Drug Targeting Organ-Specific Strategies

140 5 Delivery of Drugs and Antisense Oligonunucleotides to the Proximal Tubular Cell
Figure 5.11. Time course of clearance from the kidney of radiolabelled LMWPs after intravenous
injection. After renal uptake, the radiolabelled protein is gradually catabolized and the radioactive
breakdown products released from the kidney, as shown by the decline of renal radioactivity over time.
between the drug and protein carrier. Consequently both the differences in rate of catabolism
between LMWPs as well as the rate of hydrolysis of the bond between the drug and carrier
may be used to manipulate the rate of drug release in the kidney. The variable migration
times of different LMWPs and their conjugates after endocytosis may have consequences for
the intracellular concentration profiles. For instance, in order to achieve relatively constant
cellular levels of the drug, an LMWP which is only slowly degraded might be preferred as a
drug carrier. In contrast, if short-term peak levels of the drug are preferred, treatment with a
rapidly processed protein (with a short migration time) may be a more appropriate choice.
Certain drugs (e.g. peptides and nucleotides) should be released before entering lysosomes
to prevent inactivation by degradative enzymes. For such drugs, a prolonged endosomal migration
time combined with simple hydrolysis of the drug–protein linkage in the acidic environment
of the endosomes, will be preferred to achieve adequate drug release and prevent
an abortive route to the lysosomes.
5.3.3.2 Renal Catabolism of Naproxen–Lysozyme
The coupling of 2 moles of naproxen to 1 mole of lysozyme did not affect the catabolism of
lysozyme in rat kidney [66,75]. After delivery to the kidney, naproxen in the form of naprox-