title: Chemotherapy for gastric cancer by finely tailoring anti-Her2 anchored dual targeting immunomicelles.
abstract: Micelles with high in vivo serum stability and intratumor accumulation post intravenous (i.v.) injection are highly desired for promoting chemotherapy. Herein, we finely synthesized and tailored well-defined anti-Her2 antibody Fab fragment conjugated immunomicelles (FCIMs), which showed interesting dual targeting function. The thermosensitive poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide)(118) (PID(118)) shell with volume phase transition temperature (VPTT: 39 °C) and the anchored anti-Her2 Fab moiety contributed to the passive and active targeting, respectively. The doxorubicin (DOX) loading capacity of such FCIMs was successfully increased about 2 times by physically enhanced hydrophobicity of inner reservoir without structural deformation. The cellular uptake and intracellular accumulation of DOX by temperature regulated passive and antibody navigated active targeting was 4 times of Doxil. The cytotoxicity assay against Her2 overexpression gastric cancer cells (N87s) showed that the IC50 of the FCIMs was ≈ 9 times lower than that of Doxil under cooperatively targeting by Fab at T > VPTT. FCIMs showed high serum stability by increasing the corona PID(118) chain density (S(corona)/N(agg)). In vivo tissue distribution was evaluated in Balb/c nude mice bearing gastric cancer. As observed by the IVIS(®) imaging system, the intratumor accumulation of such finely tailored FCIMs system was obviously promoted 24 h post i.v. administration. Due to the high stability and super-targeting, the in vivo xenografted gastric tumor growth was significantly inhibited with relative tumor volume <2 which was much smaller than ≈ 5 of the control. Consequently, such finely tailored FCIMs with anti-Her2 active and temperature regulated passive dual tumor-targeting function show high potent in chemotherapy.
authors.affiliation: International Joint Cancer Institute, The Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, PR China. liwei.dds@gmail.com
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: He
authors.initials: H
authors.lastname: Zhao
authors.forename: Weizhu
authors.initials: W
authors.lastname: Qian
authors.forename: Huafei
authors.initials: H
authors.lastname: Li
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Zengwei
authors.initials: Z
authors.lastname: Ye
authors.forename: Ge
authors.initials: G
authors.lastname: Zhang
authors.forename: Mao
authors.initials: M
authors.lastname: Xia
authors.forename: Jinfeng
authors.initials: J
authors.lastname: Li
authors.forename: Jie
authors.initials: J
authors.lastname: Gao
authors.forename: Bohua
authors.initials: B
authors.lastname: Li
authors.forename: Geng
authors.initials: G
authors.lastname: Kou
authors.forename: Jianxin
authors.initials: J
authors.lastname: Dai
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Yajun
authors.initials: Y
authors.lastname: Guo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D003956:Dialysis; D004317:Doxorubicin / Q000494:pharmacology / Q000627:therapeutic use; D016503:Drug Delivery Systems / Q000379:methods*; D004705:Endocytosis / Q000187:drug effects; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions / Q000187:drug effects; D007140:Immunoglobulin Fab Fragments / Q000276:immunology*; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D019344:Lactic Acid / Q000138:chemical synthesis / Q000737:chemistry; D051379:Mice; D008819:Mice, Nude; D008823:Micelles; D011100:Polyglycolic Acid / Q000138:chemical synthesis / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*; D015203:Reproducibility of Results; D044967:Serum / Q000378:metabolism; D012997:Solvents; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013696:Temperature; D014018:Tissue Distribution / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D004317:Doxorubicin; D007140:Immunoglobulin Fab Fragments; D019344:Lactic Acid; D008823:Micelles; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D018719:Erb-b2 Receptor Tyrosine Kinases; D012997:Solvents; C508053:ERBB2 protein, human