PURPOSE: This phase 1/2 study aimed to evaluate the safety and preliminary efficacy of combining disulfiram and copper (DSF/Cu) with radiation therapy (RT) and temozolomide (TMZ) in patients with newly diagnosed glioblastoma (GBM). METHODS AND MATERIALS: Patients received standard RT and TMZ with DSF (250-375 mg/d) and Cu, followed by adjuvant TMZ plus DSF (500 mg/d) and Cu. Pharmacokinetic analyses determined drug concentrations in plasma and tumors using high-performance liquid chromatography-mass spectrometry. RESULTS: Thirty-three patients, with a median follow-up of 26.0 months, were treated, including 12 IDH-mutant, 9 NF1-mutant, 3 BRAF-mutant, and 9 other IDH-wild-type cases. In the phase 1 arm, 18 patients were treated; dose-limiting toxicity probabilities were 10% (95% CI, 3%-29%) at 250 mg/d and 21% (95% CI, 7%-42%) at 375 mg/d. The phase 2 arm treated 15 additional patients at 250 mg/d. No significant difference in overall survival or progression-free survival was noted between IDH- and NF1-mutant cohorts compared with institutional counterparts treated without DSF/Cu. However, extended remission occurred in 3 BRAF-mutant patients. Diethyl-dithiocarbamate-copper, the proposed active metabolite of DSF/Cu, was detected in plasma but not in tumors. CONCLUSIONS: The maximum tolerated dose of DSF with RT and TMZ is 375 mg/d. DSF/Cu showed limited clinical efficacy for most patients. However, promising efficacy was observed in BRAF-mutant GBM, warranting further investigation.

• MeSH
• alkylační protinádorové látky terapeutické užití   farmakokinetika   MeSH
• chemoradioterapie * metody   MeSH
• disulfiram * terapeutické užití   farmakokinetika   aplikace a dávkování   MeSH
• doba přežití bez progrese choroby MeSH
• dospělí MeSH
• glioblastom * radioterapie   genetika   mortalita   terapie   farmakoterapie   MeSH
• isocitrátdehydrogenasa genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• měď * krev   terapeutické užití   MeSH
• nádory mozku * radioterapie   mortalita   genetika   terapie   MeSH
• protoonkogenní proteiny B-Raf genetika   MeSH
• senioři MeSH
• temozolomid * terapeutické užití   farmakokinetika   aplikace a dávkování   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze I MeSH
• klinické zkoušky, fáze II MeSH
• Názvy látek
• alkylační protinádorové látky MeSH
• disulfiram * MeSH
• isocitrátdehydrogenasa MeSH
• měď * MeSH
• protoonkogenní proteiny B-Raf MeSH
• temozolomid * MeSH

Direct drug delivery to the cochlea is associated with the risk of irreversible damage to the ear. In this study, liposome and polymersome nanoparticles (NPs), both formed from amphiphilic molecules (lipids in liposomes and block copolymers in polymersomes), were tested as potential tools for drug delivery to the cochlea via application onto the round window membrane in adult mice (strain C3H). One day after round window membrane application, both types of NPs labeled with fluorescent markers were identified in the spiral ganglion in all cochlear turns without producing any distinct morphological or functional damage to the inner ear. NPs were detected, although to a lesser extent, in the organ of Corti and the lateral wall. The potential of liposome and polymersome NPs as therapeutic delivery systems into the cochlea via the round window membrane was evaluated using disulfiram, a neurotoxic agent, as a model payload. Disulfiram-loaded NP delivery resulted in a significant decrease in the number of spiral ganglion cells starting 2 days postapplication, with associated pronounced hearing loss reaching 20-35 dB 2 weeks postapplication as assessed through auditory brainstem responses. No changes in hair cell morphology and function (as assessed by recording otoacoustic emissions) were detected after disulfiram-loaded NP application. No effects were observed in controls where solution of free disulfiram was similarly administered. The results demonstrate that liposome and polymersome NPs are capable of carrying a payload into the inner ear that elicits a biological effect, with consequences measurable by a functional readout.

• MeSH
• apoptóza účinky léků   MeSH
• Cortiho orgán účinky léků   ultrastruktura   MeSH
• cytotoxiny aplikace a dávkování   farmakologie   MeSH
• disulfiram aplikace a dávkování   farmakologie   MeSH
• fenestra rotunda účinky léků   metabolismus   ultrastruktura   MeSH
• ganglion spirale cytologie   účinky léků   MeSH
• kaspasa 3 metabolismus   MeSH
• kochlea účinky léků   metabolismus   ultrastruktura   MeSH
• lékové transportní systémy metody   MeSH
• liposomy analýza   MeSH
• myši MeSH
• nanočástice analýza   MeSH
• povrchově aktivní látky chemie   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cytotoxiny MeSH
• disulfiram MeSH
• kaspasa 3 MeSH
• liposomy MeSH
• povrchově aktivní látky MeSH