Nanosized Drug Delivery Vectors and the Reticuloendothelial System - Intracellular Delivery: Fundamentals and Applications - page 173

4.3 Alternatives to PEGylation

In addition to PEG, several other materials have been used to improve plasma
circulation times and avoid reticuloendothelial uptake of liposomes, including mono-
sialoganglioside GM1, hydrogenated phosphatidylinositol and glucuronide conju-
gates. Studies in mice and in vitro in isolated murine bone marrow macrophages have
demonstrated that the inclusion of only 5% GM1 into the liposome structure has the
capacity to significantly reduce uptake of the liposome into RES organs (Allen et al.
1991a, b ). This is reportedly due to the capacity of GM1 to prevent opsonisation of
the liposome. In vitro , as the molar ratio of GM1 increases, so too does uptake of the
liposomes by macrophages (Allen et al. 1991a ). In vivo , uptake into the liver and
spleen over 24 h can be halved when compared to liposomes of similar composition
(Allen et al. 1991b ). At molar ratios of GM1 or PEG in the range 5-10, however, PEG
appears to be superior to GM1 in vitro at reducing the macrophage uptake of lipo-
somes, although interestingly, this is not reflected by in vivo observations that show
equivalent RES avoiding capacity (Allen et al. 1991a, b ).
Although hydrogenated phosphatidylinositol (HPI) has not been widely incorpo-
rated into the design of long circulating liposomes, some research has been conducted
by Alberto Gabizon who has shown in general that increasing the proportion of HPI
into the liposome structure increases blood retention and decreases uptake by the liver
and spleen up to a molar ratio of 41% HPI which results in increased uptake by the
liver with a concomitant decrease in uptake by the spleen on account of the massive
increase in anionic charge (Gabizon and Papahadjopoulos 1992 ). Thus, on account of
the long circulating behavior of HPI-liposomes, Gabizon has demonstrated improved
tumour biodistribution and anti-tumour efficacy of chemotherapeutic drug loaded
liposomes composed of approximately 5 mol% of HPI in tumour bearing mice
(Gabizon 1992 ; Gabizon et al. 1989 ; Gabizon and Papahadjopoulos 1988 ).
The glucuronide conjugate palmityl-D-glucuronide has demonstrated some
capacity to improve the blood circulation time of liposomes in mice by reducing
liver uptake, however it also increases the proportion of a dose taken up by the
spleen by approximately 15%, 12 h after IV dosing (Oku et al. 1992 ). On account
of the increased plasma blood exposure, tumour accumulation of modified lipo-
somes is increased when compared to unmodified liposomes. However, this effect
of the glucuronide is only seen in mice, since administration of palmityl-D-
glucuronide modified liposomes in rats results in an increase in blood clearance and
an increase in uptake by the liver and spleen, presumably via the action of comple-
ment factors (Liu et al. 1995b ).

4.4 Choice of Lipids for Construction of Colloids

As described in the previous sections, certain structural features of a nanoparticle
can render it a target for uptake by reticuloendothelial organs. This applies both to
surface and structural features. Although a number of surface modifications have