title: A54 Peptide Modified and Redox-Responsive Glucolipid Conjugate Micelles for Intracellular Delivery of Doxorubicin in Hepatocarcinoma Therapy.
abstract: Redox-responsive nanomaterials applied in drug delivery systems (DDS) have attracted an increasing attention in pharmaceutical research as a carrier for antitumor therapy. However, there would be unwanted drug release from a redox-responsive DDS with no selection at nontarget sites, leading to undesirable toxicities in normal tissues and cells. Here, an A54 peptide modified and PEGylated reduction cleavable glucolipid conjugate (A54-PEG-CSO-ss-SA, abbreviated to APCssA) was designed for intracellular delivery of doxorubicin (DOX). The synthesized APCssA could be assembled via micellization self-assembly in aqueous water above the critical micelle concentration (54.9 μg/mL) and exhibited a high drug encapsulation efficiency (77.92%). The APCssA micelles showed an enhanced redox sensitivity in that the disulfide bond could be degraded quickly and the drug would be released from micelles in 10 mM levels of glutathione (GSH). The cellular uptake studies highlighted the affinity of APCssA micelles toward the hepatoma cells (BEL-7402) compared to that toward HepG2 cells. In contrast with the nonresponsive conjugate, the drug was released from APCssA micelles more quickly in 10 mM level of GSH concentration (tumor cells). Moreover, the DOX-loaded APCssA micelles displayed an increased cytotoxicity which was 1.6- to 2.0-fold that of unmodified and nonresponsive micelles. In vivo, the APCssA micelles had stronger distribution to liver and hepatoma tissue and prolonged the circulation and retention time, while the drug release only occurred in the tumor tissue. The APCssA/DOX showed the tumor inhibition rate equal to that of commercial doxorubicin hydrochloric without negative consequence. This study suggested that the APCssA/DOX showed promising potential to treat the tumor for its special tumor targeting, selective intracellular drug release, enhanced antitumor activity, and reduced toxicity on normal tissues.
authors.affiliation: College of Pharmaceutical Science, Zhejiang University , 866 Yuhangtang Road, Hangzhou 310058, PR China.
authors.forename: Na
authors.initials: N
authors.lastname: Liu
authors.affiliation: College of Pharmaceutical Science, Zhejiang University , 866 Yuhangtang Road, Hangzhou 310058, PR China.
authors.forename: Yanan
authors.initials: Y
authors.lastname: Tan
authors.affiliation: College of Pharmaceutical Science, Zhejiang University , 866 Yuhangtang Road, Hangzhou 310058, PR China.
authors.forename: Yingwen
authors.initials: Y
authors.lastname: Hu
authors.affiliation: College of Pharmaceutical Science, Zhejiang University , 866 Yuhangtang Road, Hangzhou 310058, PR China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Meng
authors.affiliation: College of Pharmaceutical Science, Zhejiang University , 866 Yuhangtang Road, Hangzhou 310058, PR China.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Wen
authors.affiliation: College of Pharmaceutical Science, Zhejiang University , 866 Yuhangtang Road, Hangzhou 310058, PR China.
authors.forename: Jingwen
authors.initials: J
authors.lastname: Liu
authors.affiliation: College of Pharmaceutical Science, Zhejiang University , 866 Yuhangtang Road, Hangzhou 310058, PR China.
authors.forename: Bolin
authors.initials: B
authors.lastname: Cheng
authors.affiliation: College of Pharmaceutical Science, Zhejiang University , 866 Yuhangtang Road, Hangzhou 310058, PR China.
authors.forename: Hong
authors.initials: H
authors.lastname: Yuan
authors.affiliation: Department of Pharmacy, School of Medicine Science, Jiaxing University , Zhejiang 314001, PR China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Huang
authors.affiliation: College of Pharmaceutical Science, Zhejiang University , 866 Yuhangtang Road, Hangzhou 310058, PR China.
authors.forename: Fuqiang
authors.initials: F
authors.lastname: Hu
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D016503:Drug Delivery Systems; D006017:Glycolipids / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008823:Micelles; D010084:Oxidation-Reduction; D010455:Peptides / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D011897:Random Allocation; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D006017:Glycolipids; D008823:Micelles; D010455:Peptides; D004317:Doxorubicin
keywords: active targeting; chemotherapeutics cytotoxicity reduction; glycolipid-like micelles; redox-responsive; triggered release