Preparation and cytotoxicity of cisplatin-containing liposomes

Abstract

We encapsulated cisplatin into stealth pH-sensitive liposomes and studied their stability, cytotoxicity and accumulation in a human small-cell lung carcinoma cell line (GLC4) and its resistant subline (GLC4/CDDP). Since reduced cellular drug accumulation has been shown to be the main mechanism responsible for resistance in the GLC4/CDDP subline, we evaluated the ability of this new delivery system to improve cellular uptake. The liposomes were composed of dioleoylphosphatidylethanolamine (DOPE), cholesteryl hemisuccinate (CHEMS), and distearoylphosphatidylethanolamine-polyethyleneglycol 2000 (DSPE-PEG 2000 ) and were characterized by determining the encapsulation percentage as a function of lipid concentration. Among the different formulations, DOPE/CHEMS/DSPE-PEG liposomes (lipid concentration equal to 40 mM) encapsulated cisplatin more efficiently than other concentrations of liposomes (about 20.0%, mean diameter of 174 nm). These liposomes presented good stability in mouse plasma which was obtained using a 0.24-M EDTA solution (70% cisplatin was retained inside the liposomes after 30 min of incubation). Concerning cytotoxic effects, they are more effective (1.34-fold) than free cisplatin for growth inhibition of the human lung cancer cell line A549. The study of cytotoxicity to GLC4 and GLC4/ CDDP cell lines showed similar IC 50 values (approximately 1.4 µM), i.e., cisplatin-resistant cells were sensitive to this cisplatin formulation. Platinum accumulation in both sensitive and resistant cell lines followed the same pattern, i.e., approximately the same intracellular platinum concentration (4.0 x 10 -17 mol/cell) yielded the same cytotoxic effect. These results indicate that long-circulating pH-sensitive liposomes, also termed as stealth pH-sensitive liposomes, may present a promising delivery system for cisplatin-based cancer treatment. This liposome system proved to be able to circumvent the cisplatin resistance, whereas it was not observed when using non-long-circulating liposomes composed of phosphatidylcholine, phosphatidylserine, and cholesterol.

In vitro and in vivo study of a nanoliposomal cisplatin as a radiosensitizer

“…10 In our study, IC50 of CDDP against A549 cells was 2.35 times that of NLE-CDDP (2.63 µg/mL vs 1.12 µg/mL), which was higher than the 1.34 times reported by Carvalho et al 11 In addition, in vivo tests also demonstrated much stronger tumor inhibitions in NLE-CDDP than those in CDDP, indicating that the cytotoxicity of our NLE-CDDP was more significant than the cytotoxicity of CDDP. The strong toxicity of NLE-CDDP may be attributed to its small size (100 nm), which is smaller than that reported in the literature (174 nm).…”

Experimental design of a liposomal lipid system: A potential strategy for paclitaxel-based breast cancer treatment

“…PTX is widely used as a first-line treatment for patients with breast cancer; however, this drug is highly hydrophobic and the use of liposomes as carriers for PTX has been frequently explored [10,12,14]. Our research group has developed long-circulating and pH-sensitive liposomes containing other antitumor drugs, such as cisplatin and ursolic acid, which have showed a marked enhancement of the in vitro and in vivo anticancer activity as well as reduced toxicity [26][27][28]. These systems are generally stable at physiological pH but can undergo destabilization and acquire fusogenic properties under acid conditions at the endosomal stage, thus leading to the drug release into the cytoplasm.…”

Rhenium–platinum antitumor systems

“…Liposomal cisplatin was shown to be more effective and less toxic to non-cancer cells in liposomal forms in comparison with solutions. Also, long-circulating liposomes are considered to overcome drug resistance [40][41][42][43] and in general present a promising delivery system for cisplatin-based cancer treatment.…”