title: Integrinβ6-targeted immunoliposomes mediate tumor-specific drug delivery and enhance therapeutic efficacy in colon carcinoma.
abstract: OBJECTIVE
  Adjuvant chemotherapy is one of the significant treatments for colon cancer in clinic. However, it does not achieve the desired therapeutic efficacy, largely due to chemotherapeutic resistance. Integrinβ6 (ITGB6) is expressed in malignant colonic epithelia, but not in normal epithelia, and is associated with the progression, metastasis, and chemotherapeutic resistance of colon cancer. Accordingly, it is necessary to design therapeutic approaches for efficient and targeted drug delivery into ITGB6-positive cancer cells to improve chemotherapeutic efficacy in colon cancer.
  
  
  METHODS
  PEGylated liposomes were employed to design ITGB6-targeted immunoliposomes, which have ITGB6 monoclonal antibodies (mAbs) conjugated. We evaluated the ITGB6-targeted immunoliposomes internalization into colon cancer cells and examined 5-fluorouracil (5-FU)-induced cellular apoptosis produced by ITGB6-targeted immunoliposomes+5-FU. In addition, the biodistribution and antitumor efficiency of ITGB6-targeted immunoliposomes were observed in vivo.
  
  
  RESULTS
  ITGB6-targeted immunoliposomes enhanced cellular internalization in ITGB6-positive colon cancer cells compared with liposomes. Furthermore, the ITGB6-targeted immunoliposome internalization was dependent on the ITGB6 expression level on cellular surface. ITGB6-targeted immunoliposomes decreased the 5-FU IC50 more than 90% in HT-29 and SW480β6 cells relative to liposomes. Moreover, when loaded with 5-FU, ITGB6-targeted immunoliposomes produced an approximately 1.5-fold higher 5-FU-induced cellular apoptosis rate than liposomes. In vivo, the therapeutic activity of ITGB6-targeted immunoliposomes+5-FU was significantly superior, resulting in 25% to 35% reduction of tumor weight compared with 5-FU or liposomes+5-FU.
  
  
  CONCLUSIONS
  ITGB6-targeted immunoliposomes provide a highly efficient approach for targeted drug delivery in colon cancer and thus offer the potential of a novel and promising anticancer strategy for clinical therapy.
authors.affiliation: Department of Hepatobiliary Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, P.R. China. Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Public Health, Jinan, Shandong, P.R. China.
authors.forename: Benjia
authors.initials: B
authors.lastname: Liang
authors.affiliation: Department of Hepatobiliary Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, P.R. China.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Shahbaz
authors.affiliation: School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong, P.R. China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Hepatobiliary Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, P.R. China. Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Public Health, Jinan, Shandong, P.R. China.
authors.forename: Huijie
authors.initials: H
authors.lastname: Gao
authors.affiliation: Department of Hepatobiliary Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, P.R. China.
authors.forename: Ruliang
authors.initials: R
authors.lastname: Fang
authors.affiliation: Department of Hepatobiliary Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, P.R. China. Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Public Health, Jinan, Shandong, P.R. China.
authors.forename: Zhengchuan
authors.initials: Z
authors.lastname: Niu
authors.affiliation: Department of Hepatobiliary Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, P.R. China. Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Public Health, Jinan, Shandong, P.R. China.
authors.forename: Song
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Hepatobiliary Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, P.R. China. Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Public Health, Jinan, Shandong, P.R. China.
authors.forename: Ben
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Hepatobiliary Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, P.R. China. Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Public Health, Jinan, Shandong, P.R. China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Sun
authors.affiliation: Department of Hepatobiliary Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, P.R. China.
authors.forename: Weibo
authors.initials: W
authors.lastname: Niu
authors.affiliation: Department of Hepatobiliary Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, P.R. China.
authors.forename: Enyu
authors.initials: E
authors.lastname: Liu
authors.affiliation: Department of Hepatobiliary Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, P.R. China.
authors.forename: Jiayong
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Hepatobiliary Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, P.R. China. NiuJun001@hotmail.com.
authors.forename: Jun
authors.initials: J
authors.lastname: Niu
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D002277:Carcinoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000494:pharmacology; D015870:Gene Expression; D006801:Humans; D039641:Integrin beta Chains / Q000235:genetics / Q000378:metabolism*; D008081:Liposomes; D051379:Mice; D058990:Molecular Targeted Therapy; D010316:Particle Size; D014018:Tissue Distribution; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D039641:Integrin beta Chains; D008081:Liposomes; C072170:integrin beta6; D005472:Fluorouracil