Drug Targeting Organ-Specific Strategies

6 1 Drug Targeting: Basic Concepts and Novel Advances
1.2.5 Lipoproteins
Endogenous lipid particles such as LDL and HDL containing a lipid and apoprotein moiety
can be seen as ‘natural targeted liposomes’. The lipid core can be used to incorporate
lipophilic drugs or lipophilic pro-drugs [21], covalent binding of the drug to the carrier is not
necessary here.The apolipoprotein moiety of these particles can be glycosylated or modified
with other (receptor) targeting ligands. Furthermore, modifications at the level of glycolipid
incorporation can be employed to introduce targeting moieties. As with the liposomes, the
size and charge of the particles determine their behaviour in vivo. Large particles will not
easily pass the endothelial barrier of organs containing blood vessels with a continuous endothelial
cell lining.
The majority of the research on the use of LDL and HDL particles has been devoted to
the targeting of drugs to the liver [22]. With respect to hepatocyte targeting, antiviral agents
and anti-malaria drugs are good candidates for being delivered to the site using lactosylated
lipoproteins [23]. Kupffer cells and sinusoidal endothelial cells in the liver can more specifically
be reached using oxidized and acetylated LDL. Uptake of both LDL derivatives takes
place via scavenger receptors [24,25]. To overcome the difficulties in isolation and handling
of the lipoproteins, various artificial supramolecular systems have been developed to mimic
endogenous lipoproteins. Examples of these are lipoprotein-mimicking biovectorized systems
[26] and lipid variants of the nanoparticles described below [27].
1.2.6 Microspheres and Nanoparticles
Microspheres and nanoparticles often consist of biocompatible polymers and belong either
to the soluble or the particle type carriers. Besides the aforementioned HPMA polymeric
backbone, carriers have also been prepared using dextrans, ficoll, sepharose or poly-L-lysine
as the main carrier body. More recently alginate nanoparticles have been described for the
targeting of antisense oligonucleotides [28]. As with other polymeric carrier systems, the
backbone can be modified with e.g. sugar molecules or antibody fragments to introduce cellular
specificity.
Nanoparticles are smaller (0.2–0.5 µm) than microspheres (30–200 µm) and may have a
smaller drug loading capacity than the soluble polymers. Formulation of drugs into the
nanoparticles can occur at the surface of the particles and at the inner core, depending on the
physicochemical characteristics of the drug. The site of drug incorporation significantly affects
its release rate from the particle [29]. After systemic administration they quickly distribute
to and subsequently become internalized by the cells of the phagocytic system. Even
coating of these carriers with PEG does not completely divert them from distribution to the
phagocytes in liver and spleen. Consequently, intracellular infections in Kupffer cells and
other macrophages are considered a useful target for these systems.
Besides parenteral application of microspheres and nanoparticles for cell selective delivery
of drugs, they have more recently been studied for their application in oral delivery of
peptides and peptidomimetics [30]. Immunological tolerance induction against beta-lactoglobulin
could be achieved by application of this protein in a poly-lactic-glycolide microsphere
formulation [31].