title: Effective targeting of gemcitabine to pancreatic cancer through PEG-cored Flt-1 antibody-conjugated dendrimers.
abstract: Tumor-targeted delivery of anticancer drugs using dendrimers has been recognized as a promising strategy to increase efficiency and reduce adverse effects of chemotherapy. Herein, we developed a dendrimer-based drug delivery system targeting Flt-1 (a receptor for vascular endothelial growth factors (VEGF)) receptor to improve therapeutic efficacy of gemcitabine in pancreatic cancer. Synthesized polyethylene glycol (PEG)-cored PAMAM dendrimers, which bear anionic carboxylic acid groups on the surface were modified with PEG chains, which were then conjugated with Flt-1 antibody. Following structural and chemical characterization studies, gemcitabine HCl-dendrimer inclusion complexes were successfully prepared. These complexes were efficiently engulfed by Flt-1 expressing pancreatic cancer cells, which enhanced the cytotoxicity of gemcitabine. Moreover, pancreatic tumors established in mice were highly targeted by PEG-cored Flt-1 antibody-conjugated dendrimers and increased accumulation of these gemcitabine-loaded complexes exhibited satisfactory in vivo anti-cancer efficacy. In conclusion, dendrimer-based targeted delivery of chemotherapeutics may serve as a promising approach for the treatment of malignancies such as pancreatic cancer that do not benefit from conventional chemotherapy.
authors.affiliation: Department of Pharmaceutical Technology, Faculty of Pharmacy, Hacettepe University, 06100, Ankara, Turkey.
authors.forename: Kıvılcım
authors.initials: K
authors.lastname: Öztürk
authors.affiliation: Department of Basic Oncology, Hacettepe University Cancer Institute, 06100, Ankara, Turkey.
authors.forename: Güneş
authors.initials: G
authors.lastname: Esendağlı
authors.affiliation: Department of Chemistry, Faculty of Arts and Sciences, Yıldız Technical University, 34210, Istanbul, Turkey.
authors.forename: Mustafa Ulvi
authors.initials: MU
authors.lastname: Gürbüz
authors.affiliation: Department of Chemistry, Faculty of Arts and Sciences, Yıldız Technical University, 34210, Istanbul, Turkey.
authors.forename: Metin
authors.initials: M
authors.lastname: Tülü
authors.affiliation: Department of Pharmaceutical Technology, Faculty of Pharmacy, Hacettepe University, 06100, Ankara, Turkey. Electronic address: scalis@hacettepe.edu.tr.
authors.forename: Sema
authors.initials: S
authors.lastname: Çalış
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D050091:Dendrimers / Q000737:chemistry*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004337:Drug Carriers / Q000737:chemistry*; D004339:Drug Compounding; D065546:Drug Liberation; D006801:Humans; D008297:Male; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry*; D013499:Surface Properties; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D050091:Dendrimers; D004337:Drug Carriers; C104700:PAMAM Starburst; D003841:Deoxycytidine; D011092:Polyethylene Glycols; D040281:Vascular Endothelial Growth Factor Receptor-1; D000093542:Gemcitabine
keywords: Cell culture; Dendrimers; Gemcitabine; Pancreatic cancer; Targeted drug delivery; Tumor-bearing mice