title: In vivo activity of gemcitabine-loaded PEGylated small unilamellar liposomes against pancreatic cancer.
abstract: Gemcitabine (GEM) is presently the standard option for the treatment of advanced pancreatic cancer (PC). We investigated the in vitro and in vivo antitumor potential of GEM-loaded PEGylated liposomes (L-GEM) as a novel agent for the treatment of PC. In vitro analysis of antitumor activity against human PC cell lines, BXPC-3 and PSN-1, showed a significant time- and dose-dependent reduction of cell viability following exposure to L-GEM as compared to free GEM [at 72 h, IC(50): 0.009 vs. 0.027 microM (P = 0.003) for BXPC-3 and 0.003 vs. 0.009 microM (P < 0.001) for PSN1, respectively]. Confocal laser scanning microscopy demonstrated an effective liposome/cell interaction and internalization process following 3-h cell exposure to L-GEM. The in vivo antitumor activity of L-GEM was investigated in a cohort of SCID mice bearing BxPC-3 or PSN-1 xenografts. Animals were i.p. treated with L-GEM (5 mg/kg), or a threefold increased dose of free GEM (15 mg/kg), or empty liposomes or vehicle, twice a week for 35 days. A significant higher inhibition of tumor growth in mice treated with L-GEM versus free GEM (P = 0.006 and P = 0.004 for BXPC-3 and PSN-1, respectively) or control groups (P = 0.0001), translated in a survival advantage of L-GEM treated animals versus other groups. Pharmacokinetic studies showed enhancement of systemic bioavailability of L-GEM (t (1/2) = 8 h) versus to GEM (t (1/2) = 1.5 h). Our findings demonstrate that L-GEM is an effective agent against PC and exerts higher antitumor activity as compared to free GEM with no appreciable increase in toxicity. These results provide the pre-clinical rational for L-GEM clinical development for the treatment of PC patients.
authors.affiliation: Department of Pharmacobiological Sciences, University Magna Graecia, Campus Salvatore Venuta, Catanzaro, Italy.
authors.forename: Donato
authors.initials: D
authors.lastname: Cosco
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bulotta
authors.forename: Monica
authors.initials: M
authors.lastname: Ventura
authors.forename: Christian
authors.initials: C
authors.lastname: Celia
authors.forename: Teresa
authors.initials: T
authors.lastname: Calimeri
authors.forename: Gino
authors.initials: G
authors.lastname: Perri
authors.forename: Donatella
authors.initials: D
authors.lastname: Paolino
authors.forename: Nicola
authors.initials: N
authors.lastname: Costa
authors.forename: Paola
authors.initials: P
authors.lastname: Neri
authors.forename: Pierosandro
authors.initials: P
authors.lastname: Tagliaferri
authors.forename: Pierfrancesco
authors.initials: P
authors.lastname: Tassone
authors.forename: Massimo
authors.initials: M
authors.lastname: Fresta
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D004337:Drug Carriers; D006207:Half-Life; D006801:Humans; D008081:Liposomes; D051379:Mice; D016513:Mice, SCID; D018613:Microscopy, Confocal; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D011092:Polyethylene Glycols / Q000737:chemistry; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D004337:Drug Carriers; D008081:Liposomes; D003841:Deoxycytidine; D011092:Polyethylene Glycols; D000093542:Gemcitabine