FACTORS INFLUENCING THE RETENTION AND CHEMICAL-STABILITY OF POLY(ETHYLENE GLYCOL)-LIPID CONJUGATES INCORPORATED INTO LARGE UNILAMELLAR VESICLES

被引:128
作者
PARR, MJ
ANSELL, SM
CHOI, LS
CULLIS, PR
机构
[1] The University of British Columbia, Department of Biochemistry and Molecular Biology, Faculty of Medicine, Vancouver, BC V6T 1Z3
来源
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES | 1994年 / 1195卷 / 01期
关键词
LIPOSOME; POLY(ETHYLENE GLYCOL); DRUG DELIVERY SYSTEM; STABILITY; EXCHANGE; BIODISTRIBUTION;
D O I
10.1016/0005-2736(94)90004-3
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Poly(ethylene glycol)(PEG)-lipid anchor conjugates can prolong the circulation lifetimes of liposomes following intravenous injection. In this work we investigate the influence of the lipid anchor and the nature of the chemical link between the PEG and lipid moieties on circulation life time. It is shown th at incorporation of N-(monomethoxypoly(ethylene glycol)(2000)-succinyl)-1-palmitoyl-2-oleoylphosphatidylethanolamide (MePEG(2000)-S-POPE) into large unilamellar vesicles (LUVs) composed of distearoylphosphatidylcholine (DSPC) and cholesterol (DSPC/cholesterol/MePEG(2000)-S-POPE, 50:45:5, mol/mol) results in only small increases in the circulation lifetimes as observed in mice. This is shown to be due to rapid removal of the hydrophilic coating in vivo, which likely arises from exchange of the entire PEG-lipid conjugate from the liposomal membrane, although chemical breakdown of the PEG-lipid conjugate is also possible. The chemical stability of four different linkages was tested, including succinate, carbamate and amide linkages between MePEG derivatives and the amino head group of PE, as well as a direct link to the phosphate head group of phosphatidic acid (PA). The succinate linkage was found to be the most labile. The anchoring capability of DSPE as compared to POPE in PEG-PE conjugates was also examined. It is shown that incorporation of MePEG(2000)-S-DSPE conjugates into DSPC/cholesterol LUVs results in little loss of the PEG coating in vivo, long circulation lifetimes and reduced chemical breakdown of the PEG-lipid conjugate. This work establishes that DSPE is a considerably more effective anchor for PEG(2000) than POPE and that the chemical stability of PEG-PE conjugates is sensitive to the nature of the linkage and exchangeability of the PEG-PE complex. We suggest that retention of the PEG coating is of paramount importance for prolonged circulation lifetimes.
引用
收藏
页码:21 / 30
页数:10
相关论文
共 28 条
[1]   PHARMACOKINETICS OF STEALTH VERSUS CONVENTIONAL LIPOSOMES - EFFECT OF DOSE [J].
ALLEN, TM ;
HANSEN, C .
BIOCHIMICA ET BIOPHYSICA ACTA, 1991, 1068 (02) :133-141
[2]   LIPOSOMES CONTAINING SYNTHETIC LIPID DERIVATIVES OF POLY(ETHYLENE GLYCOL) SHOW PROLONGED CIRCULATION HALF-LIVES INVIVO [J].
ALLEN, TM ;
HANSEN, C ;
MARTIN, F ;
REDEMANN, C ;
YAUYOUNG, A .
BIOCHIMICA ET BIOPHYSICA ACTA, 1991, 1066 (01) :29-36
[3]   LARGE UNILAMELLAR LIPOSOMES WITH LOW UPTAKE INTO THE RETICULOENDOTHELIAL SYSTEM [J].
ALLEN, TM ;
CHONN, A .
FEBS LETTERS, 1987, 223 (01) :42-46
[4]  
BARTLETT GR, 1959, J BIOL CHEM, V234, P466
[5]   LIPOSOMES FOR THE SUSTAINED DRUG RELEASE INVIVO [J].
BLUME, G ;
CEVC, G .
BIOCHIMICA ET BIOPHYSICA ACTA, 1990, 1029 (01) :91-97
[6]   SEPARATION OF LARGE UNILAMELLAR LIPOSOMES FROM BLOOD COMPONENTS BY A SPIN COLUMN PROCEDURE - TOWARDS IDENTIFYING PLASMA-PROTEINS WHICH MEDIATE LIPOSOME CLEARANCE INVIVO [J].
CHONN, A ;
SEMPLE, SC ;
CULLIS, PR .
BIOCHIMICA ET BIOPHYSICA ACTA, 1991, 1070 (01) :215-222
[7]  
CHONN A, 1992, J BIOL CHEM, V267, P18759
[8]   PROCESSING OF DIFFERENT LIPOSOME MARKERS AFTER INVITRO UPTAKE OF IMMUNOGLOBULIN-COATED LIPOSOMES BY RAT-LIVER MACROPHAGES [J].
DERKSEN, JTP ;
MORSELT, HWM ;
SCHERPHOF, GL .
BIOCHIMICA ET BIOPHYSICA ACTA, 1987, 931 (01) :33-40
[9]   CONTRIBUTION OF COMPLEMENT-SYSTEM ON DESTABILIZATION OF LIPOSOMES COMPOSED OF HYDROGENATED EGG PHOSPHATIDYLCHOLINE IN RAT FRESH PLASMA [J].
FUNATO, K ;
YODA, R ;
KIWADA, H .
BIOCHIMICA ET BIOPHYSICA ACTA, 1992, 1103 (02) :198-204
[10]   LIPOSOME FORMULATIONS WITH PROLONGED CIRCULATION TIME IN BLOOD AND ENHANCED UPTAKE BY TUMORS [J].
GABIZON, A ;
PAPAHADJOPOULOS, D .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1988, 85 (18) :6949-6953