Drug Targeting Organ-Specific Strategies

282 11 Development of Proteinaceous Drug Targeting Constructs
Table 11.2. Targets for peptide homing devices identified by phage display.
Target tissue Molecular target References
Tumour cells; angiogenic Melanoma- associated [36]
endothelial cells antigen
Lung vasculature Membrane dipeptidase [37]
Endothelial cells in inflammatory
lesions
E-selectin [38]
Skeletal and cardiac muscle Unknown [35]
Tumour vasculature avβ3 and αvβ5 integrin [34] [39, 40]
Tumour vasculature Aaminopeptidase N [41]
Tumour cells Sialyl Lewis x antigen [42]
11.3.4 Modifications of the Physicochemical Properties of the Protein
Apart from the incorporation of small functional groups in a protein that recognize specific
receptors, a more general modification of the physicochemical properties of the protein
can also lead to selective drug targeting. For instance, the coupling of lipophilic drug molecules
to a carrier protein like serum albumin can result in cell-specific uptake of the conjugate
by the non-parenchymal cells of the liver, i.e. the Kupffer and endothelial cells [8,11].
Competition experiments with poly-anionic substrates for the type B scavenger receptor,
demonstrated that this receptor was involved in the clearance of such conjugates [8]. Two
changes in the physicochemical properties of the protein in particular conjugates could be responsible
for the affinity for the scavenger receptor: either the increase in net negative
charge, due to the removal of primary amino groups in the protein, or the increased hydrophobicity
of the proteinaceous structure [11].
Another approach that results in an altered surface-charge of the protein, is the derivatization
of lysine residues with negatively charged substituents. Several carboxylic acids, such
as succinic acid (Suc), aconitic acid (Aco) or maleic acid (Mal), have been used for this purpose.Anionized
proteins are preferentially accumulated in the liver endothelial cells, but uptake
by macrophages in the liver and spleen has also been observed [9,44]. Interestingly,
while this approach resulted in an increased scavenger receptor-mediated uptake in the liver
of large proteins like albumin or catalase, the uptake of anionized LMWPs like superoxide
dismutase (SOD) and LZM was only slightly affected [44]. Instead, Suc-LZM might be an interesting
carrier for delivery of drug substances to the bladder, since its excretion into the
urine was greater than that of drug–LZM conjugates [45]. Although liver targeting of SOD
could not be achieved via succinylation of the LMWP, the attachment of negatively charged
polymeric substituents like DIVEMA (DIVEMA: copolymer of divinyl ether and maleic anhydride)
did result in an increased liver accumulation, as did the attachment of galactose or
mannose sugar residues [46,47].
Another target defined for anionized albumins are cells of the immune system that have
been infected with the human immunodeficiency virus (HIV). Suc-HSA and Aco-HSA are
potent inhibitors of HIV-1 replication in vitro [48]. Thus, anionized albumins can be regarded
as pharmacologically active proteins, that can be used either as such, or as dual-active con-