title: In vitro investigation of multidrug nanoparticles for combined therapy with gemcitabine and a tyrosine kinase inhibitor: Together is not better.
abstract: Combined therapy with gemcitabine and tyrosine-kinase inhibitors (i.e., sunitinib) has already demonstrated important benefits in pancreatic cancer treatment. Further therapeutic advantage could be achieved by their co-loading in a single nanoscale system, which enables (i) the co-existence of drugs with different mechanisms of action and pharmacokinetic profiles and (ii) the fine tuning of their release rate overcoming the rapid clearance often observed with free drugs. In this context, the already validated squalenoylation approach has been applied to the design of a multidrug nanoparticle (NP) made by co-self-assembly of the squalene-based prodrugs of gemcitabine (SQGem) and sunitinib (SQSun). We hypothesized that co-delivering of SQGem and SQSun in a single nanoparticle was capable to increase their cytotoxicity on MIA PaCa-2 pancreatic cancer cells compared to the monodrug NPs. Nevertheless, multidrug NPs (i.e., SQGem/SQSun NPs) were as efficient as the physical mixture of the individual monodrug NPs (SQGem NPs + SQSun NPs) thus suggesting that the cytotoxicity raised from the exposure of the cells simultaneously to the two bioconjugates rather than to their original loading into a single or two different nanoparticles. To be noted that the lack of differences in static 2D cultures does not exclude a different behavior in dynamic conditions in vivo.
authors: Institut Galien Paris-Sud, UMR 8612, CNRS, Univ. Paris-Sud, Université Paris-Saclay, Faculté de Pharmacie, 5 rue JB Clément, 92296 Châtenay-Malabry, France. Electronic address: simona.mura@u-psud.fr.
authors: Simona
authors: S
authors: Mura
authors: Institut Galien Paris-Sud, UMR 8612, CNRS, Univ. Paris-Sud, Université Paris-Saclay, Faculté de Pharmacie, 5 rue JB Clément, 92296 Châtenay-Malabry, France.
authors: Eric
authors: E
authors: Buchy
authors: Department of Pharmaceutical Technology, Faculty of Pharmacy, Hacettepe University, Ankara 06100, Turkey.
authors: Gizem
authors: G
authors: Askin
authors: Institut Galien Paris-Sud, UMR 8612, CNRS, Univ. Paris-Sud, Université Paris-Saclay, Faculté de Pharmacie, 5 rue JB Clément, 92296 Châtenay-Malabry, France.
authors: Fanny
authors: F
authors: Cayre
authors: Institut Galien Paris-Sud, UMR 8612, CNRS, Univ. Paris-Sud, Université Paris-Saclay, Faculté de Pharmacie, 5 rue JB Clément, 92296 Châtenay-Malabry, France.
authors: Julie
authors: J
authors: Mougin
authors: Institut Galien Paris-Sud, UMR 8612, CNRS, Univ. Paris-Sud, Université Paris-Saclay, Faculté de Pharmacie, 5 rue JB Clément, 92296 Châtenay-Malabry, France.
authors: Sandrine
authors: S
authors: Gouazou
authors: Institut Galien Paris-Sud, UMR 8612, CNRS, Univ. Paris-Sud, Université Paris-Saclay, Faculté de Pharmacie, 5 rue JB Clément, 92296 Châtenay-Malabry, France.
authors: Dunja
authors: D
authors: Sobot
authors: Institut Galien Paris-Sud, UMR 8612, CNRS, Univ. Paris-Sud, Université Paris-Saclay, Faculté de Pharmacie, 5 rue JB Clément, 92296 Châtenay-Malabry, France; Dipartimento di Scienza e Tecnologia del Farmaco, Università di Torino, via Pietro Giuria 9, 10125 Torino, Italy.
authors: Sabrina
authors: S
authors: Valetti
authors: Dipartimento di Scienza e Tecnologia del Farmaco, Università di Torino, via Pietro Giuria 9, 10125 Torino, Italy.
authors: Barbara
authors: B
authors: Stella
authors: Institut Galien Paris-Sud, UMR 8612, CNRS, Univ. Paris-Sud, Université Paris-Saclay, Faculté de Pharmacie, 5 rue JB Clément, 92296 Châtenay-Malabry, France.
authors: Didier
authors: D
authors: Desmaele
authors: Institut Galien Paris-Sud, UMR 8612, CNRS, Univ. Paris-Sud, Université Paris-Saclay, Faculté de Pharmacie, 5 rue JB Clément, 92296 Châtenay-Malabry, France. Electronic address: patrick.couvreur@u-psud.fr.
authors: Patrick
authors: P
authors: Couvreur
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D046529:Microscopy, Electron, Transmission; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry / Q000648:ultrastructure; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D011758:Pyrroles / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D000077210:Sunitinib; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D003841:Deoxycytidine; D000077210:Sunitinib; D000093542:Gemcitabine
keywords: Combined therapy; Gemcitabine; Nanoparticles; Pancreatic cancer; Sunitinib