Drug Targeting Organ-Specific Strategies

5.3 Renal Delivery Using Macromolecular Carriers: The Low Molecular Weight Protein Approach 143
tion of the protein leakage. However, it should be noted that tubular reabsorption of LMW-
Ps is only slightly reduced during adriamycin-induced chronic proteinuria [92]. With respect
to LMWP catabolism, the data suggest that protein overload will lead to reduced proteolytic
degradation. In that case, an acid labile spacer or a disulfide bond should be chosen to
guarantee an adequate rate of drug release.
We found a difference in susceptibility to proteinuria between cationic LMWP cytochrome-c
and neutral LMWP myoglobulin with respect to their catabolism. This may indicate
that the effect of proteinuria on LMWP catabolism is determined by the proximal tubular
segment in which the LMWPs and the protein overload are processed [88,89,93,94]. We
speculate that, through coupling to a specific LMWP, drugs can be delivered specifically to
those proximal tubular cells that are predominantly affected by proteinuria.This might be essential
for drugs chosen to protect the tubular cell from further damage by proteinuria. In addition,
it may be possible to use certain LMWPs as drug carriers to circumvent the proteinuria-affected
cells. In that case, treatment of diseases unrelated to proteinuria will not be hindered
by the severity of proteinuria.
5.3.6 Renal Delivery of High Doses of LMWPs
The renal cell responsible for the uptake of LMWPs is the proximal tubular cell. LMWPs are
relatively freely filtered by the glomerulus and subsequently reabsorbed by the proximal
tubular cell by megalin/gp330 receptor-mediated endocytosis [95]. In healthy individuals, the
relatively moderate amounts of endogenous LMWPs are completely reabsorbed by the
proximal tubular cells. However, for drug targeting purposes, larger doses of LMWP may be
required. We compared the urinary loss of intact LMWP after intravenous administration of
different doses of LMWP by either single dose injections or by continuous infusions in
healthy rats. From these studies, we concluded that after a continuous low-dose infusion the
non-reabsorbed fraction is considerably less than that after single high-dose injections. However,
infusion could not entirely prevent the loss of intact LMWP into the urine (the loss was
8% of the dose after 100 mg lysozyme kg –1 over 6 h and rose to 33% following
1000 mg lysozyme kg –1 over 6 h).
Cojocel et al. demonstrated clear adverse effects after relatively high doses of lysozyme
[96]. We studied these aspects in more detail and concluded that lysozyme should be given
in a dose of less than 100 mg –1 kg –1 over 6 h to minimize the negative effects on systemic
blood pressure, glomerular filtration and renal blood flow. From these data, it emerged that
LMWPs are suitable to serve as drug carriers to the proximal tubular cell of the kidney. However,
the conjugate should preferably be administered in low-dose by constant infusion to
limit the systemic and renal toxicity and to reduce the urinary loss of the intact conjugate
(unpublished data).
5.3.7 Limitations of the LMWP Strategy of Drug Delivery to the Kidney
Among the disadvantages of the LMWP strategy for the treatment of chronic renal disease
are the requirement for parenteral administration and the possible immunogenicity of the