Biomedical Engineering Reference
In-Depth Information
extrusion using polycarbonate filters with defined pore size (Hunt
and Papahadjopoulos, 1985, US patent 4,529,561 licensed by UCSF
to LTI). All these three laboratories used diff erent lipid compositions
in order to achieve the same goal of extended circulation time, RES
avoidance, and intra-tumor accumulation. Terry Allen achieved it
by inclusion of sphingomyelin and GM1 ganglioside as liposome-
membrane components. Alberto Gabizon was using hydrogenated
phosphatidylinositol (HPI) that he included in small liposomes
composed of “solid” high-T
m
) lipids and cholesterol (Gabizon and
Papahadjopoulos, 1988), while LTI scientists started working with
DSPE-PEG [(Annie Yau-Yang's idea combined with Carl Redmann's
chemical synthesis (Woodle et al., 1991, US patent 5,013,556; Woodle
et al., 1990, rev. in Woodle and Lasic, 1992, and in Woodle 1993)].
LTI was not the only group to work with PEG-DSPE: At the same
time Volodia Torchilin and Leaf Huang and their teams joined forces
and worked on it too (Klivanov et al., 1990), as well as Gregor Cevc's
lab in Munich (Blume and Cevc, 1990). A comprehensive review on
pegylated liposomes is described in many of the papers of
Stealth
Liposomes
(1995), a book edited by Dan Lasic and Frank Martin.
12.4.4
The Lesson Learned from Pegylated Proteins
The inspiration and motivation to start working with pegylated
lipids like PEG-DSPE came to Annie Yau-Yang and others at LTI
from pioneering research in the 1970s by Frank Davis, Abraham
Abuchowski, and colleagues who foresaw the potential of the
conjugation of polyethylene glycol (PEG) to proteins (Abuchowski
et al., 1977; Abuchowski founded Enzon, Inc., which brought three
pegylated drugs to the market. Various length (>350-50,000 Da)
chains of PEG polymer are available. Low-molecular-weight drugs
were also pegylated. However, the main pegylated products so far
are a few proteins and one liposomal formulation — Doxil
®
(the
topic of this review article). For peptides and proteins (including
antibody fragments), mainly relatively large PEG polymers of >5000
Da were used. It was found that pegylation helps improve safety and
efficacy as well as reduce the immunogenicity of many therapeutics
(Veronese and Harries, 2002; Veronese and Pasut, 2005). The
suggested mechanism by which pegylation works is that it is a result
of the alterations it produces in the physicochemical properties of
the molecule to which the PEG residue is covalently attached. These
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