Drug Targeting Organ-Specific Strategies

102 4 Cell Specific Delivery of Anti-Inflammatory Drugs to Hepatic Cells
layer. Some of the opsonizing proteins that have been found to play a role are complement
factors [100] and fibronectin [101].The opsonization of liposomes by plasma proteins, in particular
complement factors C3bi and C5a, affects the cell selectivity of this carrier, causing
uptake by the RES and by neutrophils [102]. The uptake of liposomes containing the negatively-charged
phospholipid phophatidylserine (PS) is still a matter of debate. These liposomes
may be taken up by the RES via specific PS receptors or via scavenger receptors, but
here too uptake appears to be mediated predominantly by plasma proteins that bind in a PSspecific
manner to liposomes [103]. The influence of plasma proteins on the uptake route of
PS-containing liposomes was shown by Kamps et al. In vitro studies with liposomes containing
30% PS showed scavenger receptor-mediated uptake in KCs and SECs, but subsequent
in vivo studies did not reveal a significant contribution of scavenger receptors to the KC uptake
of these liposomes [104]. Specific scavenger-mediated uptake of liposomes by SECs was
achieved by coating liposomes with negatively-charged albumins [105].
Lipoproteins are endogenous carriers for the transport of cholesterol and other lipids in
the blood circulation and can be regarded as ‘natural liposomes’. Because they are endogenous,
they are not immunogenic and escape recognition by the RES. They are cleared from
the circulation by specific lipoprotein receptors that recognize the apolipoproteins [106].
They can be directed to non-lipoprotein receptors as well, by chemical modification of the
apolipoprotein moiety. Specific scavenger receptor-mediated uptake by SECs was achieved
by the acetylation of LDL, whereby oxidized LDL was specifically taken up by KCs via the
scavenger receptors and lactosylated LDL via the galactose-particle receptors [106–108].
The lipid core can be used to incorporate lipophilic drugs, whereas more hydrophilic drugs
have to be provided with a lipophilic anchor to enable incorporation. Oleyl, retinyl and cholesteryl
residues have been used for this purpose [109]. Chemical derivatization will however,
alter the pharmacological activity of the parent drug in most cases. The anchors should
therefore be easily removable inside the cell, yielding the original drugs. These liposomes
have not as yet been used much to target drugs to KCs and SECs. Just one study described
the enhancement of the tumouricidal activity of KCs with the immunomodulator muramyldipeptide
incorporated in lactosylated LDL [110].
4.5.1.3 Carriers with Intrinsic Anti-inflammatory Activity
Another approach to drug targeting is the use of carriers with an intrinsic pharmacological
activity. In this ‘dual targeting’ strategy a beneficial effect is achieved both from the carrier itself
and the drug it carries. The negatively-charged HSA carriers, for instance, developed for
the targeting of drugs to HIV-infected cells, exert strong antiviral activity themselves [111].
Possible carriers with intrinsic anti-inflammatory activity are superoxide dismutase (SOD)
and alkaline phosphatase (AP).
SOD is a major oxygen free radical scavenging enzyme, which may therefore have beneficial
effects in liver fibrosis. Through mannosylation or coupling to the polyanion DIVEMA,
SOD was made more liver specific. Both conjugates showed superior inhibition of intrahepatic
ROS production in fibrotic rats as compared to unmodified SOD. DIVEMA-SOD, however,
exhibited the most potent inhibitory effects [112].Although their mode of action is most
probably extracellular free radical scavenging, Man-SOD and DIVEMA-SOD are likely to