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.

Cyclodextrin Diethyldithiocarbamate Copper II Inclusion Complexes: A Promising Chemotherapeutic Delivery System against Chemoresistant Triple Negative Breast Cancer Cell Lines

“…Diethyldithiocarbamate copper (II) (DDC-Cu) consists of two molecules of diethyldithiocarbamic acid (DDC), a disulfiram (DS) metabolite, with one ion of copper II [ 1 , 2 ]. DS, clinically used as an anti-alcoholism drug, has been recently shown to possess potent anticancer activities against a wide range of cancers including colon, breast, lung, prostate, ovarian, cervical and brain cancers [ 1 , 3 , 4 ]. Additionally, the anticancer activity of DS includes effective termination of drug-resistant cancer stem cells (CSCs) and reverses chemoresistance [ 3 , 5 ].…”

“…DS, clinically used as an anti-alcoholism drug, has been recently shown to possess potent anticancer activities against a wide range of cancers including colon, breast, lung, prostate, ovarian, cervical and brain cancers [ 1 , 3 , 4 ]. Additionally, the anticancer activity of DS includes effective termination of drug-resistant cancer stem cells (CSCs) and reverses chemoresistance [ 3 , 5 ]. However, the biological instability of DS in bloodstream has severely limited its clinical use in anti-cancer therapy [ 3 ].…”

Overexpression of Mucin 1 Suppresses the Therapeutical Efficacy of Disulfiram against Canine Mammary Tumor

“…The volume of tumor size was calculated as follows: V = L × W 2 /2, of which W corresponds to the width and L to the length. Seven days later, the average volume of tumor reached~100 mm 3 , mice were then randomly assigned into two groups and treated with or without disulfiram (50 mg/kg) daily for another 21…”

“…Recently, studies emphasized the anti-tumor activity of disulfiram in breast cancer, pancreatic ductal adenocarcinoma, colorectal cancer, prostate cancer, etc. [ 19 , 20 , 21 , 22 ]. It was shown that disulfiram inhibited the proliferation and migration of tumor cells, promoted apoptosis, and reduced the resistance of tumor cells against chemotherapy and radiotherapy by interfering with different intracellular signals (PI3K/Akt, NF-kB, MAPK, p97/NPL4, ALDH, and proteosome) [ 23 , 24 , 25 ], which highlighted the role of disulfiram in inhibiting the growth and metastasis of tumors [ 19 ].…”

Preparation and evaluation of a Rubropunctatin-loaded liposome anticancer drug carrier

“…However, encapsulation systems such as b-CDs or liposomes provide a molecular shield for photolabile drugs, thereby delaying their photodegradation. 35,36 Therefore, our study compared and analyzed the photostability of Rubropunctatin on its own and with R-Liposome.…”