Gemcitabine-loaded PEGylated unilamellar liposomes vs GEMZAR: biodistribution, pharmacokinetic features and in vivo antitumor activity.
The systemic efficacy of the chemotherapeutic agents presently used to treat solid tumors is limited by their low therapeutic index. Previously, our research group improved the in vitro antitumoral activity of gemcitabine, an anticancer agent rapidly deaminated to the inactive metabolite 2',2'-difluorodeoxyuridine, entrapping it into unilamellar pegylated liposomes made up of 1,2-dipalmitoyl-snglycero-3-phosphocholine monohydrate/cholesterol/N-(carbonyl-methoxypolyethylene glycol-2000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine (6:3:1 molar ratio). In this work, we investigated the in vivo efficiency of the gemcitabine liposomal formulation (5mg/kg) with respect to the antitumoral commercial product GEMZAR (50mg/kg) on an anaplastic thyroid carcinoma xenograft model obtaining similar effects in terms of inhibition of tumor mass proliferation after 4weeks of treatment. The investigation of the carrier biodistribution and the drug pharmacokinetic profile furnished the rationalization of the efficacy of the vesicular system containing the active compound 10-fold less concentrated; in fact, liposomes promoted the concentration of the drug inside the tumor and they increased its plasmatic half-life. In addition, no signs of blood toxicity were observed when vesicular devices of effective doses of the drug were used.
Paolino
Donatella
D
Department of Experimental and Clinical Medicine, University Magna Graecia of Catanzaro, Campus Universitario S. Venuta - Building of BioSciences, Viale Europa, I-88100 Germaneto (CZ), Italy.
Cosco
Donato
D
Racanicchi
Leda
L
Trapasso
Elena
E
Celia
Christian
C
Iannone
Michelangelo
M
Puxeddu
Efisio
E
Costante
Giuseppe
G
Filetti
Sebastiano
S
Russo
Diego
D
Fresta
Massimo
M
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics; D002626:Chemistry, Pharmaceutical; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D005467:Floxuridine / Q000031:analogs & derivatives; D006207:Half-Life; D008081:Liposomes / Q000493:pharmacokinetics; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D011092:Polyethylene Glycols; D020849:Raloxifene Hydrochloride; D014018:Tissue Distribution; D053835:Unilamellar Liposomes; D000093542:Gemcitabine
D000970:Antineoplastic Agents; D008081:Liposomes; D053835:Unilamellar Liposomes; D005467:Floxuridine; D003841:Deoxycytidine; D011092:Polyethylene Glycols; D020849:Raloxifene Hydrochloride; C028210:monomethoxypolyethylene glycol; C084565:2',2'-difluoro-2'-deoxyuridine; D000093542:Gemcitabine