title: Hyaluronic acid-coated liposomes for active targeting of gemcitabine.
abstract: The aim of this work was the preparation, characterization, and preliminary evaluation of the targeting ability toward pancreatic adenocarcinoma cells of liposomes containing the gemcitabine lipophilic prodrug [4-(N)-lauroyl-gemcitabine, C12GEM]. Hyaluronic acid (HA) was selected as targeting agent since it is biodegradable, biocompatible, and can be chemically modified and its cell surface receptor CD44 is overexpressed on various tumors. For this purpose, conjugates between a phospholipid, the 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE), and HA of two different low molecular weights 4800 Da (12 disaccharidic units) and 12,000 Da (32 disaccharidic units), were prepared, characterized, and introduced in the liposomes during the preparation. Different liposomal formulations were prepared and their characteristics were analyzed: size, Z potential, and TEM analyses underline a difference in the HA-liposomes from the non-HA ones. In order to better understand the HA-liposome cellular localization and to evaluate their interaction with CD44 receptor, confocal microscopy studies were performed. The results demonstrate that HA facilitates the recognition of liposomes by MiaPaCa2 cells (CD44(+)) and that the uptake increases with increase in the polymer molecular weight. Finally, the cytotoxicity of the different preparations was evaluated and data show that incorporation of C12GEM increases their cytotoxic activity and that HA-liposomes inhibit cell growth more than plain liposomes. Altogether, the results demonstrate the specificity of C12GEM targeting toward CD44-overexpressing pancreatic adenocarcinoma cell line using HA as a ligand.
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, University of Torino, Italy. Electronic address: silvia.arpicco@unito.it.
authors.forename: Silvia
authors.initials: S
authors.lastname: Arpicco
authors.forename: Carlotta
authors.initials: C
authors.lastname: Lerda
authors.forename: Elisa
authors.initials: E
authors.lastname: Dalla Pozza
authors.forename: Chiara
authors.initials: C
authors.lastname: Costanzo
authors.forename: Nicolas
authors.initials: N
authors.lastname: Tsapis
authors.forename: Barbara
authors.initials: B
authors.lastname: Stella
authors.forename: Massimo
authors.initials: M
authors.lastname: Donadelli
authors.forename: Ilaria
authors.initials: I
authors.lastname: Dando
authors.forename: Elias
authors.initials: E
authors.lastname: Fattal
authors.forename: Luigi
authors.initials: L
authors.lastname: Cattel
authors.forename: Marta
authors.initials: M
authors.lastname: Palmieri
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D016503:Drug Delivery Systems; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics; D006820:Hyaluronic Acid / Q000737:chemistry*; D008081:Liposomes; D008970:Molecular Weight; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010714:Phosphatidylethanolamines / Q000737:chemistry; D011355:Prodrugs
chemical_list: C000591226:4-(N)-lauroylgemcitabine; D000964:Antimetabolites, Antineoplastic; D018960:Hyaluronan Receptors; D008081:Liposomes; D010714:Phosphatidylethanolamines; D011355:Prodrugs; D003841:Deoxycytidine; C007510:1,2-dipalmitoyl-3-phosphatidylethanolamine; D006820:Hyaluronic Acid
keywords: Active targeting; CD44; Gemcitabine; Hyaluronic acid; Liposomes; Pancreatic cancer