title: Magnetic single-walled carbon nanotubes as efficient drug delivery nanocarriers in breast cancer murine model: noninvasive monitoring using diffusion-weighted magnetic resonance imaging as sensitive imaging biomarker.
abstract: OBJECTIVE
  Targeting doxorubicin (DOX) by means of single-walled carbon nanotube (SWCNT) nanocarriers may help improve the clinical utility of this highly active therapeutic agent. Active targeting of SWCNTs using tumor-specific antibody and magnetic attraction by tagging the nanotubes with iron oxide nanoparticles can potentially reduce the unnecessary side effects and provide enhanced theranostics. In the current study, the in vitro and in vivo efficacy of DOX-loaded SWCNTs as theranostic nanoprobes was evaluated in a murine breast cancer model.
  
  
  METHODS
  Iron-tagged SWCNTs conjugated with Endoglin/CD105 antibody with or without DOX were synthetized and extensively characterized. Their biocompatibility was assessed in vitro in luciferase (Luc2)-expressing 4T1 (4T1-Luc2) murine breast cancer cells using TiterTACS™ Colorimetric Apoptosis Detection Kit (apoptosis induction), poly (ADP-ribose) polymerase (marker for DNA damage), and thiobarbituric acid-reactive substances (oxidative stress generation) assays, and the efficacy of DOX-loaded SWCNTs was evaluated by measuring the radiance efficiency using bioluminescence imaging (BLI). Tumor progression and growth were monitored after 4T1-Luc2 cells inoculation using noninvasive BLI and magnetic resonance imaging (MRI) before and after subsequent injection of SWCNT complexes actively and magnetically targeted to tumor sites.
  
  
  RESULTS
  Significant increases in apoptosis, DNA damage, and oxidative stress were induced by DOX-loaded SWCNTs. In addition, a tremendous decrease in bioluminescence was observed in a dose- and time-dependent manner. Noninvasive BLI and MRI revealed successful tumor growth and subsequent attenuation along with metastasis inhibition following DOX-loaded SWCNTs injection. Magnetic tagging of SWCNTs was found to produce significant discrepancies in apparent diffusion coefficient values providing a higher contrast to detect treatment-induced variations as noninvasive imaging biomarker. In addition, it allowed their sensitive noninvasive diagnosis using susceptibility-weighted MRI and their magnetic targeting using an externally applied magnet.
  
  
  CONCLUSIONS
  Enhanced therapeutic efficacy of DOX delivered through antibody-conjugated magnetic SWCNTs was achieved. Further, the superiority of apparent diffusion coefficient measurements using diffusion-weighted MRI was found to be a sensitive imaging biomarker for assessment of treatment-induced changes.
authors.affiliation: Department of Radiological Sciences, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Achraf
authors.initials: A
authors.lastname: Al Faraj
authors.affiliation: Department of Clinical Lab Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Abjal Pasha
authors.initials: AP
authors.lastname: Shaik
authors.affiliation: Department of Radiological Sciences, King Saud University, Riyadh, Saudi Arabia ; Prince Naif Health Research Center, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Asma Sultana
authors.initials: AS
authors.lastname: Shaik
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers; D001943:Breast Neoplasms / Q000175:diagnosis / Q000188:drug therapy*; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000494:pharmacology; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D008279:Magnetic Resonance Imaging; D058185:Magnetite Nanoparticles / Q000737:chemistry*; D051379:Mice; D008807:Mice, Inbred BALB C; D037742:Nanotubes, Carbon / Q000737:chemistry*
chemical_list: D015415:Biomarkers; D058185:Magnetite Nanoparticles; D037742:Nanotubes, Carbon; D004317:Doxorubicin
keywords: breast cancer; carbon nanotubes; diffusion-weighted MRI; drug delivery systems; magnetic resonance imaging; nanomedicine