title: Inhibiting the growth of pancreatic adenocarcinoma in vitro and in vivo through targeted treatment with designer gold nanotherapeutics.
abstract: BACKGROUND
  Pancreatic cancer is one of the deadliest of all human malignancies with limited options for therapy. Here, we report the development of an optimized targeted drug delivery system to inhibit advanced stage pancreatic tumor growth in an orthotopic mouse model. METHODPRINCIPAL FINDINGS: Targeting specificity in vitro was confirmed by preincubation of the pancreatic cancer cells with C225 as well as Nitrobenzylthioinosine (NBMPR - nucleoside transporter (NT) inhibitor). Upon nanoconjugation functional activity of gemcitabine was retained as tested using a thymidine incorporation assay. Significant stability of the nanoconjugates was maintained, with only 12% release of gemcitabine over a 24-hour period in mouse plasma. Finally, an in vivo study demonstrated the inhibition of tumor growth through targeted delivery of a low dose of gemcitabine in an orthotopic model of pancreatic cancer, mimicking an advanced stage of the disease.
  
  
  CONCLUSIONS
  We demonstrated in this study that the gold nanoparticle-based therapeutic containing gemcitabine inhibited tumor growth in an advanced stage of the disease in an orthotopic model of pancreatic cancer. Future work would focus on understanding the pharmacokinetics and combining active targeting with passive targeting to further improve the therapeutic efficacy and increase survival.
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Kudgus
authors.forename: Annamaria
authors.initials: A
authors.lastname: Szabolcs
authors.forename: Jameel Ahmad
authors.initials: JA
authors.lastname: Khan
authors.forename: Chad A
authors.initials: CA
authors.lastname: Walden
authors.forename: Joel M
authors.initials: JM
authors.lastname: Reid
authors.forename: J David
authors.initials: JD
authors.lastname: Robertson
authors.forename: Resham
authors.initials: R
authors.lastname: Bhattacharya
authors.forename: Priyabrata
authors.initials: P
authors.lastname: Mukherjee
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001826:Body Fluids / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D015198:Designer Drugs / Q000627:therapeutic use*; D004195:Disease Models, Animal; D006046:Gold / Q000627:therapeutic use; D006801:Humans; D007150:Immunohistochemistry; D008027:Light; D008297:Male; D053768:Metal Nanoparticles / Q000627:therapeutic use / Q000648:ultrastructure; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D058726:Nanoconjugates / Q000627:therapeutic use / Q000648:ultrastructure; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D012542:Scattering, Radiation; D055672:Static Electricity; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D015198:Designer Drugs; D058726:Nanoconjugates; D003841:Deoxycytidine; D006046:Gold; D000093542:Gemcitabine