Biomedical Engineering Reference
In-Depth Information
as the “liposome-forming lipid”; (2) cholesterol, which is needed
to eliminate phase transitions and to increase physical stability
in biological fluids; (3) a negatively charged phospholipid as a
source of the negative charge needed to increase and stabilize
doxorubicin association (partition) to the liposomes' membranes.
During eight years (1980-1988), we studied the fabrication and the
physicochemical properties of many liposomal compositions loaded
with doxorubicin. For these, we compared small unilamellar, large
unilamellar, large oligolamellar, and large multilamellar liposomes,
referred to as SUV, LUV, OLV, and MLV, respectively. In all of the above,
most doxorubicin was associated with the liposomes' bilayer(s).
We also studied short- and long-term physical stability (defined
by changes in size distribution and drug-to-lipid mole ratio), and
chemical stability of the lipids and the doxorubicin of the formulation.
In our in vivo studies in mice, we studied pharmacokinetics (PK) and
biodistribution (BD) in normal and tumor-bearing mice, as well
as toxicity and tolerability in rodents, and finally their therapeutic
efficacy in tumor-bearing mice (several models). The specific in
vitro screening parameters included efficiency of drug capture
(encapsulation = association), preservation of in vitro cytotoxicity (on
tumor cells in culture), and the stability of drug-liposome association
in body fluids. The in vivo screening parameters included in vivo tissue
distribution with special focus on levels in the heart, and anticancer
activity. Representative tumor models relevant to liver tumor were
used. Toxicological evaluation included general toxicology and
cardiotoxicity. The technical screening included critical analysis of
the factors involved in the pharmaceutical development with focus on
shelf life, wet versus lyophilized formulations, quality control tests,
etc. Our studies on this system are described in many publications
(Gabizon et al., 1982; Gabizon et al., 1983; Gabizon et al., 1985;
Gabizon et al., 1986a, 1986b; Gabizon et al., 1988a, 1988b; Gabizon
et al., 1989a, 1989b; Druckman et al., 1989; Goren et al., 1990; Goren
D. (Ph.D. thesis, 1990); Amselem et al., 1993]. Our studies clearly
demonstrated that the negatively charged lipids (at physiological pH)
in the formulation were essential to meet the needs of high efficiency
of doxorubicin encapsulation. The fact that the level of drug loading
(capture) is ~50-fold higher than the trapped aqueous volume
determined by 3 H-inulin (Amslem et al., 1990; Haran et al., 1993)
indicated that most of the captured drug is not in the intraliposome
aqueous phase but rather associated with the negatively charged
 
Search WWH ::




Custom Search