title: Ligand-directed stearic acid grafted chitosan micelles to increase therapeutic efficacy in hepatic cancer.
abstract: Targeted delivery system would be an interesting platform to enhance the therapeutic effect and to reduce the side effects of anticancer drugs. In this study, we have developed lactobionic acid (LA)-modified chitosan-stearic acid (CS-SA) (CSS-LA) to deliver doxorubicin (DOX) to hepatic cancer cells. The average particle size of CSS-LA/DOX was ∼100 nm with a high entrapment efficiency of >95%. Drug release studies showed that DOX release from pH-sensitive micelles is significantly faster at pH 5.0 than at pH 7.4. The LA conjugated micelles showed enhanced cellular uptake in HepG2 and BEL-7402 liver cancer cells than free drug and unconjugated micelles. Consistently, CSS-LA/DOX showed enhanced cell cytotoxicity in these two cell lines. Annexin-V/FITC and PI based apoptosis assay showed that the number of living cells greatly reduced in this group with marked presence of necrotic and apoptotic cells. LA-conjugated carrier induced typical chromatic condensation of cells; membrane blebbing and apoptotic bodies began to appear. In vivo, CSS-LA/DOX showed an excellent tumor regression profile with no toxic side effects. The active targeting moiety, long circulation profile, and EPR effect contributed to its superior anticancer effect in HepG2 based tumor. Our results showed that polymeric micelles conjugated with LA increased the therapeutic availability of DOX in the liver cancer cell based solid tumor without any toxic side effects. The active targeting ligand conjugated nanoparticulate system could be a promising therapeutic strategy in the treatment of hepatic cancers.
authors.affiliation: Department of Hepatobiliary, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University , Shanghai 200438, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yang
authors.forename: Sheng-Xian
authors.initials: SX
authors.lastname: Yuan
authors.forename: Ling-Hao
authors.initials: LH
authors.lastname: Zhao
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.forename: Jun-Sheng
authors.initials: JS
authors.lastname: Ni
authors.forename: Zhen-Guang
authors.initials: ZG
authors.lastname: Wang
authors.forename: Chuan
authors.initials: C
authors.lastname: Lin
authors.forename: Meng-Chao
authors.initials: MC
authors.lastname: Wu
authors.forename: Wei-Ping
authors.initials: WP
authors.lastname: Zhou
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D048271:Chitosan / Q000737:chemistry*; D004187:Disaccharides / Q000737:chemistry; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use*; D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems / Q000379:methods; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy*; D008819:Mice, Nude; D008823:Micelles; D011108:Polymers / Q000737:chemistry*; D013229:Stearic Acids / Q000737:chemistry*; D023041:Xenograft Model Antitumor Assays
chemical_list: D004187:Disaccharides; D004337:Drug Carriers; D008823:Micelles; D011108:Polymers; D013229:Stearic Acids; C031183:stearic acid; C005608:lactobionic acid; D004317:Doxorubicin; D048271:Chitosan
keywords: antitumor efficacy; apoptosis; doxorubicin; lactobionic acid; polymeric micelles