title: Antitumoral activity of PEG-gemcitabine prodrugs targeted by folic acid.
abstract: Gemcitabine, 2',2'-difluoro-2'-deoxycytidine (dFdC), is an antitumor agent effective in the treatment of several solid tumors but its use is hampered by short plasma half-life, rapid metabolism and low selectivity towards tumor tissue. To overcome these limits, bioconjugates of gemcitabine were studied using poly(ethylene glycol) as polymeric carrier. Two types of conjugates were prepared, non-targeted and folic acid targeted conjugates. The formers were obtained starting from mPEG-OH of 5 and 20 kDa with linear or branched structure. The folic acid targeted conjugates, differing for the drug loading, were prepared exploiting a heterobifunctional PEG that allowed a consecutive coupling of the targeting agent and the drug. Folic acid was chosen as targeting agent because its receptor is often over-expressed in many tumors. To increase the polymer drug payload, the bicarboxylic amino acid, aminoadipic acid, was used. All conjugates were able to release the drug in a pH-dependent manner with no role of enzymes. The pharmacokinetic profiles are strictly related to the polymer molecular weight and the folic acid targeting increased 2-3 times the affinity towards the cells over-expressing folic acid receptors. These results are promising and encourage in vivo studies on these conjugates that act as polymeric prodrugs.
authors.affiliation: Pharmaceutical Sciences Department, University of Padua, Via F. Marzolo 5, 35143 Padua, Italy. gianfranco.pasut@unipd.it
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Pasut
authors.forename: Fabiana
authors.initials: F
authors.lastname: Canal
authors.forename: Lisa
authors.initials: L
authors.lastname: Dalla Via
authors.forename: Silvia
authors.initials: S
authors.lastname: Arpicco
authors.forename: Francesco M
authors.initials: FM
authors.lastname: Veronese
authors.forename: Oddone
authors.initials: O
authors.lastname: Schiavon
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003564:Cytidine Deaminase / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D004337:Drug Carriers / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D004355:Drug Stability; D005260:Female; D005492:Folic Acid / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000188:drug therapy; D011092:Polyethylene Glycols / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011355:Prodrugs / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D004337:Drug Carriers; D011355:Prodrugs; D003841:Deoxycytidine; D011092:Polyethylene Glycols; D005492:Folic Acid; D003564:Cytidine Deaminase; D000093542:Gemcitabine