title: Codelivery of Doxorubicin and shAkt1 by Poly(ethylenimine)-Glycyrrhetinic Acid Nanoparticles To Induce Autophagy-Mediated Liver Cancer Combination Therapy.
abstract: Combination therapy has been developed as a promising therapeutic approach for hepatocellular carcinoma therapy. Here we report a low toxicity and high performance nanoparticle system that was self-assembled from a poly(ethylenimine)-glycyrrhetinic acid (PEI-GA) amphiphilic copolymer as a versatile gene/drug dual delivery nanoplatform. PEI-GA was synthesized by chemical conjugation of hydrophobic GA moieties to the hydrophilic PEI backbone via an acylation reaction. The PEI-GA nanocarrier could encapsulate doxorubicin (DOX) efficiently with loading level about 12% and further condense DNA to form PEI-GA/DOX/DNA complexes to codeliver drug and gene. The diameter of the complexes is 102 ± 19 nm with zeta potential of 19.6 ± 0.2 mV. Furthermore, the complexes possess liver cancer targeting ability and could promote liver cancer HepG2 cell internalization. Apoptosis of cells could be induced by chemotherapy of DOX, and PI3K/Akt/mTOR signaling pathway acts a beneficial effect on the modulation of autophagy. Here, it is revealed that utilizing PEI-GA/DOX/shAkt1 complexes results in effective autophagy and apoptosis, which are useful to cause cell death. The induction of superfluous autophagy is reported to induce type-II cell death and also could increase the sensity of chemotherapy to tumor cells. In this case, combining autophagy and apoptosis is meaningful for oncotherapy. In this study, PEI-GA/DOX/shAkt1 has demonstrated favorable tumor target ability, little side effects, and ideal antitumor efficacy.
authors.affiliation: Department of Pharmaceutics, The Affiliated Hospital of Xuzhou Medical College , 99 West Huaihai Road, Xuzhou, Jiangsu 221002, China.
authors.forename: Feng-Zhen
authors.initials: FZ
authors.lastname: Wang
authors.forename: Lei
authors.initials: L
authors.lastname: Xing
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau , Macao 999078, China.
authors.forename: Zheng-hai
authors.initials: ZH
authors.lastname: Tang
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau , Macao 999078, China.
authors.forename: Jin-Jian
authors.initials: JJ
authors.lastname: Lu
authors.forename: Peng-Fei
authors.initials: PF
authors.lastname: Cui
authors.forename: Jian-Bing
authors.initials: JB
authors.lastname: Qiao
authors.forename: Lei
authors.initials: L
authors.lastname: Jiang
authors.forename: Hu-Lin
authors.initials: HL
authors.lastname: Jiang
authors.forename: Li
authors.initials: L
authors.lastname: Zong
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry* / Q000627:therapeutic use; D006034:Glycyrrhetinic Acid / Q000737:chemistry*; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry* / Q000627:therapeutic use; D011094:Polyethyleneimine / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000737:chemistry*
chemical_list: D011108:Polymers; D034741:RNA, Small Interfering; D004317:Doxorubicin; D011094:Polyethyleneimine; D051057:Proto-Oncogene Proteins c-akt; D006034:Glycyrrhetinic Acid
keywords: autophagy; combination therapy; glycyrrhetinic acid; liver cancer targeting; self-assembled