Chemotherapy for gastric cancer by finely tailoring anti-Her2 anchored dual targeting immunomicelles

• Published in: Biomaterials 2012-07, Vol.33 (21), p.5349-5362
• Main Authors: Li, Wei, Zhao, He, Qian, Weizhu, Li, Huafei, Zhang, Li, Ye, Zengwei, Zhang, Ge, Xia, Mao, Li, Jinfeng, Gao, Jie, Li, Bohua, Kou, Geng, Dai, Jianxin, Wang, Hao, Guo, Yajun
• Format: Article
• Language: English
• Subjects: Advanced Basic Science; Animals; Antibodies; Antibody; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Biomedical materials; Block copolymer; Cancer; Cell Death - drug effects; Cell Line, Tumor; Chemotherapy; Dentistry; Dialysis; Doxorubicin - pharmacology; Doxorubicin - therapeutic use; Drug Delivery Systems - methods; Endocytosis - drug effects; Gastric tumor inhibition; Humans; Hydrophobic and Hydrophilic Interactions - drug effects; Immunoglobulin Fab Fragments - immunology; Immunomicelles; In vivo tests; Intracellular Space - drug effects; Intracellular Space - metabolism; Lactic Acid - chemical synthesis; Lactic Acid - chemistry; Mice; Mice, Nude; Micelles; Polyglycolic Acid - chemical synthesis; Polyglycolic Acid - chemistry; Receptor, ErbB-2 - immunology; Reproducibility of Results; Serum - metabolism; Serum stability; Solvents; Stability; Stomach Neoplasms - drug therapy; Stomach Neoplasms - pathology; Surgical implants; Temperature; Tissue Distribution - drug effects; Tumor accumulation; Tumors
• ISSN: 0142-9612; 1878-5905
• DOI: 10.1016/j.biomaterials.2012.04.016

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 (PID118 ) 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 PID118 chain density ( Scorona / Nagg ). 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