title: Micelle Mixtures for Coadministration of Gemcitabine and GDC-0449 To Treat Pancreatic Cancer.
abstract: Hedgehog (Hh) signaling plays an important role in the development and metastasis of pancreatic ductal adenocarcinoma (PDAC). Although gemcitabine (GEM) has been used as a first-line therapy for PDAC, its rapid metabolism and short plasma half-life restrict its use as a single chemotherapy. Combination therapy with more than one drug is a promising approach for treating cancer. Herein, we report the use of methoxy poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylene carbonate)-graft-dodecanol (mPEG-b-PCC-g-DC) copolymer for conjugating GEM and encapsulating a Hh inhibitor, vismodegib (GDC-0449), into its hydrophobic core for treating PDAC. Our objective was to determine whether the micelle mixtures of these two drugs could show better response in inhibiting Hh signaling pathway and restraining the proliferation and metastasis of pancreatic cancer. The in vivo stability of GEM significantly increased after conjugation, which resulted in its increased antitumor efficacy. Almost 80% of encapsulated GDC-0449 and 19% conjugated GEM were released in vitro at pH 5.5 in 48 h in a sustained manner. The invasion, migration, and colony forming features of MIA PaCa-2 cells were significantly inhibited by micelle mixture carrying GEM and GDC-0449. Remarkable increase in PARP cleavage and Bax proved increased apoptosis by this combination formulation compared to individual micelles. This combination therapy efficiently inhibited tumor growth, increased apoptosis, reduced Hh ligands PTCH-1 and Gli-1, and lowered EMT-activator ZEB-1 when injected to athymic nude mice bearing subcutaneous tumor generated using MIA PaCa-2 cells compared to monotherapy as observed from immunohistochemical analysis. In conclusion, micelle mixtures carrying GEM and GDC-0449 have the potential to treat pancreatic cancer.
authors.affiliation: Department of Pharmaceutical Sciences, University of Nebraska Medical Center , Omaha, Nebraska 68198, United States.|Department of Pharmaceutical Technology, Faculty of Pharmacy, Istanbul University , Istanbul, Turkey.
authors.forename: Melek
authors.initials: M
authors.lastname: Karaca
authors.affiliation: Department of Pharmaceutical Sciences, University of Nebraska Medical Center , Omaha, Nebraska 68198, United States.
authors.forename: Rinku
authors.initials: R
authors.lastname: Dutta
authors.affiliation: Department of Pharmaceutical Technology, Faculty of Pharmacy, Istanbul University , Istanbul, Turkey.
authors.forename: Yildiz
authors.initials: Y
authors.lastname: Ozsoy
authors.affiliation: Department of Pharmaceutical Sciences, University of Nebraska Medical Center , Omaha, Nebraska 68198, United States.
authors.forename: Ram I
authors.initials: RI
authors.lastname: Mahato
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy; D000813:Anilides / Q000008:administration & dosage* / Q000737:chemistry*; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000737:chemistry; D017209:Apoptosis / Q000187:drug effects; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry; D007851:Dodecanol / Q000737:chemistry; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008823:Micelles; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D011407:Propane / Q000031:analogs & derivatives / Q000737:chemistry; D011725:Pyridines / Q000008:administration & dosage* / Q000737:chemistry*; D015398:Signal Transduction / Q000187:drug effects; D000093542:Gemcitabine
chemical_list: D000813:Anilides; D000964:Antimetabolites, Antineoplastic; C538724:HhAntag691; D008823:Micelles; D011108:Polymers; D011725:Pyridines; D003841:Deoxycytidine; D007851:Dodecanol; D011092:Polyethylene Glycols; C045990:propylene carbonate; D011407:Propane; D000093542:Gemcitabine
keywords: GDC-0449; combination therapy; gemcitabine; hedgehog signaling; pancreatic cancer; polymeric micelles