Disposition characteristics of glycosylated poly(amino acids) as liver cell-specific drug carrier

被引:25
作者
Akamatsu, K [1 ]
Imai, M [1 ]
Yamasaki, Y [1 ]
Nishikawa, M [1 ]
Takakura, Y [1 ]
Hashida, M [1 ]
机构
[1] Kyoto Univ, Grad Sch Pharmaceut Sci, Dept Drug Delivery Res, Sakyo Ku, Kyoto 6068501, Japan
关键词
drug carrier; glycosylation; hepatic targeting; pharmacokinetics; poly(L-glutamic acid); poly(L-lysine);
D O I
10.3109/10611869808997897
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Potentials of glycosylated poly(amino acids) as carriers of drugs and/or polynucleotides to the liver were studied in mice in detail. Poly-L-glutamic acid (PLGA) and poly-l-lysine (PLL) were selected as carrier backbones and modified with 2-imino-2-methoxyethyl 1-thiogalactoside or mannoside to obtain galactosylated and mannosylated derivatives. After intravenous injection in mice at a dose of 1mg/kg, Gal-PLGA and Man-PLGA were selectively taken up by the liver parenchymal cells (PC) and liver nonparenchymal cells (NPC), respectively. Moreover, the uptake of Gal-PLGA and Man-PLGA by the liver were significantly inhibited by the presence of Gal-BSA and Man-BSA, respectively. On the other hand, PLL was targeted to the liver without glycosylation. However, Gal-PLL and Man-PLL showed higher accumulation in the liver than unmodified PLL. Although Gal-PLL and Man-PLL showed different distribution between PC and NPC from that of PLL, the effect of the modifications was less pronounced than the cases of PLGA derivatives. In addition, these glycosylated poly(amino acids) investigated, regardless of the type of amino acid or the sugar grafted, were rapidly degraded to be eluted in the low molecular weight fractions in a gel filtration chromatography. These results suggest that glycosylated PLGAs can be useful carriers of low molecular drugs to the liver cells through conjugation, while glycosylated PLLs could be targetable carriers to the cells after the reduction of their cationic charge by complex formation with polynucleotides.
引用
收藏
页码:229 / 239
页数:11
相关论文
共 34 条
[1]   Synthesis and biodistribution study of liver-specific prostaglandin E-1 polymeric conjugate [J].
Akamatsu, K ;
Nishikawa, M ;
Takakura, Y ;
Hashida, M .
INTERNATIONAL JOURNAL OF PHARMACEUTICS, 1997, 155 (01) :65-74
[2]  
ARANO Y, 1994, J NUCL MED, V35, P890
[3]   GLOMERULAR PERMSELECTIVITY - BARRIER FUNCTION BASED ON DISCRIMINATION OF MOLECULAR-SIZE AND CHARGE [J].
BRENNER, BM ;
HOSTETTER, TH ;
HUMES, HD .
AMERICAN JOURNAL OF PHYSIOLOGY, 1978, 234 (06) :F455-F460
[4]   Carrier Design: Biodistribution of Branched Polypeptides with a Poly(L-lysine) Backbone [J].
Clegg, J. A. ;
Hudecz, F. ;
Mezoe, G. ;
Pimm, M. V. ;
Szekerke, M. ;
Baldwin, R. W. .
BIOCONJUGATE CHEMISTRY, 1990, 1 (06) :425-430
[5]   LECTIN-SPECIFIC TARGETING OF BETA-GLUCOCEREBROSIDASE TO DIFFERENT LIVER-CELLS VIA GLYCOSYLATED LIPOSOMES [J].
DAS, PK ;
MURRAY, GJ ;
ZIRZOW, GC ;
BRADY, RO ;
BARRANGER, JA .
BIOCHEMICAL MEDICINE, 1985, 33 (01) :124-131
[6]  
DUNCAN JR, 1993, J NUCL MED, V34, P1728
[7]  
FONG DM, 1994, HEPATOLOGY, V20, P1602
[8]   HEPATIC AND INTRAHEPATIC TARGETING OF AN ANTIINFLAMMATORY AGENT WITH HUMAN SERUM-ALBUMIN AND NEOGLYCOPROTEINS AS CARRIER MOLECULES [J].
FRANSSEN, EJF ;
JANSEN, RW ;
VAALBURG, M ;
MEIJER, DKF .
BIOCHEMICAL PHARMACOLOGY, 1993, 45 (06) :1215-1226
[9]  
GONSHO A, 1994, BIOL PHARM BULL, V17, P275
[10]  
GOTO M, 1994, J CONTROL RELEASE, V28, P223