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Enhanced doxorubicin delivery to hepatocellular carcinoma cells via CD147 antibody-conjugated immunoliposomes
Authors:Jian Wang  Zhitao Wu  Guoyu Pan  Junsheng Ni  Fangyuan Xie  Beige Jiang  Lixin Wei  Jie Gao  Weiping Zhou
Affiliation:1. Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China;2. Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China;3. Department of Pharmaceutical Sciences, Second Military Medical University, Shanghai, China;4. Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI, USA;5. Department of Pharmacy, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China;6. Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
Abstract:
HAb18G/CD147, an important marker in the progression of hepatocellular carcinoma (HCC), is highly expressed on the surface of HCC cells. To increase the therapeutic efficacy of Doxil (PEGylated liposomal doxorubicin) against HCC, we constructed CD147-targeted doxorubicin-loaded immunoliposomes (Anti-CD147 ILs-DOX) by conjugating F(ab’)2 of a CD147-specific monoclonal antibody to DSPE-PEG-MAL, and then inserted the antibody-conjugated polymer to Doxil. Anti-CD147 ILs-DOX delivered DOX to CD147-overexpressing HCC cells specifically and efficiently in vitro and in vivo, resulting in enhanced therapeutic effects than non-targeted controls. Strikingly, Anti-CD147 ILs-DOX reduced the CD133-positive fraction of HCC cells, suggesting its potential in reducing the number of HCC stem cells. Pharmacokinetic and biodistribution studies of Anti-CD147 ILs-DOX confirmed its long circulation time and efficient accumulation in tumors. The superior antitumor effects of Anti-CD147 ILs-DOX than other treatments were demonstrated in both HCC cells and patient-derived HCC xenograft models. Anti-CD147 ILs-DOX represent a novel approach for targeted HCC therapy.
Keywords:HCC  hepatocellular carcinoma  DOX  doxorubicin  Anti-CD147 ILs-DOX  Anti-CD147 immunoliposomes containing doxorubicin  Ls-DOX  liposomal doxorubicin  EPR  enhanced permeability and retention effect  PDI  polydispersity index  2-IT  2-iminothiolane hydrochloride  PBS  phosphate buffered solution  DMEM  Dulbecco's modification of Eagle's medium  FBS  fetal bovine serum  CCK-8  cell counting kit-8  DSPE-PEG-MAL  1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[maleimide(polyethylene glycol)-2000]  SDS-PAGE  sodium dodecyl sulfate-polyacrylamide gel electrophoresis  DAPI  4′,6-diamidino-2-phenylindole  FCM  flow cytometry  max  maximum plasma concentration  half-life  AUC  area under curve  CL  clearance  d  apparent volume of distribution  MRT  mean residence time  IC50  half maximal inhibitory concentration  PEG  polyethyleneglycol  PDC  patient-derived cell  PDX  patient-derived xenograft  MTD  maximum tolerated dose  IHC  immunohistochemistry  MFI  mean fluorescence intensity  BSA  albumin from bovine serum  MMP  matrix metalloproteinase  CD147  Antibody  Liposomes  Doxorubicin  Hepatocellular carcinoma
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