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Development of Injectable PEGylated Liposome Encapsulating Disulfiram for Colorectal Cancer Treatment.

ABSTRACT: 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.

SUBMITTER: Najlah M

PROVIDER: S-EPMC6920821 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Development of Injectable PEGylated Liposome Encapsulating Disulfiram for Colorectal Cancer Treatment.

Najlah Mohammad M Said Suliman Ammar A Tolaymat Ibrahim I Kurusamy Sathishkumar S Kannappan Vinodh V Elhissi Abdelbary M A AMA Wang Weiguang W

Pharmaceutics 20191114 11

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, nam ...[more]

PMID: 31739556

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Project description:PurposePrevious studies indicate that 99mTc- and fluorescent-labeled c[Cys-Thr-Pro-Ser-Pro-Phe-Ser-His-Cys]OH (TCP-1) peptides were able to detect colorectal cancer (CRC) and tumor-associated vasculature. This study was designed to characterize the targeting properties of PEGylated and non-PEGylated TCP-1 peptides for CRC imaging.ProceduresCell uptake of cyanine 7 (Cy7)-labeled TCP-1 probes (Cy7-PEG4-TCP-1 and Cy7-TCP-1) was investigated in three CRC cell lines (human, HCT116 and HT29; mouse, CT26). Xenograft and orthotopic CRC tumor models with HCT116 and CT26 cells were used to characterize biodistribution and CRC tumor-targeting properties of TCP-1 fluorescence and radioligand with and without PEGylation, [99mTc]Tc-HYNIC-PEG4-TCP-1 vs. [99mTc]Tc-HYNIC-TCP-1.ResultsFluorescence images showed that TCP-1 probes were distributed in the cytoplasm and nucleus of CRC cells. When CT26 cells were treated with unlabeled TCP-1 peptide prior to the cell incubation with Cy7-PEG4-TCP-1, cell fluorescent signals were significantly reduced relative to the cells without blockade. Relative to Cy7-TCP-1, superior brilliance and visibility of fluorescence was observed in the tumor with Cy7-PEG4-TCP-1 and maintained up to 18 h post-injection. [99mTc]Tc-HYNIC-PEG4-TCP-1 images in xenograft and orthotopic CRC models demonstrated that TCP-1 PEGylation preserved tumor-targeting capability of TCP-1, but its distribution (%ID/g) in the liver and intestine was higher than that of [99mTc]Tc-HYNIC-TCP-1 (1.51 ± 0.29 vs 0.53 ± 0.12, P < 0.01). Better tumor visualization by [99mTc]Tc-HYNIC-TCP-1 was observed in the orthotopic CRC model due to lower intestinal radioactivity.ConclusionsTCP-1-based probes undergo endocytosis and localize in the cytoplasm and nucleus of human and mouse CRC cells. Tumor detectability of fluorescent TCP-1 peptide with a PEG4 spacer is promising due to its enhanced tumor binding affinity and rapid clearance kinetics from nontumor tissues. Non-PEGylated [99mTc]Tc-HYNIC-TCP-1 exhibits lower nonspecific accumulation in the liver and gastrointestinal tract and might have better capability for detecting CRC lesions in clinical sites. TCP-1 may represent an innovative targeting molecule for detecting CRC noninvasively.

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Development of Injectable PEGylated Liposome Encapsulating Disulfiram for Colorectal Cancer Treatment.

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Development of Injectable PEGylated Liposome Encapsulating Disulfiram for Colorectal Cancer Treatment.

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