RESUMEN
As a clinical anti-glioma agent, the therapeutic effect of carmustine (BCNU) was largely decreased because of the drug resistance mediated by O6-alkylguanine-DNA alkyltransferase (AGT) and the blood-brain barrier (BBB). To overcome these obstacles, we synthesized a BCNU-loaded hypoxia/esterase dual stimulus-activated nanomicelle, abbreviated as T80-HACB/BCNU NPs. In this nano-system, Tween 80 acts as the functional coating on the surface of the micelle to facilitate transport across the BBB. Hyaluronic acid (HA) with active tumor-targeting capability was linked with the hypoxia-sensitive AGT inhibitors (O6-azobenzyloxycarbonyl group) via an esterase-activated ester bond. The obtained T80-HACB/BCNU NPs had an average particle size of 232.10 ± 10.66 nm, the zeta potential of -18.13 ± 0.91 mV, and it showed high drug loading capacity, eximious biocompatibility and dual activation of hypoxia/esterase drug release behavior. The obtained T80-HACB/BCNU NPs showed enhanced cytotoxicity against hypoxic T98G and SF763 cells with IC50 at 132.2 µM and 133.1 µM, respectively. T80 modification improved the transportation of the micelle across an in vitro BBB model. The transport rate of the T80-HACB/Cou6 NPs group was 12.37 %, which was 7.6-fold (p<0.001) higher than the micelle without T80 modification. T80-HACB/BCNU NPs will contribute to the development of novel CENUs chemotherapies with high efficacy.
Asunto(s)
Antineoplásicos Alquilantes , Carmustina , Hipoxia de la Célula , Nanopartículas , Elastasa Pancreática , Polisorbatos , Polisorbatos/química , Micelas , Elastasa Pancreática/química , Elastasa Pancreática/metabolismo , Carmustina/síntesis química , Carmustina/química , Antineoplásicos Alquilantes/química , Antineoplásicos Alquilantes/farmacología , Nanopartículas/química , Nanopartículas/toxicidad , Ácido Hialurónico/química , Humanos , Línea Celular Tumoral , Dextranos/química , Sistemas de Liberación de Medicamentos , Apoptosis/efectos de los fármacosAsunto(s)
Carmustina/efectos adversos , Animales , Antineoplásicos Alquilantes/efectos adversos , Antineoplásicos Alquilantes/síntesis química , Antineoplásicos Alquilantes/química , Antineoplásicos Alquilantes/toxicidad , Pruebas de Carcinogenicidad , Carmustina/síntesis química , Carmustina/química , Carmustina/toxicidad , Guías como Asunto , Humanos , Ratones , Modelos Biológicos , Exposición Profesional/efectos adversos , Exposición Profesional/legislación & jurisprudencia , RatasAsunto(s)
Anhídridos/síntesis química , Antineoplásicos Alquilantes/síntesis química , Neoplasias Encefálicas/tratamiento farmacológico , Carmustina/síntesis química , Sistemas de Liberación de Medicamentos/métodos , Anhídridos/farmacocinética , Antineoplásicos Alquilantes/farmacocinética , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacocinética , Carmustina/farmacocinética , Ácidos Decanoicos/química , Ácidos Decanoicos/farmacocinética , Preparaciones de Acción Retardada , Combinación de Medicamentos , Almacenaje de Medicamentos , Peso Molecular , Poliésteres/química , Poliésteres/farmacocinética , Espectrofotometría InfrarrojaRESUMEN
Benzene is a widely known carcinogen and a cause of bone-marrow toxicity and leukaemia in humans. para-Benzoquinone is a stable metabolite of benzene. Its reaction with deoxycytidine, deoxyadenosine and deoxyguanosine produces the major stable exocyclic compounds (3-hydroxy)-1,N4-benzetheno-2'-deoxycytidine, (9-hydroxy)-1,N6-benzetheno-2'-deoxyadenosine and (7-hydroxy)-1,N2-benzetheno-2'-deoxyguanosine, respectively, on a large scale and at high yield. The desired products were identified by fast atom bombardment-mass spectrometry, proton nuclear magnetic resonance and UV spectroscopy. These adducts were converted to the fully protected phosphoramidites and incorporated site-specifically into a series of oligonucleotides. 1,N6-Ethano-2'-deoxyadenosine is one of the exocyclic adducts formed during DNA reaction with the antitumour agent, 1,3-bis(2-chloroethyl)nitrosourea. This compound was synthesized on a large scale with a high yield (62%) and then was converted to the phosphoramidite and incorporated site-specifically into oligonucleotides. The coupling efficiency of the incorporation of all these adducts was high (> or = 93%). After de-protection and purification of these oligomers, enzymatic hydrolysis and analysis by high-performance liquid chromatography confirmed the presence of the adduct in the oligomers. These oligomers are being used to investigate the biochemical and physical properties of these adducts.
Asunto(s)
Benzoquinonas/síntesis química , Carmustina/síntesis química , Aductos de ADN/síntesis química , Secuencia de Bases , Cromatografía Líquida de Alta Presión , Desoxiadenosinas/metabolismo , Desoxicitidina/metabolismo , Desoxiguanosina/metabolismo , Modelos Químicos , Datos de Secuencia Molecular , Oligonucleótidos/síntesis químicaRESUMEN
Carbon-11-labeled SarCNU [N-(2-chloroethyl)-N-nitroso-N'-(carboxamidomethylene)-N'-(methyl) - [11C]-urea], a potential chemotherapeutic agent, has been prepared by the nitrosation of the corresponding urea, N-(2-chloroethyl)-N'-(carboxamidomethylene)-N'-(methyl) [11C]urea (SarCU). SarCU was prepared by reacting sarcosinamide with [11C]-2-chloroethylisocyanate, which was itself prepared by reacting [11C]-phosgene with 2-chloroethylamine hydrochloride suspended in dioxane. The synthesis yielded [11C]SarCNU with an average radiochemical purity of 95% in an average overall radiochemical yield of 18% relative to the activity measured at the end of [11C]phosgene introduction.