Development of cationic pH-sensitive liposomes with Gemcitabine loading and Fucoidan-coating against pancreatic cancer cells

Gemcitabine (GEM) holds vast promise for tumor therapy, whereas clinical practices fails to meet expectations. One of the reasons is that GEM is quickly transported to lysosomes after being taken up by tumor cells and is hydrolyzed to lose pharmacological activity. In this study, a pH-sensitive cationic liposome (DPPC: DOTAP: CHEMS: DSPE-mPEG2000, pSLs) loaded GEM with fucoidan (FU) coating was designed to enhance the bioavailability of GEM and improve the chemotherapeutic effect in pancreatic ductal adenocarcinoma. FU separated by anion exchange and size exclusion chromatography was coated onto liposomes surface through electrostatic adsorption. FU can deliver drug-loaded liposomes to the tumor site precisely. The results showed that FU-pSLs-GEM had a larger size and lower potential compared to pSLs-GEM, and both could maintain stable structure within 30 days. In vitro release studies demonstrated that pH-sensitive liposomes could release drugs more quickly under acidic conditions. FU-pSLs-GEM showed strong anti-tumor activity in vitro, and exerted efficacy more quickly in Capan-1 cells compared to pSLs-GEM and free GEM. Cell uptake studies showed that cells internalize FU-pSLs-GEM via a clathrin-mediated endocytosis pathway and uptake more drug under acidic conditions. Overall, we demonstrated that FU-pSLs-GEM endosomal escape could improve the bioavailability of GEM, making it a promising drug delivery system.