Drug Targeting Organ-Specific Strategies

carrier is an homogenous product. In contrast, polymeric carriers are non-homogeneous by
nature. Finally, some proteins have unique characteristics that relate to their complex tertiary
or quaternary structures. For instance, the binding affinity of the protein to its natural receptor
can be the driving force for the selective targeting of the construct. Other interesting carrier
proteins are those that are pharmacologically active themselves. Such intrinsically active
proteins can be used as active drug substances, or as carriers for small drug molecules in socalled
dual active conjugates [4]. Table 11.1 lists examples of carrier proteins that will be discussed
in the following sections of this chapter.
11.2.1 Albumin
An important feature of the carrier protein is the size of the macromolecule. Small proteins
with a molecular weight lower than about 60 kDa, are rapidly cleared from the bloodstream
by glomerular filtration in the kidney [5]. By choosing a carrier protein with an adequately
high molecular weight, renal filtration can be prevented. Being sufficiently large to prevent
renal filtration, but at the same time small enough for efficient tissue penetration, the albumin
molecule has an ideal molecular weight (70 kDa). For this reason, serum albumins from
different origins, such as human (HSA), bovine (BSA) or the albumin type autologous to the
species in which the conjugate is being tested, have been the carrier of choice for many drug
targeting preparations.Two types of drug–albumin conjugates have been reported. First, simple
drug–albumin conjugates which accumulate in the target tissue by passive extravasation
have been described for the delivery of various anti-cancer drugs to solid tumours [6]. Due to
several factors, such as elevated levels of vascular permeability factors and an impaired lymphatic
drainage, tumour blood vessels show an enhanced permeability and retention of
macromolecules [7]. Preferably, a low number of drug molecules should be conjugated per albumin
molecule, since otherwise the construct may undergo enhanced uptake by scavenger
receptors in the liver and spleen [8]. On the other hand, specific uptake by scavenger receptors
has been exploited for the delivery of anti-inflammatory drugs to the liver [9–11].
The second type of drug–albumin conjugate comprises those in which the albumin protein
functions as a backbone for both conjugated drug molecules and homing devices.This type of
structure will selectively accumulate in the target tissue by binding to cell surface receptors,
a process called active targeting. The binding of the construct to the target cells is primarily
driven by the qualities of the homing device, such as type and spatial orientation of the targeting
moiety, rather than by the characteristics of the original carrier backbone. Therefore,
similar structures can be prepared using carrier proteins other than albumin.
11.2.2 Low Molecular Weight Proteins
11.2 The Carrier 277
As stated earlier, proteins with a molecular weight lower than that of albumin are able to
pass through the glomerular membrane in the kidney. Consequently, such low molecular
weight proteins (LMWPs) are rapidly removed from the bloodstream. Following glomerular
filtration, LMWPs are reabsorbed in the proximal tubular cells of the kidney. Since this
process makes the kidney the major catabolic site for these proteins, they can be used as car-