Quercetin, a multifunctional therapeutic agent, is used in various types of cancer. However, its therapeutic effect is limited by virtue of poorly aqueous solubility and instability in the physiological medium. To overcome these limitations, we aimed (i) to design quercetin loaded liposomes with unlinked-PEG4000 with regard to not only surface modification but also solubility enhancement, and (ii) to investigate the antineoplastic effects on HeLa cells. PEG4000 increased the quercetin solubility 2.2 fold. PEG4000 modified liposomes displayed small particle size (254 ± 69 nm), low polydispersity index (0.236 ± 0.018), favorable zeta potential (–35.4 ± 0.6 mV), high quercetin encapsulation efficiency (87.6 ± 5.6%), and drug loading (22.2 ± 6.9%). The homogeneity and particle size of stable PEGylated liposomes were proved by transmission electron microscopy. The drug release was reached up to 65.1 ± 3.8% in 6 h. The IC 50 value of quercetin loaded PEGylated liposomes was 16.3 μg/mL on HeLa cells, while that of quercetin was 88.3 μg/mL. PEGylated liposomes remarkably hampered the adherence and colony formation ability of cells according to crystal violet staining tests. The convenience of PEGylated liposomes for the parenteral application was stated by the hemolysis assay. The high-throughput screening assays based on AO/PI staining proved the drastic decrease of viable cell count. Moreover, qPCR tests based on gene expression levels revealed that the quercetin loaded PEGylated liposomes treatment could be more effective than free quercetin on the mitochondrial apoptosis of HeLa cells. These promising results allow considering further in vivo studies for efficient cancer treatment with quercetin loaded PEG4000 modified liposomes.
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