Rutenio/administración & dosificación
7.
Nat Commun ; 12(1): 3393, 2021 06 07.
Artículo en Inglés | MEDLINE | ID: mdl-34099712

RESUMEN

The iron gall ink-triggered chemical corrosion of hand-written documents is a big threat to Western cultural heritages, which was demonstrated to result from the iron gall (GA-Fe) chelate-promoted reactive oxygen species generation. Such a phenomenon has inspired us to apply the pro-oxidative mechanism of GA-Fe to anticancer therapy. In this work, we construct a composite cancer nanomedicine by loading gallate into a Fe-engineered mesoporous silica nanocarrier, which can degrade in acidic tumor to release the doped Fe3+ and the loaded gallate, forming GA-Fe nanocomplex in situ. The nanocomplex with a highly reductive ligand field can promote oxygen reduction reactions generating hydrogen peroxide. Moreover, the resultant two-electron oxidation form of GA-Fe is an excellent Fenton-like agent that can catalyze hydrogen peroxide decomposition into hydroxyl radical, finally triggering severe oxidative damage to tumors. Such a therapeutic approach by intratumoral synthesis of GA-Fe nano-metalchelate may be instructive to future anticancer researches.


Asunto(s)
Antineoplásicos/administración & dosificación , Ácido Gálico/administración & dosificación , Hierro/administración & dosificación , Nanopartículas del Metal/administración & dosificación , Neoplasias/tratamiento farmacológico , Animales , Antineoplásicos/química , Antineoplásicos/metabolismo , Catálisis , Complejos de Coordinación/administración & dosificación , Complejos de Coordinación/química , Complejos de Coordinación/metabolismo , Portadores de Fármacos/química , Femenino , Ácido Gálico/química , Ácido Gálico/metabolismo , Células HeLa , Células Endoteliales de la Vena Umbilical Humana , Humanos , Peróxido de Hidrógeno/química , Peróxido de Hidrógeno/metabolismo , Concentración de Iones de Hidrógeno , Radical Hidroxilo/química , Radical Hidroxilo/metabolismo , Inyecciones Intravenosas , Hierro/química , Hierro/metabolismo , Ligandos , Nanopartículas del Metal/química , Ratones , Neoplasias/patología , Oxidación-Reducción , Oxígeno/metabolismo , Dióxido de Silicio/química , Ensayos Antitumor por Modelo de Xenoinjerto
8.
Eur J Pharm Biopharm ; 165: 174-184, 2021 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-34015471

RESUMEN

The development of Fe-coordination polymer-based nanoparticles, with safe and high anti-tumor effects, for the treatment of tumor is facing challenges such as limited resources and poor targeting. In this study, we prepared Fe-polyhydroxy coordination polymer nanoparticles (TA-Fe@MNPs), based on tartaric acid (TA)-Fe(III) coordination polymer as the new photothermal agent, mannose (M) as the target, and bovine serum albumin (BSA) and polyethyleneimine (PEI) as the carrier materials, and investigated them for targeting the multifunctional therapy of tumors. The TA-Fe@MNPs synthesized via a simple coordination of Fe3+ with TA, bovine serum albumin, and polyethyleneimine under ambient conditions exhibited an appropriate size (~125 nm), electrically neutral surfaces, good biocompatibility, and low normal cell toxicity. The TA-Fe@MNPs are the first to exhibit a remarkable photothermal performance. They also showed a pH-sensitive Fenton-like response that was further enhanced via glutathione response. Interestingly, after a single injection, the TA-Fe@MNPs could be retained at the tumor site for 36 h with an effective photothermal dose, which was attributed to the reduced protein adsorption and slow elimination in tumor cells with the aid of M modification and carrier materials, while that for the TA-Fe@NPs did so for only 2 h. Tumor ablation was demonstrated by in vivo photothermal and chemokinetic therapy using TA-Fe@MNPs, and their safety was evident from the weight changes and blood parameters. These results indicated that the TA-Fe@MNPs, as new photothermal and CDT agents, have the potential to be used in clinical tumor therapy nanoplatforms.


Asunto(s)
Complejos de Coordinación/administración & dosificación , Portadores de Fármacos/química , Neoplasias/tratamiento farmacológico , Fármacos Fotosensibilizantes/administración & dosificación , Animales , Línea Celular Tumoral , Complejos de Coordinación/química , Complejos de Coordinación/farmacocinética , Modelos Animales de Enfermedad , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Compuestos Férricos/química , Humanos , Concentración de Iones de Hidrógeno , Masculino , Ratones , Nanopartículas/química , Neoplasias/patología , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacocinética , Terapia Fototérmica/métodos , Polietileneimina/química , Ratas , Albúmina Sérica Bovina/química , Tartratos/química , Nanomedicina Teranóstica/métodos , Distribución Tisular
9.
Bioorg Med Chem Lett ; 37: 127840, 2021 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-33556570

RESUMEN

The transmetalation reaction between zinc dithiocarbamates functionalized with organic groups and the cation fac-[99mTc(H2O)3(CO)3]+ has been studied as a new strategy to bind biomolecules to this radionuclide for preparing radiopharmaceuticals with high molar activity. All complexes were obtained in high yields by heating at moderate temperatures and without subsequent purification. The chemical identity was ascertained by HPLC comparison with the homologous rhenium complexes. Stability studies in cysteine solution and serum have shown a good stability of the coordination set fac-[99mTc(CO)3(SS)(P)]. Preliminary biological studies of the radiocomplex functionalized with D-(+)-glucosamine with carcinoma cells have been performed.


Asunto(s)
Complejos de Coordinación/química , Radiofármacos/química , Tecnecio/farmacocinética , Zinc/química , Animales , Complejos de Coordinación/administración & dosificación , Complejos de Coordinación/farmacocinética , Ratones , Radiofármacos/administración & dosificación , Radiofármacos/farmacocinética , Tomografía Computarizada por Tomografía Computarizada de Emisión de Fotón Único , Tecnecio/administración & dosificación , Tecnecio/química , Distribución Tisular , Zinc/administración & dosificación , Zinc/farmacocinética
10.
Metallomics ; 13(2)2021 02 02.
Artículo en Inglés | MEDLINE | ID: mdl-33595653

RESUMEN

The organo-osmium complex [OsII(ɳ6-p-cym)(PhAzPy-NMe2)I]+ (FY26) exhibits promising in vitro antitumour activity against mouse hepatocarcinoma Hepa1-6 and other mouse or human cancer cell lines. Here, we drastically enhance water solubility of FY26 through the replacement of the PF6- counter-anion with chloride using a novel synthesis method. FY26⋅PF6 and FY26⋅Cl displayed similar in vitro cytotoxicity in two cancer cell models. We then show the moderate and late anticancer efficacy of FY26⋅PF6 and FY26⋅Cl in a subcutaneous murine hepatocarcinoma mouse model. Both efficacy and tolerability varied according to FY26 circadian dosing time in hepatocarcinoma tumour-bearing mice. Tumour and liver uptake of the drug were determined over 48 h following FY26⋅Cl administration at Zeitgeber time 6 (ZT6), when the drug is least toxic (in the middle of the light span when mice are resting). Our studies suggest the need to administer protracted low doses of FY26 at ZT6 in order to optimize its delivery schedule, for example through the use of chrono-releasing nanoparticles.


Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Complejos de Coordinación/uso terapéutico , Neoplasias Hepáticas/tratamiento farmacológico , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Complejos de Coordinación/administración & dosificación , Complejos de Coordinación/efectos adversos , Complejos de Coordinación/farmacocinética , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , Distribución Tisular
11.
Nat Commun ; 12(1): 145, 2021 01 08.
Artículo en Inglés | MEDLINE | ID: mdl-33420008

RESUMEN

Radiation therapy can potentially induce immunogenic cell death, thereby priming anti-tumor adaptive immune responses. However, radiation-induced systemic immune responses are very rare and insufficient to meet clinical needs. Here, we demonstrate a synergetic strategy for boosting radiation-induced immunogenic cell death by constructing gadolinium-hemin based nanoscale coordination polymers to simultaneously perform X-ray deposition and glutathione depletion. Subsequently, immunogenic cell death is induced by sensitized radiation to potentiate checkpoint blockade immunotherapies against primary and metastatic tumors. In conclusion, nanoscale coordination polymers-sensitized radiation therapy exhibits biocompatibility and therapeutic efficacy in preclinical cancer models, and has the potential for further application in cancer radio-immunotherapy.


Asunto(s)
Complejos de Coordinación/administración & dosificación , Muerte Celular Inmunogénica/efectos de los fármacos , Nanopartículas/administración & dosificación , Neoplasias/radioterapia , Radioinmunoterapia/métodos , Animales , Línea Celular Tumoral/trasplante , Terapia Combinada/métodos , Complejos de Coordinación/química , Modelos Animales de Enfermedad , Femenino , Gadolinio/administración & dosificación , Gadolinio/química , Hemina/administración & dosificación , Hemina/química , Humanos , Muerte Celular Inmunogénica/efectos de la radiación , Ratones , Nanopartículas/química , Neoplasias/inmunología , Neoplasias/patología , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/inmunología , Estrés Oxidativo/efectos de la radiación , Polímeros/química
12.
Curr Radiopharm ; 14(2): 121-130, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-32990551

RESUMEN

BACKGROUND: Due to its overexpression in a variety of tumor types, the chemokine receptor 4 (CXCR4) represents a highly relevant diagnostic and therapeutic target in nuclear oncology. Recently, [68Ga]Ga-DOTA-Pentixafor has emerged as an excellent imaging agent for positron emission tomography (PET) of CXCR4 expression in vivo. Preparation conditions may influence the quality and in vivo behaviour of this tracer and no standard procedure for the quality controls (QCs) is available. OBJECTIVE: The developed analytical test method was validated because a specific monograph in the Pharmacopoeia is not available for [68Ga]Ga-DOTA-Pentixafor. METHOD: A stepwise approach was used based on the quality by design (QbD) concept of the ICH Q2 (R1) and Q8 (Pharmaceutical Development) guidelines in accordance with the regulations and requirements of EANM, SNM, IAEA and WHO. RESULTS: The purity and quality of the radiopharmaceutical obtained according to the proposed method were found to be high enough to safely administrate it to patients. Excellent linearity was found between 0.5 and 4 µg/mL, with a correlation coefficient (r2) for calibration curves being equal to 0.999, the average coefficient of variation (CV%) < 2% and average bias% that did not deviate more than 5% for all concentrations. CONCLUSION: This study developed a new rapid and simple HPLC method of analysis for the routine QCs of [68Ga]Ga-DOTA-Pentixafor to guarantee the high quality of the finished product before release.


Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Complejos de Coordinación/química , Péptidos Cíclicos/química , Tomografía de Emisión de Positrones , Radiofármacos/química , Complejos de Coordinación/administración & dosificación , Radioisótopos de Galio/química , Humanos , Péptidos Cíclicos/administración & dosificación , Radioquímica , Radiofármacos/administración & dosificación , Receptores CXCR4
13.
Surgery ; 169(1): 162-167, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-32446596

RESUMEN

BACKGROUND: Peptide receptor radionuclide therapy is a targeted therapy used to treat unresectable somatostatin receptor-positive neuroendocrine tumors. The objective of this study was to evaluate response rates among neuroendocrine tumors of different primaries and identify factors relevant to future treatment strategies. METHODS: We retrospectively reviewed patients who received peptide receptor radionuclide therapy for neuroendocrine tumors from 2018 to 2019 at our institution. Patients were assessed with computed tomography/magnetic resonance imaging and 68Ga-DOTATATE-positron emission tomography before and after 2 or 4 cycles of peptide receptor radionuclide therapy. Tumor response was evaluated by RECIST 1.1. Statistics included multinomial logistic regression models and Fisher exact test. RESULTS: Twenty-seven patients underwent 92 cycles of peptide receptor radionuclide therapy: pancreas (n = 11), small bowel (n = 7), and other (n = 9) neuroendocrine tumors. Overall, 30% (8 of 27) had partial response, 59% (16 of 27) stable disease, and 11% (3 of 27) progressed. Pancreatic neuroendocrine tumors responded differently from small bowel neuroendocrine tumors regardless of cycle number (P = .01). The majority of pancreatic neuroendocrine tumors (6 of 11) had partial response to peptide receptor radionuclide therapy, while all small bowel neuroendocrine tumors had stable disease. Pancreatic neuroendocrine tumors stable after 2 cycles were more likely to respond to additional cycles versus other neuroendocrine tumors (probability: 60% vs 11%). CONCLUSION: Patients with unresectable advanced or metastatic pancreatic neuroendocrine tumors may benefit from a full course of peptide receptor radionuclide therapy, whereas other neuroendocrine tumors appear less likely to respond. Large prospective studies are needed to confirm these findings.


Asunto(s)
Complejos de Coordinación/administración & dosificación , Neoplasias Intestinales/radioterapia , Tumores Neuroendocrinos/radioterapia , Octreótido/análogos & derivados , Neoplasias Pancreáticas/radioterapia , Neoplasias Gástricas/radioterapia , Anciano , Esquema de Medicación , Femenino , Humanos , Infusiones Intravenosas , Neoplasias Intestinales/diagnóstico , Neoplasias Intestinales/secundario , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Tumores Neuroendocrinos/diagnóstico , Tumores Neuroendocrinos/secundario , Octreótido/administración & dosificación , Compuestos Organometálicos/administración & dosificación , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/secundario , Tomografía de Emisión de Positrones/métodos , Criterios de Evaluación de Respuesta en Tumores Sólidos , Estudios Retrospectivos , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/secundario , Resultado del Tratamiento
14.
Eur J Med Chem ; 213: 113064, 2021 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-33279292

RESUMEN

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder which is globally responsible for millions of fatalities per year. Management of T2DM typically involves orally administered anti-hyperglycaemic drugs in conjunction with dietary interventions. However, the current conventional therapy seems to be largely ineffective as patients continue to develop complications such as cardiovascular diseases, blindness and kidney failure. Existing alternative treatment entails the administration of organic therapeutic pharmaceuticals, but these drugs have various side effects such as nausea, headaches, weight gain, respiratory and liver damage. Transition metal complexes have shown promise as anti-diabetic agents owing to their diverse mechanisms of activity. In particular, selected ruthenium compounds have exhibited intriguing biological behaviours as Protein Tyrosine Phosphatase (PTP) 1B and Glycogen Synthase Kinase 3 (GSK-3) inhibitors, as well as aggregation suppressants for the human islet amyloid polypeptide (hIAPP). This focussed review serves as a survey on studies pertaining to ruthenium compounds as metallo-drugs for T2DM. Herein, we also provide perspectives on directions to fully elucidate in vivo functions of this class of potential metallopharmaceuticals. More specifically, there is still a need to investigate the pharmacokinetics of ruthenium drugs in order to establish their biodistribution patterns which will affirm whether these metal complexes are substitutionally inert or serve as pro-drugs. In addition, embedding oral-administered ruthenium complexes into bio-compatible polymers can be a prospective means of enhancing stability during drug delivery.


Asunto(s)
Complejos de Coordinación/química , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores Enzimáticos/química , Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Hipoglucemiantes/química , Proteínas Tirosina Fosfatasas/antagonistas & inhibidores , Compuestos de Rutenio/química , Administración Oral , Animales , Materiales Biocompatibles/química , Complejos de Coordinación/administración & dosificación , Complejos de Coordinación/farmacocinética , Portadores de Fármacos/química , Liberación de Fármacos , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/farmacocinética , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/farmacocinética , Polipéptido Amiloide de los Islotes Pancreáticos/metabolismo , Nanoestructuras/química , Polímeros/química , Profármacos/química , Profármacos/farmacología , Agregado de Proteínas , Relación Estructura-Actividad , Distribución Tisular
15.
Pharm Res ; 37(10): 193, 2020 Sep 10.
Artículo en Inglés | MEDLINE | ID: mdl-32914377

RESUMEN

PURPOSE: The incidence of breast cancer worldwide has been on the rise since the late 1970s, and it has become a common tumor that threatens women's health. Aminoglutethimide (AG) is a common treatment of breast cancer. However, current treatments require frequent dosing that results in unstable plasma concentration and low bioavailability, risking serious adverse reactions. Our goal was to develop a molecularly imprinted polymer (MIP) based delivery system to control the release of AG and demonstrate the availability of this drug delivery system (DDS), which was doped with carbon nanotube with aid of metal-organic gel. METHODS: Preparation of MIP was optimized by key factors including composition of formula, ratio of monomers and drug loading concentration. RESULTS: By using multi-walled carbon nanotubes (MWCNT) and metal-organic gels (MOGs), MIP doubled the specific surface area, pore volume tripled and the IF was 1.6 times than the reference. Compared with commercial tablets, the relative bioavailability was 143.3% and a more stable release appeared. CONCLUSIONS: The results highlight the influence of MWCNT and MOGs on MIP, which has great potential as a DDS.


Asunto(s)
Aminoglutetimida/química , Antineoplásicos Hormonales/química , Complejos de Coordinación/química , Sistemas de Liberación de Medicamentos/métodos , Nanotubos de Carbono/química , Aminoglutetimida/administración & dosificación , Aminoglutetimida/farmacocinética , Animales , Antineoplásicos Hormonales/administración & dosificación , Antineoplásicos Hormonales/farmacocinética , Complejos de Coordinación/administración & dosificación , Compuestos Férricos/química , Geles/administración & dosificación , Geles/química , Humanos , Células MCF-7 , Masculino , Impresión Molecular/métodos , Ratas , Ácidos Tricarboxílicos/química
16.
J Inorg Biochem ; 212: 111214, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32919249

RESUMEN

We have synthesized a set of bombesin derivatives with the aim of exploring their tumor targeting properties to deliver metal-based chemotherapeutics into cancer cells. Peptide QRLGNQWAVGHLL-NH2 (BN3) was selected based on its high internalization in gastrin-releasing peptide receptor (GRPR)-overexpressing PC-3 cells. Three metallopeptides were prepared by incorporating the terpyridine Pt(II) complex [PtCl(cptpy)]Cl (1) (cptpy = 4'-(4-carboxyphenyl)-2,2':6,2″-terpyridine) at the N-terminus of BN3 or at the NƐ- or Nα-amino group of an additional Lys residue (1-BN3, Lys-1-BN3 and 1-Lys-BN3, respectively). 1-Lys-BN3 displayed the best cytotoxic activity (IC50: 19.2 ±â€¯1.7 µM) and similar ability to intercalate into DNA than complex 1. Moreover, the polypyridine Ru(II) complex [Ru(bpy)2)(cmbpy)](PF6)2 (2) (bpy = 2,2'-bipyridine; cmbpy = 4-methyl-2,2'-bipyridine-4'-carboxylic acid), with proven activity as photosensitizer, was coupled to BN3 leading to metallopeptide 2-Lys-BN3. Upon photoactivation, 2-Lys-BN3 displayed 2.5-fold higher cytotoxicity against PC-3 cells (IC50: 7.6 ±â€¯1.0 µM) than complex 2. To enhance the accumulation of the drugs into the cell nucleus, the nuclear localization signal (NLS) PKKKRKV was incorporated at the N-terminus of BN3. NLS-BN3 displayed higher cellular internalization along with nuclear biodistribution. Accordingly, metallopeptides 1-NLS-BN3 and 2-NLS-BN3 showed increased cytotoxicity (IC50: 12.0 ±â€¯1.1 µM and 2.3 ±â€¯1.1 µM). Interestingly, the phototoxic index of 2-NLS-BN3 was 8-fold higher than that of complex 2. Next, the selectivity towards cancer cells was explored using 1BR3.G fibroblasts. Higher selectivity indexes were obtained for 1-NLS-BN3 and 2-NLS-BN3 than for the unconjugated complexes. These results prove NLS-BN3 effective for targeted delivery of metallodrugs to GRPR-overexpressing cells and for enhancing the cytotoxic efficacy of metal-based photosensitizers.


Asunto(s)
Antineoplásicos/administración & dosificación , Bombesina/análogos & derivados , Núcleo Celular/efectos de los fármacos , Complejos de Coordinación/administración & dosificación , Sistemas de Liberación de Medicamentos , Compuestos de Platino/administración & dosificación , Compuestos de Rutenio/administración & dosificación , Secuencia de Aminoácidos , Antineoplásicos/farmacología , Bombesina/administración & dosificación , Línea Celular Tumoral , Complejos de Coordinación/farmacología , Ensayo de Cambio de Movilidad Electroforética , Humanos , Microscopía de Fuerza Atómica , Señales de Localización Nuclear , Compuestos de Platino/farmacología , Compuestos de Rutenio/farmacología , Espectrometría de Fluorescencia/métodos , Espectrometría de Masa por Ionización de Electrospray
17.
Proc Natl Acad Sci U S A ; 117(30): 17535-17542, 2020 07 28.
Artículo en Inglés | MEDLINE | ID: mdl-32661159

RESUMEN

Mismatch repair (MMR) deficiencies are a hallmark of various cancers causing accumulation of DNA mutations and mismatches, which often results in chemotherapy resistance. Metalloinsertor complexes, including [Rh(chrysi)(phen)(PPO)]Cl2 (Rh-PPO), specifically target DNA mismatches and selectively induce cytotoxicity within MMR-deficient cells. Here, we present an in vivo analysis of Rh-PPO, our most potent metalloinsertor. Studies with HCT116 xenograft tumors revealed a 25% reduction in tumor volume and 12% increase in survival with metalloinsertor treatment (1 mg/kg; nine intraperitoneal doses over 20 d). When compared to oxaliplatin, Rh-PPO displays ninefold higher potency at tumor sites. Pharmacokinetic studies revealed rapid absorption of Rh-PPO in plasma with notable accumulation in the liver compared to tumors. Additionally, intratumoral metalloinsertor administration resulted in enhanced anticancer effects, pointing to a need for more selective delivery methods. Overall, these data show that Rh-PPO inhibits xenograft tumor growth, supporting the strategy of using Rh-PPO as a chemotherapeutic targeted to MMR-deficient cancers.


Asunto(s)
Antineoplásicos/farmacología , Complejos de Coordinación/farmacología , Rodio , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Antineoplásicos/farmacocinética , Disparidad de Par Base/efectos de los fármacos , Complejos de Coordinación/administración & dosificación , Complejos de Coordinación/química , Complejos de Coordinación/farmacocinética , Reparación de la Incompatibilidad de ADN/efectos de los fármacos , Modelos Animales de Enfermedad , Células HCT116 , Humanos , Ratones , Estructura Molecular , Rodio/química , Distribución Tisular , Ensayos Antitumor por Modelo de Xenoinjerto
18.
Toxicol In Vitro ; 67: 104922, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32590028

RESUMEN

Cisplatin is widely used to treat different types of cancer, but its severe side effects are the major disadvantage of this treatment. Therefore, other metals are currently the subject of research in the rational development of anticancer drugs, such as copper, that has been demonstrated to be promising in this scenario. Here, we evaluated the effects of two novel copper complexes against breast cancer cell lines, and also examined the influence of overexpressing copper transporter 1 (CTR1) on the cytotoxicity of these complexes. Complex (1) [Cu(sdmx-)2(phen)] showed low IC50 values, induced intense cell morphological changes and arrested the cell cycle at the sub-G1 phase in cancer cells. Complex (1) was tested in transfected cells overexpressing the CTR1 receptor in order to compare its steric effects with a less bulky ligand and more labile complex (2) [CuCl2(impy)]. A significant reduction of IC50 value was observed in CTR1 overexpressing cells for complex (2) (32 µM to 20 µM) as compared to (1) (2.78 µM to 3.41 µM), evidencing a possible uptake through copper reduction (Cu+2 â†’ Cu+1) mediated by CTR1. Thus, considering that CTR1 is a mediator of metallodrugs uptake, the development of strategies that use rational drug design is important in order to improve the therapeutic efficacy through greater specificity and consecutive reduction of side effects. Here we show the example for the case of copper(II) complexes.


Asunto(s)
Antineoplásicos/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Complejos de Coordinación/administración & dosificación , Transportador de Cobre 1/genética , Cobre/administración & dosificación , Neoplasias de la Mama/genética , Ciclo Celular/efectos de los fármacos , Línea Celular , Supervivencia Celular/efectos de los fármacos , Humanos
19.
Chem Commun (Camb) ; 56(46): 6193-6196, 2020 Jun 11.
Artículo en Inglés | MEDLINE | ID: mdl-32432578

RESUMEN

We report a bimetallic complex [Ir4Ho2(pq)8(H2dcbpy)4(OAc)2] (denoted as Ir4Ho2, pq = 2-phenylquinoline, H2dcppy = 2,2'-bipyridine-3,3'-dicarboxylic acid) and its application for radiotherapy/radiodynamic therapy (RT/RDT). In a tumor xenograft mouse model, Ir4Ho2 exerted a tumor-suppressive effect through efficient low-dose RT/RDT.


Asunto(s)
Complejos de Coordinación/administración & dosificación , Holmio/administración & dosificación , Iridio/administración & dosificación , Neoplasias/tratamiento farmacológico , Neoplasias/radioterapia , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Complejos de Coordinación/química , Holmio/química , Células Endoteliales de la Vena Umbilical Humana , Humanos , Iridio/química , Liposomas , Ratones Endogámicos BALB C , Neoplasias/patología
20.
Biomater Sci ; 8(11): 3193-3201, 2020 Jun 07.
Artículo en Inglés | MEDLINE | ID: mdl-32373851

RESUMEN

Outfitted with abundant hydrogen bonding and coordination active groups, carboxymethyl chitosan (CMC) possesses a class of naturally occurring ligands for coordination with metal ions, establishing its excellent potential for various fields. Herein, by incorporating the naturally derived CMC into a thermally reconfigurable agarose (Agar) gel medium, a novel type of metal-biopolymer coordinated double network hydrogel (DN gel) was successfully fabricated via the strong coordination interactions. The interpenetrated CMC was confirmed to retain its excellent chelating abilities within the bulk gel matrix, which resulted in a series of metal-coordinated DN gels through spontaneous self-associative complexation with metal ions such as Cu2+, Zn2+, Ni2+, Co2+, Fe3+, and Cr3+. Moreover, these two types of physical cross-links are functionally independent and reversible, which enables the programming of the hydrogel with multi-functionality, including pH-regulated shape memory behavior, multi-staged self-healing properties and durable antibacterial activities. Thus, we believe that the successful preparation of such a coordination-driven DN gel will lead to the development of biopolymer-based multifunctional hydrogels, as well as provide new insight into nanocomponent assembly and soft electronic biosensing systems for biomedical applications.


Asunto(s)
Agar , Antibacterianos , Quitosano/análogos & derivados , Complejos de Coordinación , Hidrogeles , Metales Pesados , Agar/administración & dosificación , Agar/química , Antibacterianos/administración & dosificación , Antibacterianos/química , Quitosano/administración & dosificación , Quitosano/química , Complejos de Coordinación/administración & dosificación , Complejos de Coordinación/química , Escherichia coli/efectos de los fármacos , Escherichia coli/crecimiento & desarrollo , Hidrogeles/administración & dosificación , Hidrogeles/química , Enlace de Hidrógeno , Concentración de Iones de Hidrógeno , Metales Pesados/administración & dosificación , Metales Pesados/química
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA