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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.