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Poly lactic-co-glycolic acid controlled delivery of disulfiram to target liver cancer stem-like cells.

ABSTRACT: Disulfiram (DS), an anti-alcoholism drug, shows very strong cytotoxicity in many cancer types. However its clinical application in cancer treatment is limited by the very short half-life in the bloodstream. In this study, we developed a poly lactic-co-glycolic acid (PLGA)-encapsulated DS protecting DS from the degradation in the bloodstream. The newly developed DS-PLGA was characterized. The DS-PLGA has very satisfactory encapsulation efficiency, drug-loading content and controlled release rate in vitro. PLGA encapsulation extended the half-life of DS from shorter than 2minutes to 7hours in serum. In combination with copper, DS-PLGA significantly inhibited the liver cancer stem cell population. CI-isobologram showed a remarkable synergistic cytotoxicity between DS-PLGA and 5-FU or sorafenib. It also demonstrated very promising anticancer efficacy and antimetastatic effect in liver cancer mouse model. Both DS and PLGA are FDA approved products for clinical application. Our study may lead to repositioning of DS into liver cancer treatment.

SUBMITTER: Wang Z

PROVIDER: S-EPMC5364371 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Poly lactic-co-glycolic acid controlled delivery of disulfiram to target liver cancer stem-like cells.

Wang Zhipeng Z Tan Jiao J McConville Christopher C Kannappan Vinodh V Tawari Patricia Erebi PE Brown James J Ding Jin J Armesilla Angel L AL Irache Juan M JM Mei Qi-Bing QB Tan Yuhuan Y Liu Ying Y Jiang Wenguo W Bian Xiu-Wu XW Wang Weiguang W

Nanomedicine : nanotechnology, biology, and medicine 20160810 2

Disulfiram (DS), an anti-alcoholism drug, shows very strong cytotoxicity in many cancer types. However its clinical application in cancer treatment is limited by the very short half-life in the bloodstream. In this study, we developed a poly lactic-co-glycolic acid (PLGA)-encapsulated DS protecting DS from the degradation in the bloodstream. The newly developed DS-PLGA was characterized. The DS-PLGA has very satisfactory encapsulation efficiency, drug-loading content and controlled release rate ...[more]

PMID: 27521693

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Project description:BackgroundCancer stem cells (CSCs) possess the characteristics associated with normal stem cells and are responsible for cancer initiation, recurrence, and metastasis. CD133 is regarded as a CSCs marker of osteosarcoma, which is the most common primary bone malignancy in childhood and adolescence. Salinomycin, a polyether ionophore antibiotic, has been shown to kill various CSCs, including osteosarcoma CSCs. However, salinomycin displayed poor aqueous solubility that hinders its clinical application. The objective of this study was to develop salinomycin-loaded nanoparticles to eliminate CD133(+) osteosarcoma CSCs.MethodsThe salinomycin-loaded PEGylated poly(lactic-co-glycolic acid) nanoparticles (SAL-NP) conjugated with CD133 aptamers (Ap-SAL-NP) were developed by an emulsion/solvent evaporation method, and the targeting and cytotoxicity of Ap-SAL-NP to CD133(+) osteosarcoma CSCs were evaluated.ResultsThe nanoparticles are of desired particle size (~150 nm), drug encapsulation efficiency (~50%), and drug release profile. After 48 hours treatment of the Saos-2 CD133(+) osteosarcoma cells with drugs formulated in Ap-SAL-NP, SAL-NP, and salinomycin, the concentrations needed to kill 50% of the incubated cells were found to be 2.18, 10.72, and 5.07 μg/mL, respectively, suggesting that Ap-SAL-NP could be 4.92 or 2.33 fold more effective than SAL-NP or salinomycin, respectively. In contrast, Ap-SAL-NP was as effective as SAL-NP, and less effective than salinomycin in Saos-2 CD133(-) cells, suggesting that Ap-SAL-NP possess specific cytotoxicity toward Saos-2 CD133(+) cells. Ap-SAL-NP showed the best therapeutic effect in Saos-2 osteosarcoma xenograft mice, compared with SAL-NP or salinomycin. Significantly, Ap-SAL-NP could selectively kill CD133(+) osteosarcoma CSCs both in vitro and in vivo, as reflected by the tumorsphere formation and proportion of Saos-2 CD133(+) cells.ConclusionOur results suggest that CD133 is a potential target for drug delivery to osteosarcoma CSCs and that it is possible to significantly inhibit the osteosarcoma growth by killing CD133(+) osteosarcoma CSCs. We demonstrated that Ap-SAL-NP have the potential to target and kill CD133(+) osteosarcoma CSCs.

Dataset Information

Poly lactic-co-glycolic acid controlled delivery of disulfiram to target liver cancer stem-like cells.

Publications

Poly lactic-co-glycolic acid controlled delivery of disulfiram to target liver cancer stem-like cells.

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