title: Gemcitabine-based therapy for pancreatic cancer using the squalenoyl nucleoside monophosphate nanoassemblies.
abstract: Gemcitabine is currently the most effective agent against advanced pancreatic cancer. However, the major therapeutic hurdles using gemcitabine include rapid inactivation by blood deaminases and fast development of cell chemoresistance, induced by down-regulation of deoxycytidine kinase or nucleoside transporters. To overcome the above drawbacks we designed recently a novel nanomedicine strategy based on squalenoyl prodrug of 5'-monophosphate gemcitabine (SQdFdC-MP). This amphiphilic conjugate self-organized in water into unilamellar vesicles with a mean diameter of 100 nm. In this study the antitumor efficacy of SQdFdC-MP nanoassemblies (NAs) on chemoresistant and chemosensitive pancreatic adenocarcinoma models have been investigated. Cell viability assays showed that SQdFdC-MP NAs displayed higher antiproliferative and cytotoxic effects, particularly in chemoresistant pancreatic tumor cells. In in vivo studies, SQdFdC-MP NAs decreased significantly the growth (∼70%) of human MiaPaCa2 xenografts, also preventing tumor cell invasion, whereas native dFdC did not display any anticancer activity when tumor growth inhibition was only 35% with SQdFdC NAs. These results correlated with a reduction of Ki-67 antigen and the induction of apoptosis mediated by caspase-3 activation in tumor cells. These findings demonstrated the feasibility of utilizing SQdFdC-MP NAs to make tumor cells more sensitive to gemcitabine and thus providing an efficient new therapeutic alternative for pancreatic adenocarcinoma.
authors.affiliation: Univ. Paris Sud, Institut Galien Paris Sud, UMR CNRS 8612, Faculté de Pharmacie, 5, rue J.-B. Clément, 92296 Châtenay-Malabry Cedex, France. Electronic address: andrey.maksimenko@u-psud.fr.
authors.forename: Andrei
authors.initials: A
authors.lastname: Maksimenko
authors.affiliation: Univ. Paris Sud, Institut Galien Paris Sud, UMR CNRS 8612, Faculté de Pharmacie, 5, rue J.-B. Clément, 92296 Châtenay-Malabry Cedex, France.
authors.forename: Joachim
authors.initials: J
authors.lastname: Caron
authors.affiliation: Univ. Paris Sud, Institut Galien Paris Sud, UMR CNRS 8612, Faculté de Pharmacie, 5, rue J.-B. Clément, 92296 Châtenay-Malabry Cedex, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Mougin
authors.affiliation: Univ. Paris Sud, Institut Galien Paris Sud, UMR CNRS 8612, Faculté de Pharmacie, 5, rue J.-B. Clément, 92296 Châtenay-Malabry Cedex, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Desmaële
authors.affiliation: Univ. Paris Sud, Institut Galien Paris Sud, UMR CNRS 8612, Faculté de Pharmacie, 5, rue J.-B. Clément, 92296 Châtenay-Malabry Cedex, France. Electronic address: patrick.couvreur@u-psud.fr.
authors.forename: Patrick
authors.initials: P
authors.lastname: Couvreur
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D019394:Ki-67 Antigen / Q000187:drug effects; D051379:Mice; D050997:Nanomedicine / Q000379:methods*; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry* / Q000627:therapeutic use / Q000648:ultrastructure; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011355:Prodrugs / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D013185:Squalene / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: C525919:4-(N)-tris-nor-qualenoyl-gemcitabine; D000964:Antimetabolites, Antineoplastic; D019394:Ki-67 Antigen; D011355:Prodrugs; D003841:Deoxycytidine; D013185:Squalene; D000093542:Gemcitabine
keywords: 3,3'-Diaminobenzidine (PubChem CID: 23,892); Deoxycytidine kinase; Gemcitabine; Gemcitabine hydrochloride (PubChem CID: 60,749); Gemcitabine monophosphate (PubChem CID: 71317046); MTT (PubChem CID: 64,965); Nanoassemblies; Pancreatic cancer; Penicillin (PubChem CID: 5904); Squalene (PubChem CID: 638,072); Squalenoyl prodrug; Streptomycin (PubChem CID: 19649); l-Glutamine (PubChem CID: 33,032)