Folate-mediated targeting of polymeric conjugates of gemcitabine

被引:76
作者
Cavallaro, G
Mariano, L
Salmaso, S
Caliceti, P
Gaetano, G
机构
[1] Univ Palermo, Dipartimento Chim & Tecnol Farmaceut, I-90123 Palermo, Italy
[2] Univ Padua, Dipartimento Sci Farmaceut, I-35131 Padua, Italy
关键词
polymeric conjugates; gemcitabine; polyaspartamide; folic acid; folate-mediated targeting;
D O I
10.1016/j.ijpharm.2005.10.015
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
The synthesis of two new macromolecular prodrugs for active tumor targeting was set up. Gemcitabine (2'-deoxy-2',2'-difluorocytidine) was conjugated to alpha,beta-poly(N-2-hydroxyethyl)-DL-aspartamide (PHEA) through succinyl or diglycolyl hydrolysable spacers. The targeting agent folic acid was attached to the macromolecular backbone through the aminocaproic spacer. The two conjugates [PHEA-(5'-succinylgemcitabine)-1'-carboxypentyl-folamide and PHEA-(5'-diglycolyl-gemcitabine)-1'-carboxypentyl-folamide], were purified and extensively characterised by spectroscopic (UV, IR and NMR) and chromatographic analyses to determine the correct chemical structure, the purity degree and the reaction yield. In vitro studies demonstrated that the drug release depends on the spacer arm (diglycolyil or succinyl) and incubation pH. After 30 h incubation at pH 7.4, mimicking the plasma and extracellular compartments, the gemcitabine release from the succinyl and diglycolyl derivatives was 28 and 31%, respectively. After 30 h incubation at pH 5.5, mimicking the lisosomial compartment, the drug released from both bioconjugates was lower than 13%. In plasma, the polymer conjugation increased the drug stability and provided for a sustained drug release. In vitro citotoxicity studies performed using human nasopharyngeal epidermal carcinoma KB cells demonstrated that PHEA-(5'-succinylgemcitabine)-1'-carboxypentyl-folamide displays an higher dose dependent cytotoxic effect with respect to PHEA-(5'-diglycolyl-gemcitabine)-1'-carboxypentyl-folamide. (C) 2005 Elsevier B.V. All rights reserved.
引用
收藏
页码:258 / 269
页数:12
相关论文
共 31 条
[1]   EFFICACY AND SAFETY PROFILE OF GEMCITABINE IN NON-SMALL-CELL LUNG-CANCER - A PHASE-II STUDY [J].
ABRATT, RP ;
BEZWODA, WR ;
FALKSON, G ;
GOEDHALS, L ;
HACKING, D ;
RUGG, TA .
JOURNAL OF CLINICAL ONCOLOGY, 1994, 12 (08) :1535-1540
[2]   Optimization of factors influencing the transfection efficiency of folate-PEG-folate-graft-polyethylenimine [J].
Benns, JM ;
Mahato, RI ;
Kim, SW .
JOURNAL OF CONTROLLED RELEASE, 2002, 79 (1-3) :255-269
[3]  
BRAAKHUIS BJM, 1991, CANCER RES, V51, P211
[4]   Polymeric prodrug for release of an antitumoral agent by specific enzymes [J].
Cavallaro, G ;
Pitarresi, C ;
Licciardi, M ;
Giammona, G .
BIOCONJUGATE CHEMISTRY, 2001, 12 (02) :143-151
[5]   Synthesis, physico-chemical and biological characterization of a paclitaxel macromolecular prodrug [J].
Cavallaro, G ;
Licciardi, M ;
Caliceti, P ;
Salmaso, S ;
Giammona, G .
EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS, 2004, 58 (01) :151-159
[6]  
CSOKA K, 1995, SEMIN ONCOL, V22, P47
[7]   Targeted drug conjugates: principles and progress [J].
Garnett, MC .
ADVANCED DRUG DELIVERY REVIEWS, 2001, 53 (02) :171-216
[8]  
GIAMMONA G, 1995, J CONTROL RELEASE, V33, P261, DOI 10.1016/0168-3659(94)00091-8
[9]   REACTION OF ALPHA, BETA-POLY(N-HYDROXYETHYL)-DL-ASPARTAMIDE WITH DERIVATIVES OF CARBOXYLIC-ACIDS [J].
GIAMMONA, G ;
CARLISI, B ;
PALAZZO, S .
JOURNAL OF POLYMER SCIENCE PART A-POLYMER CHEMISTRY, 1987, 25 (10) :2813-2818
[10]   WATER-SOLUBLE COPOLYMERS OF AN ANTIVIRAL AGENT - SYNTHESIS AND THEIR INTERACTION WITH A BIOMEMBRANE MODEL [J].
GIAMMONA, G ;
CARLISI, B ;
PITARRESI, G ;
CAVALLARO, G ;
LIVERI, VT .
JOURNAL OF CONTROLLED RELEASE, 1992, 22 (03) :197-204