Drug Targeting Organ-Specific Strategies

134 5 Delivery of Drugs and Antisense Oligonunucleotides to the Proximal Tubular Cell
proach, in which the kinetics of the protein carrier overrule the intrinsic kinetics of the drug
to be targeted by accumulation after the absorptive process, conjugation with amino acids or
small peptides does not necessarily lead to higher specificity for renal uptake. Therefore, for
each drug, different derivatives should be synthesized and tested for the desired kinetic profile.
5.2.2.5 The Soft Drug Concept
When drugs that are activated in the kidney are transported back into the circulation they
may be deposited elsewhere in the body. This undesirable consequence may be overcome
by using the so-called soft drug approach [52]. After administration of N-acetyl-γ-glutamyl-
CGP 18137, active CGP 18137 is specifically generated within the kidney but partly diffuses
back into the circulation. However, in the circulation, this vasodilating agent is rapidly inactivated
by a chemical reaction [49]. For reasons unknown to us, this innovative product was
not developed further. However, this example illustrates the potential of soft drugs in the
field of drug targeting. Irrespective of the fact that the drug is generated from a pro-drug or
released from a carrier, inactivation of the active compound after being released from the
kidney into the blood circulation, could evidently add to the renal selectivity and therapeutic
safety.
5.2.3 The Folate Pro-drug Approach
5.2.3.1 Introduction
The kidney has an important role in conserving folate to counteract a potential deficiency of
this essential vitamin. Circulating folate, in the form of 5-methyltetrahydrofolate, is filtered
through the glomeruli and extensively reabsorbed within the nephron into the renal vascular
circulation. The kidney contains a high affinity folate-binding protein (FBP) that is concentrated
in the proximal tubule cells [53,54]. Immunocytochemical studies have located FBP to
the brush-border membrane, endocytic vacuoles and dense apical tubules, indicating a reabsorption
of folate through endocytosis of the FBP–folate complex followed by dissociation
and recycling of FBP [55]. In this study no significant labelling was found in lysosomes at any
time, implying that there is no transport of FBP to lysosomes for degradation.
Recently it was shown that folate transport from the basolateral site occurs as readily as
that from the luminal site, indicating that changes in secretion can mediate excess urinary folate
excretion [56].
5.2.3.2 Potential Renal Selectivity of Folate Constructs
It has been hypothesized that folate receptor-mediated endocytosis can be exploited for the
selective delivery of drugs by covalent attachment to folate via its γ-carboxyl group.This concept
was primarily designed for the targeting of various biomolecules to solid tumours. For a