title: Tumor-targeted and pH-controlled delivery of doxorubicin using gold nanorods for lung cancer therapy.
abstract: BACKGROUND
  In lung cancer, the efficacy of conventional chemotherapy is limited due to poor drug accumulation in tumors and nonspecific cytotoxicity. Resolving these issues will increase therapeutic efficacy.
  
  
  METHODS
  GNR-Dox-Tf-NPs (gold nanorod-doxorubicin-transferrin-nanoparticles) were prepared by different chemical approaches. The efficacy of these nanoparticles was carried out by cell viability in lung cancer and primary coronary artery smooth muscle cells. The receptor-mediated endocytosis studies were done with human transferrin and desferrioxamine preincubation. The GNR-Dox-Tf nanoparticles induced apoptosis, and DNA damage studies were done by Western blot, H2AX foci, and comet assay.
  
  
  RESULTS
  We developed and tested a gold nanorod-based multifunctional nanoparticle system (GNR-Dox-Tf-NP) that carries Dox conjugated to a pH-sensitive linker and is targeted to the transferrin receptor overexpressed in human lung cancer (A549, HCC827) cells. GNR-Dox-Tf-NP underwent physicochemical characterization, specificity assays, tumor uptake studies, and hyperspectral imaging. Biological studies demonstrated that transferrin receptor-mediated uptake of the GNR-Dox-Tf-NP by A549 and HCC827 cells produced increased DNA damage, apoptosis, and cell killing compared with nontargeted GNR-Dox-NP. GNR-Dox-Tf-NP-mediated cytotoxicity was greater (48% A549, 46% HCC827) than GNR-Dox-NP-mediated cytotoxicity (36% A549, 39% HCC827). Further, GNR-Dox-Tf-NP markedly reduced cytotoxicity in normal human coronary artery smooth muscle cells compared with free Dox.
  
  
  CONCLUSIONS
  Thus, GNR-Dox-Tf nanoparticles can selectively target and deliver Dox to lung tumor cells and alleviate free Dox-mediated toxicity to normal cells.
authors.affiliation: Department of Pathology, Oklahoma City, OK, USA ; Stephenson Cancer Center, Oklahoma City, OK, USA.
authors.forename: Narsireddy
authors.initials: N
authors.lastname: Amreddy
authors.affiliation: Department of Pathology, Oklahoma City, OK, USA ; Stephenson Cancer Center, Oklahoma City, OK, USA.
authors.forename: Ranganayaki
authors.initials: R
authors.lastname: Muralidharan
authors.affiliation: Department of Pathology, Oklahoma City, OK, USA ; Stephenson Cancer Center, Oklahoma City, OK, USA.
authors.forename: Anish
authors.initials: A
authors.lastname: Babu
authors.affiliation: Stephenson Cancer Center, Oklahoma City, OK, USA ; Department of Radiation Oncology University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
authors.forename: Meghna
authors.initials: M
authors.lastname: Mehta
authors.affiliation: CytoViva Inc., Auburn, AL, USA.
authors.forename: Elyse V
authors.initials: EV
authors.lastname: Johnson
authors.affiliation: Stephenson Cancer Center, Oklahoma City, OK, USA ; Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
authors.forename: Yan D
authors.initials: YD
authors.lastname: Zhao
authors.affiliation: Stephenson Cancer Center, Oklahoma City, OK, USA ; Department of Radiation Oncology University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
authors.forename: Anupama
authors.initials: A
authors.lastname: Munshi
authors.affiliation: Department of Pathology, Oklahoma City, OK, USA ; Stephenson Cancer Center, Oklahoma City, OK, USA ; Graduate Program in Biomedical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
authors.forename: Rajagopal
authors.initials: R
authors.lastname: Ramesh
mesh_terms: D053453:Caspase 9 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D016503:Drug Delivery Systems / Q000379:methods*; D065546:Drug Liberation; D004705:Endocytosis / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006046:Gold / Q000737:chemistry*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008175:Lung Neoplasms / Q000188:drug therapy*; D043942:Nanotubes / Q000737:chemistry* / Q000648:ultrastructure; D011990:Receptors, Transferrin / Q000378:metabolism; D014168:Transferrin / Q000378:metabolism
chemical_list: D011990:Receptors, Transferrin; D014168:Transferrin; D006046:Gold; D004317:Doxorubicin; D053453:Caspase 9
keywords: doxorubicin; gold; lung cancer; nanoparticles; transferrin; tumor targeting