In vivo activity of gemcitabine-loaded PEGylated small unilamellar liposomes against pancreatic cancer.
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.
Cosco
Donato
D
Department of Pharmacobiological Sciences, University Magna Graecia, Campus Salvatore Venuta, Catanzaro, Italy.
Bulotta
Alessandra
A
Ventura
Monica
M
Celia
Christian
C
Calimeri
Teresa
T
Perri
Gino
G
Paolino
Donatella
D
Costa
Nicola
N
Neri
Paola
P
Tagliaferri
Pierosandro
P
Tassone
Pierfrancesco
P
Fresta
Massimo
M
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
D000964:Antimetabolites, Antineoplastic; D004337:Drug Carriers; D008081:Liposomes; D003841:Deoxycytidine; D011092:Polyethylene Glycols; D000093542:Gemcitabine