PMID- 2790807
OWN - NLM
STAT- MEDLINE
DCOM- 19891120
LR  - 20131121
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 49
IP  - 21
DP  - 1989 Nov 1
TI  - Influence of vesicle size, lipid composition, and drug-to-lipid ratio on the 
      biological activity of liposomal doxorubicin in mice.
PG  - 5922-30
AB  - The effects of vesicle size, lipid composition, and drug-to-lipid ratio on the 
      biological activity of liposomal doxorubicin in mice have been investigated using 
      a versatile procedure for encapsulating doxorubicin inside liposomes. In this 
      procedure, vesicles exhibiting transmembrane pH gradients (acidic inside) were 
      employed to achieve drug trapping efficiencies in excess of 98%. Drug-to-lipid 
      ratios as high as 0.3:1 (wt:wt) could be obtained in a manner that is relatively 
      independent of lipid composition and vesicle size. Egg phosphatidylcholine 
      (EPC)/cholesterol (55:45; mol/mol) vesicles sized through filters with a 200-nm 
      pore size and loaded employing transmembrane pH gradients to achieve a 
      doxorubicin-to-lipid ratio of 0.3:1 (wt/wt) increased the LD50 of free drug by 
      approximately twofold. Removing cholesterol or decreasing the drug-to-lipid ratio 
      in EPC/cholesterol preparations led to significant decreases in the LD50 of 
      liposomal doxorubicin whereas, the LD50 increased 4- to 6-fold when 
      distearoylphosphatidylcholine was substituted for EPC. The results suggest that 
      the stability of liposomally entrapped doxorubicin in the circulation is an 
      important factor in the toxicity of this drug in liposomal form. In contrast, the 
      antitumor activity of liposomal doxorubicin is not influenced dramatically by 
      alterations in lipid composition. Liposomal doxorubicin preparations of EPC, 
      EPC/cholesterol (55:45; mol:mol), EPC/egg phosphatidylglycerol (EPG)/cholesterol 
      (27.5:27.5:45; mol:mol), and distearoylphosphatidylcholine/cholesterol (55:45; 
      mol:mol) all demonstrated similar efficacy to that of free drug when given at 
      doses of 20 mg/kg and below. Higher dose levels of the less toxic formulations 
      could be administered, leading to enhanced increases in life span (ILS) values. 
      Variations in vesicle size, however, strongly influenced the antitumor activity 
      of liposomal doxorubicin. At a dose of 20 mg/kg, large EPC/cholesterol systems 
      are significantly less effective than free drug (with ILS values of 65% and 145%, 
      respectively). In contrast, small systems sized through filters with a 100-nm 
      pore size are more effective than free drug, resulting in an ILS of 375% and a 
      30% long term (greater than 60 days) survival rate when administered at a dose of 
      20 mg/kg. Similar size-dependent effects are observed for 
      distearoylphosphatidylcholine/cholesterol systems.
FAU - Mayer, L D
AU  - Mayer LD
AD  - Department of Biochemistry, University of British Columbia, Vancouver, Canada.
FAU - Tai, L C
AU  - Tai LC
FAU - Ko, D S
AU  - Ko DS
FAU - Masin, D
AU  - Masin D
FAU - Ginsberg, R S
AU  - Ginsberg RS
FAU - Cullis, P R
AU  - Cullis PR
FAU - Bally, M B
AU  - Bally MB
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Drug Carriers)
RN  - 0 (Liposomes)
RN  - 0 (Phosphatidylcholines)
RN  - 80168379AG (Doxorubicin)
RN  - 97C5T2UQ7J (Cholesterol)
SB  - IM
MH  - Animals
MH  - Cholesterol
MH  - Doxorubicin/*administration & dosage/pharmacokinetics/therapeutic use
MH  - Drug Carriers
MH  - Drug Stability
MH  - Female
MH  - Lethal Dose 50
MH  - Leukemia L1210/drug therapy
MH  - Liposomes
MH  - Mice
MH  - Mice, Inbred Strains
MH  - Phosphatidylcholines
MH  - Tissue Distribution
EDAT- 1989/11/01 00:00
MHDA- 1989/11/01 00:01
CRDT- 1989/11/01 00:00
PHST- 1989/11/01 00:00 [pubmed]
PHST- 1989/11/01 00:01 [medline]
PHST- 1989/11/01 00:00 [entrez]
PST - ppublish
SO  - Cancer Res. 1989 Nov 1;49(21):5922-30.