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Glycyrrhetinic acid-conjugated polymeric prodrug micelles co-delivered with doxorubicin as combination therapy treatment for liver cancer

Yang, Tong, Lan, Yang, Cao, Mei, Ma, Xueqin, Cao, Aichen, Sun, Yue, Yang, Jianhong, Li, Li, Liu, Yanhua
Colloids and surfaces 2019 v.175 pp. 106-115
apoptosis, blood circulation, cell proliferation, colloids, doxorubicin, glycyrrhizin, growth retardation, hepatoma, human cell lines, humans, micelles, models, neoplasm cells, polyethylene, synergism, therapeutics
Significant synergy of doxorubicin (DOX) and glycyrrhizic acid (GA) in inhibiting the proliferation of cancer cells was demonstrated in the human hepatocellular carcinoma cell line, HepG2. A novel polymeric prodrug micellar carrier based on polyethylene glycol-derivatized GA (PEG-Fmoc-GA), was developed for co-delivery of DOX as a combined anti-cancer treatment. The PEG-Fmoc-GA polymeric prodrug micelles achieved a more effective synergistic action on cell proliferation inhibition and apoptosis induction, when co-delivered with DOX, which can be attributed to the dual effect of the cleaved GA and loaded DOX. PEG-Fmoc-GA conjugated micelles significantly facilitated the intracellular uptake of DOX by HepG2 cells, when compared to a DOX solution alone. In addition, DOX encapsulated in PEG-Fmoc-GA micelles displayed longer blood circulation time, larger drug concentration area under the curve, decreased volume distribution and clearance than DOX solution. Biodistribution studies showed that DOX/PEG-Fmoc-GA micelles were preferentially accumulated at the tumor site. Importantly, DOX/PEG-Fmoc-GA micelles demonstrated a more pronounced therapeutic efficacy in vivo compared with DOX alone with respect to both tumor growth inhibition and overall survival in a HepG2 xenograft model. Thus, PEG-Fmoc-GA polymeric prodrug micelles represent a promising dual-function co-delivery system to achieve anti-cancer synergistic activity of DOX and GA.