Disulfiram-loaded porous PLGA microparticle for inhibiting the proliferation and migration of non-small-cell lung cancer

Wang, Chenhui; Yang, Jiebing; Han, Haobo; Chen, Jiawen; Wang, Yudi; Li, Quanshun; Li, Han

doi:10.2147/ijn.s121948

Cited by 26 publications

(13 citation statements)

References 31 publications

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“…It was demonstrated that PLGA encapsulation shielded DS from breakdown in the bloodstream and transported the intact DSF to cancer tissues (Wang et al, 2017b). The efficacy of PLGA-based DSF nanoparticles was demonstrated in a wide range of cancers using xenograft mouse models of hepatocellular carcinoma, lung cancer, ovarian cancer, and breast cancer (McConville et al, 2015;Fasehee et al, 2016;Wang et al, 2017a;Fasehee et al, 2017;Najlah et al, 2017). In addition, polymeric nanoparticles can be modified extensively to add functional groups that can be targeted for delivery to a tissue of interest.…”

Section: Nanotechnology-based Formulation Strategies For Delivery Of Disulfirammentioning

confidence: 99%

Recent Advances in Repurposing Disulfiram and Disulfiram Derivatives as Copper-Dependent Anticancer Agents

Kannappan

Ali

Small

et al. 2021

Front. Mol. Biosci.

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Copper (Cu) plays a pivotal role in cancer progression by acting as a co-factor that regulates the activity of many enzymes and structural proteins in cancer cells. Therefore, Cu-based complexes have been investigated as novel anticancer metallodrugs and are considered as a complementary strategy for currently used platinum agents with undesirable general toxicity. Due to the high failure rate and increased cost of new drugs, there is a global drive towards the repositioning of known drugs for cancer treatment in recent years. Disulfiram (DSF) is a first-line antialcoholism drug used in clinics for more than 65 yr. In combination with Cu, it has shown great potential as an anticancer drug by targeting a wide range of cancers. The reaction between DSF and Cu ions forms a copper diethyldithiocarbamate complex (Cu(DDC)2 also known as CuET) which is the active, potent anticancer ingredient through inhibition of NF-κB and ubiquitin-proteasome system as well as alteration of the intracellular reactive oxygen species (ROS). Importantly, DSF/Cu inhibits several molecular targets related to drug resistance, stemness, angiogenesis and metastasis and is thus considered as a novel strategy for overcoming tumour recurrence and relapse in patients. Despite its excellent anticancer efficacy, DSF has proven unsuccessful in several cancer clinical trials. This is likely due to the poor stability, rapid metabolism and/or short plasma half-life of the currently used oral version of DSF and the inability to form Cu(DDC)2 at relevant concentrations in tumour tissues. Here, we summarize the scientific rationale, molecular targets, and mechanisms of action of DSF/Cu in cancer cells and the outcomes of oral DSF ± Cu in cancer clinical trials. We will focus on the novel insights on harnessing the immune system and hypoxic microenvironment using DSF/Cu complex and discuss the emerging delivery strategies that can overcome the shortcomings of DSF-based anticancer therapies and provide opportunities for translation of DSF/Cu or its Cu(DDC)2 complex into cancer therapeutics.

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Section: Nanotechnology-based Formulation Strategies For Delivery Of Disulfirammentioning

confidence: 99%

Recent Advances in Repurposing Disulfiram and Disulfiram Derivatives as Copper-Dependent Anticancer Agents

Kannappan

Ali

Small

et al. 2021

Front. Mol. Biosci.

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“…Of 35 selected studies, 21 were in vitro studies (Table 1 ), 11 were in vivo studies with animal models (Table 2 ), and three were clinical trials (Table 3 ). In in vitro studies, the most studied cancer was breast cancer (five studies) [ 8 – 12 ], while the A549 non-small cell lung cancer (NSCLC) cell line was the one most commonly used cell line (four studies) [ 13 – 16 ]. Three studies examined DSF as a single agent [ 17 – 19 ], and 17 studies examined DSF in combination with metal ions (Cu, Ag), chemotherapy, or radiation therapy [ 8 – 16 , 20 – 27 ].…”

Section: Resultsmentioning

confidence: 99%

Anticancer effects of disulfiram: a systematic review of in vitro, animal, and human studies

Zhou

Wan

et al. 2022

Syst Rev

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Background and objectives Cancer morbidity and mortality rates remain high, and thus, at present, considerable efforts are focused on finding drugs with higher sensitivity against tumor cells and fewer side effects. Disulfiram (DSF), as an anti-alcoholic drug, kills the cancer cells by inducing apoptosis. Several preclinical and clinical studies have examined the potential of repurposing DSF as an anticancer treatment. This systematic review aimed to assess evidence regarding the antineoplastic activity of DSF in in vitro and in vivo models, as well as in humans. Methods Two authors independently conducted this systematic review of English and Chinese articles from the PubMed, Embase, and the Cochrane Library databases up to July 2019. Eligible in vitro studies needed to include assessments of the apoptosis rate by flow cytometry using annexin V/propidium iodide, and studies in animal models and clinical trials needed to examine tumor inhibition rates, and progression-free survival (PFS) and overall survival (OS), respectively. Data were analyzed using descriptive statistics. Results Overall, 35 studies, i.e., 21 performed in vitro, 11 based on animal models, and three clinical trials, were finally included. In vitro and animal studies indicated that DSF was associated with enhanced apoptosis and tumor inhibition rates, separately. Human studies showed that DSF prolongs PFS and OS. The greatest anti-tumor activity was observed when DSF was used as combination therapy or as a nanoparticle-encapsulated molecule. There was no noticeable body weight loss after DSF treatment, which indicated that there was no major toxicity of DSF. Conclusions This systematic review provides evidence regarding the anti-tumor activity of DSF in vitro, in animals, and in humans and indicates the optimal forms of treatment to be evaluated in future research.

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“…This instability hindered the application of DSF in the clinic. Recent studies on DSF delivery systems were primarily focused on DSF-loaded nanoparticles using mPEG-PCL or PEG-PLGA as nanocarriers [5,6,[28][29][30]. For example, Folate-receptor-targeted PLGA-PEG nanoparticles of disulfiram with good encapsulation efficiency (59.62%) were developed to delivery more disulfiram into breast cancer cells [5].…”

Section: Open Accessmentioning

confidence: 99%

“…The IC50 value decreased by 2.5-fold compared to free DSF [28]. DSF-loaded porous PLGA microparticles were successfully prepared by Wang et al with aerodynamic diameter (8.31 µm), good drug loading and antitumor efficiency using non-smallcell lung cancer A549 as a model [29]. Zhuo et al developed an injectable DSF-NPs using mPEG 5000 -PCL 5000 which improved the stability of disulfiram and enhanced the DSF concentration in the blood [30].…”

Section: Open Accessmentioning

confidence: 99%

Soybean lecithin stabilizes disulfiram nanosuspensions with a high drug-loading content: remarkably improved antitumor efficacy

Li¹,

Liu²,

Ao³

et al. 2020

J Nanobiotechnol

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Disulfiram (DSF) has been considered as "Repurposing drug" in cancer therapy in recent years based on its good antitumor efficacy. DSF is traditionally used as an oral drug in the treatment of alcoholism. To overcome its rapid degradation and instability, DSF nanosuspensions (DSF/SPC-NSps) were prepared using soybean lecithin (SPC) as a stabilizer of high drug-loaded content (44.36 ± 1.09%). Comprehensive characterization of the nanosuspensions was performed, and cell cytotoxicity, in vivo antitumor efficacy and biodistribution were studied. DSF/SPC-NSps, having a spherical appearance with particle size of 155 nm, could remain very stable in different physiological media, and sustained release. The in vitro MTT assay indicated that the cytotoxicity of DSF/SPC-NSps was enhanced remarkably compared to free DSF against the 4T1 cell line. The IC 50 value decreased by 11-fold (1.23 vs. 13.93 μg/mL, p < 0.01). DSF/SPC-NSps groups administered via intravenous injections exhibited better antitumor efficacy compared to the commercial paclitaxel injection (PTX injection) and had a dose-dependent effect in vivo. Notably, DSF/SPC-NSps exhibited similar antitumor activity following oral administration as PTX administration via injection into a vein. These results suggest that the prepared nanosuspensions can be used as a stable delivery vehicle for disulfiram, which has potential application in breast cancer chemotherapy.

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Disulfiram-loaded porous PLGA microparticle for inhibiting the proliferation and migration of non-small-cell lung cancer

Cited by 26 publications

References 31 publications

Recent Advances in Repurposing Disulfiram and Disulfiram Derivatives as Copper-Dependent Anticancer Agents

Recent Advances in Repurposing Disulfiram and Disulfiram Derivatives as Copper-Dependent Anticancer Agents

Anticancer effects of disulfiram: a systematic review of in vitro, animal, and human studies

Soybean lecithin stabilizes disulfiram nanosuspensions with a high drug-loading content: remarkably improved antitumor efficacy

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