Disulfiram-loaded copper sulfide nanoparticles for potential anti-glioma therapy

Lan, Qing-Hua; Du, Chu-Chu; Yu, Run-Jie; Zhai, Jiaoyuan; Shi, Yannan; Kou, Longfa; Xiao, Jian; Lu, Cui-Tao; Zhao, Ying‐Zheng; Yao, Qing

doi:10.1016/j.ijpharm.2021.120978

Cited by 20 publications

(18 citation statements)

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“…Considering the difficulties in translating the promising preclinical work to clinical benefit, future work needs to focus on novel application methods or treatment synergies, and some novel strategies have recently been published . Disulfiram may also play a role as radiosensitizer and may have a clinical benefit under different circumstances than provided in our trial …”

Section: Discussionmentioning

confidence: 99%

Effect of Disulfiram and Copper Plus Chemotherapy vs Chemotherapy Alone on Survival in Patients With Recurrent Glioblastoma

et al. 2023

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ImportanceDisulfiram has demonstrated broad antitumoral effect in several preclinical studies. One of the proposed indications is for the treatment of glioblastoma.ObjectiveTo evaluate the efficacy and safety of disulfiram and copper as add-on to alkylating chemotherapy in patients with recurrent glioblastoma.Design, Setting, and ParticipantsThis was a multicenter, open-label, randomized phase II/III clinical trial with parallel group design. Patients were recruited at 7 study sites in Sweden and 2 sites in Norway between January 2017 and November 2020. Eligible patients were 18 years or older, had a first recurrence of glioblastoma, and indication for treatment with alkylating chemotherapy. Patients were followed up until death or a maximum of 24 months. The date of final follow-up was January 15, 2021. Data analysis was performed from February to September 2022.InterventionsPatients were randomized 1:1 to receive either standard-of-care (SOC) alkylating chemotherapy alone, or SOC with the addition of disulfiram (400 mg daily) and copper (2.5 mg daily).Main Outcomes and MeasuresThe primary end point was survival at 6 months. Secondary end points included overall survival, progression-free survival, adverse events, and patient-reported quality of life.ResultsAmong the 88 patients randomized to either SOC (n = 45) or SOC plus disulfiram and copper (n = 43), 63 (72%) were male; the mean (SD) age was 55.4 (11.5) years. There was no significant difference between the study groups (SOC vs SOC plus disulfiram and copper) in 6 months survival (62% [26 of 42] vs 44% [19 of 43]; P = .10). Median overall survival was 8.2 months (95% CI, 5.4-10.2 months) with SOC and 5.5 months (95% CI, 3.9-9.3 months) with SOC plus disulfiram and copper, and median progression-free survival was 2.6 months (95% CI, 2.4-4.6 months) vs 2.3 months (95% CI, 1.7-2.6 months), respectively. More patients in the SOC plus disulfiram and copper group had adverse events grade 3 or higher (34% [14 of 41] vs 11% [5 of 44]; P = .02) and serious adverse events (41% [17 of 41] vs 16% [7 of 44]; P = .02), and 10 patients (24%) discontinued disulfiram treatment because of adverse effects.Conclusions and RelevanceThis randomized clinical trial found that among patients with recurrent glioblastoma, the addition of disulfiram and copper to chemotherapy, compared with chemotherapy alone, resulted in significantly increased toxic effects, but no significant difference in survival. These findings suggest that disulfiram and copper is without benefit in patients with recurrent glioblastoma.Trial RegistrationClinicalTrials.gov Identifier: NCT02678975; EUDRACT Identifier: 2016-000167-16

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Section: Discussionmentioning

confidence: 99%

Effect of Disulfiram and Copper Plus Chemotherapy vs Chemotherapy Alone on Survival in Patients With Recurrent Glioblastoma

et al. 2023

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“…The combination regimen comprised 500 mg of DSF daily plus 50 mg of zinc gluconate or 2 mg of Cu gluconate three times daily ( Ekinci et al, 2019 ). It has been shown that DSF/Cu sulphide (CuS) nanocomplexes (Tf-DSF/CuS) modified with transferrin (Tf) exhibit high cytotoxic effects in vitro ( Lan et al, 2021 ). The CuS nanoparticles enable them to accumulate specifically and within tumor tissue by enhancing the permeability and retention (EPR) effect of the tumor tissue ( Lan et al, 2021 ).…”

Section: Combination Therapy Of Disulfirammentioning

confidence: 99%

“…It has been shown that DSF/Cu sulphide (CuS) nanocomplexes (Tf-DSF/CuS) modified with transferrin (Tf) exhibit high cytotoxic effects in vitro ( Lan et al, 2021 ). The CuS nanoparticles enable them to accumulate specifically and within tumor tissue by enhancing the permeability and retention (EPR) effect of the tumor tissue ( Lan et al, 2021 ). The metallic nature of the nanoparticles enhanced the drug-loading capacity by forming Cu complexes on the CuS surface ( Lan et al, 2021 ).…”

Section: Combination Therapy Of Disulfirammentioning

confidence: 99%

“…The CuS nanoparticles enable them to accumulate specifically and within tumor tissue by enhancing the permeability and retention (EPR) effect of the tumor tissue ( Lan et al, 2021 ). The metallic nature of the nanoparticles enhanced the drug-loading capacity by forming Cu complexes on the CuS surface ( Lan et al, 2021 ). Additionally, the use of a long-wavelength laser in the near-infrared (700–1000 nm) region activated the photothermal effect of the nanoparticles, resulting in minimal damage to normal tissue from tumor ablation ( Lan et al, 2021 ).…”

Section: Combination Therapy Of Disulfirammentioning

confidence: 99%

“…The metallic nature of the nanoparticles enhanced the drug-loading capacity by forming Cu complexes on the CuS surface ( Lan et al, 2021 ). Additionally, the use of a long-wavelength laser in the near-infrared (700–1000 nm) region activated the photothermal effect of the nanoparticles, resulting in minimal damage to normal tissue from tumor ablation ( Lan et al, 2021 ). Besides Cu, DSF can act through zinc chelation to inhibit the activities of MMP-2 and MMP-9 ( Kast and Halatsch, 2012 ).…”

Section: Combination Therapy Of Disulfirammentioning

confidence: 99%

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Disulfiram in glioma: Literature review of drug repurposing

Zhong

Liu²,

Shi³

et al. 2022

Front. Pharmacol.

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Gliomas are the most common malignant brain tumors. High-grade gliomas, represented by glioblastoma multiforme (GBM), have a poor prognosis and are prone to recurrence. The standard treatment strategy is tumor removal combined with radiotherapy and chemotherapy, such as temozolomide (TMZ). However, even after conventional treatment, they still have a high recurrence rate, resulting in an increasing demand for effective anti-glioma drugs. Drug repurposing is a method of reusing drugs that have already been widely approved for new indication. It has the advantages of reduced research cost, safety, and increased efficiency. Disulfiram (DSF), originally approved for alcohol dependence, has been repurposed for adjuvant chemotherapy in glioma. This article reviews the drug repurposing method and the progress of research on disulfiram reuse for glioma treatment.

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