Membrane Loaded Copper Oleate PEGylated Liposome Combined with Disulfiram for Improving Synergistic Antitumor Effect In Vivo

Zhou, Licheng; Yang, Liu; Yang, Chulei; Liu, Yi; Chen, Qiuyue; Pan, Wenli; Cai, Qing; Luo, Lifeng; Liu, Lu; Jiang, Shan; He, Haibing; Yin, Tian; Tang, Xing

doi:10.1007/s11095-018-2414-5

Cited by 31 publications

(25 citation statements)

References 31 publications

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“…These results are also supported by a recent study using DSPE-PEG 2000 -based PEGylated copper oleate liposome (Cu(OI)2-L) for targeted delivery in cancer. Pharmacokinetic studies demonstrated that Cu(OI)2-L had a prolonged circulation time compared to that of injected copper oleate solution [46]. However, no stability study results in serum were shown and the feasibility (and compatibility) of combining DS with Cu +2 in the same dosage form should be investigated in depth.…”

Section: Resultsmentioning

confidence: 99%

Development of Injectable PEGylated Liposome Encapsulating Disulfiram for Colorectal Cancer Treatment

et al. 2019

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Disulfiram (DS), an anti-alcoholism medicine, shows strong anti-cancer activity in the laboratory, but the application in clinics for anti-cancer therapy has been limited by its prompt metabolism. Conventional liposomes have shown limited ability to protect DS. Therefore, the aim of this study is to develop PEGylated liposomes of DS for enhanced bio-stability and prolonged circulation. PEGylated liposomes were prepared using ethanol-based proliposome methods. Various ratios of phospholipids, namely: hydrogenated soya phosphatidylcholine (HSPC) or dipalmitoyl phosphatidylcholine (DPPC) and N-(Carbonyl-methoxypolyethylenglycol-2000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE-PEG2000) with cholesterol were used. DS was dissolved in the alcoholic solution in different lipid mol% ratios. The size of the resulting multilamellar liposomes was reduced by high-pressure homogenization. Liposomal formulations were characterized by size analysis, zeta potential, drug loading efficiency and stability in horse serum. Small unilamellar vesicles (SUVs; nanoliposomes) were generated with a size of approximately 80 to 120 nm with a polydispersity index (PDI) in the range of 0.1 to 0.3. Zeta potential values of all vesicles were negative, and the negative surface charge intensity tended to increase by PEGylation. PEGylated liposomes had a smaller size (80–90 nm) and a significantly lower PDI. All liposomes showed similar loading efficiencies regardless of lipid type (HSPC or DPPC) or PEGylations. PEGylated liposomes provided the highest drug biostability amongst all formulations in horse serum. PEGylated DPPC liposomes had t1/2 =77.3 ± 9.6 min compared to 9.7 ± 2.3 min for free DS. In vitro cytotoxicity on wild type and resistant colorectal cancer cell lines was evaluated by MTT assay. All liposomal formulations of DS were cytotoxic to both the wild type and resistant colorectal cancer cell lines and were able to reverse chemoresistance at low nanomolar concentrations. In conclusion, PEGylated liposomes have a greater potential to be used as an anticancer carrier for disulfiram.

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Section: Resultsmentioning

confidence: 99%

Development of Injectable PEGylated Liposome Encapsulating Disulfiram for Colorectal Cancer Treatment

et al. 2019

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“…A major barrier towards the development of [Cu(S 2 CNEt 2 ) 2 ] and related complexes derived from non-polar secondary amines is their extremely poor water solubility (<1 mg mL −1 ). There are a number of possible ways around this, one being to co-deliver disulfiram and Cu(II) such that they react and generate [Cu(S 2 CNEt 2 ) 2 ] within the tumour microenvironment [268][269][270]. This can be done in a number of ways, the most common being the incorporation of disulfiram and Cu(II) into a polymeric nanoparticle, for example as reported by Pu and co-workers who used a poly(ethylene glycol) (PEG)-b-poly(ester carbonate) (PEC) composite [270].…”

Section: Anticancer Agentsmentioning

confidence: 99%

Copper Dithiocarbamates: Coordination Chemistry and Applications in Materials Science, Biosciences and Beyond

Hogarth

Onwudiwe

2021

Inorganics

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Copper dithiocarbamate complexes have been known for ca. 120 years and find relevance in biology and medicine, especially as anticancer agents and applications in materials science as a single-source precursor (SSPs) to nanoscale copper sulfides. Dithiocarbamates support Cu(I), Cu(II) and Cu(III) and show a rich and diverse coordination chemistry. Homoleptic [Cu(S2CNR2)2] are most common, being known for hundreds of substituents. All contain a Cu(II) centre, being either monomeric (distorted square planar) or dimeric (distorted trigonal bipyramidal) in the solid state, the latter being held together by intermolecular C···S interactions. Their d9 electronic configuration renders them paramagnetic and thus readily detected by electron paramagnetic resonance (EPR) spectroscopy. Reaction with a range of oxidants affords d8 Cu(III) complexes, [Cu(S2CNR2)2][X], in which copper remains in a square-planar geometry, but Cu–S bonds shorten by ca. 0.1 Å. These show a wide range of different structural motifs in the solid-state, varying with changes in anion and dithiocarbamate substituents. Cu(I) complexes, [Cu(S2CNR2)2]−, are (briefly) accessible in an electrochemical cell, and the only stable example is recently reported [Cu(S2CNH2)2][NH4]·H2O. Others readily lose a dithiocarbamate and the d10 centres can either be trapped with other coordinating ligands, especially phosphines, or form clusters with tetrahedral [Cu(μ3-S2CNR2)]4 being most common. Over the past decade, a wide range of Cu(I) dithiocarbamate clusters have been prepared and structurally characterised with nuclearities of 3–28, especially exciting being those with interstitial hydride and/or acetylide co-ligands. A range of mixed-valence Cu(I)–Cu(II) and Cu(II)–Cu(III) complexes are known, many of which show novel physical properties, and one Cu(I)–Cu(II)–Cu(III) species has been reported. Copper dithiocarbamates have been widely used as SSPs to nanoscale copper sulfides, allowing control over the phase, particle size and morphology of nanomaterials, and thus giving access to materials with tuneable physical properties. The identification of copper in a range of neurological diseases and the use of disulfiram as a drug for over 50 years makes understanding of the biological formation and action of [Cu(S2CNEt2)2] especially important. Furthermore, the finding that it and related Cu(II) dithiocarbamates are active anticancer agents has pushed them to the fore in studies of metal-based biomedicines.

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“…chelate with copper ion [17,18,20]. For example, DSF/Cu selectively killed human breast cancer cell MDA-MB-231 and lymphocytic leukemia cells in the blood system, but it produced little impact on MCF-10A, normal breast epithelial cells, and normal lymphocytes [11,[21][22][23].…”

Section: Open Accessmentioning

confidence: 99%

“…Several mechanisms of disulfiram cytotoxicity were reported, including irreversible inhibition of aldehyde dehydrogenase (ALDH) and the P-glycoprotein (P-gp) multidrug efflux pump [11,12], superoxide dismutase (SOD) [13,14] and activating nuclear factor-κB (NF-κB) [15,16]. The ability of DSF to chelate divalent cations, such as copper and zinc, also improves its biological activity against tumors [17,18]. Copper plays a critical part in oxidation-reduction reactions and the generation of reactive oxygen species (ROS) in both tumor and normal cell.…”

Section: Introductionmentioning

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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Membrane Loaded Copper Oleate PEGylated Liposome Combined with Disulfiram for Improving Synergistic Antitumor Effect In Vivo

Abstract: The Cu(OI)-L was suitable to be employed in combination with disulfiram for tumor treatment and can also open up opportunities for targeted delivery of copper.

Cited by 31 publications

References 31 publications

Development of Injectable PEGylated Liposome Encapsulating Disulfiram for Colorectal Cancer Treatment

Development of Injectable PEGylated Liposome Encapsulating Disulfiram for Colorectal Cancer Treatment

Copper Dithiocarbamates: Coordination Chemistry and Applications in Materials Science, Biosciences and Beyond

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

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