Drug Targeting Organ-Specific Strategies

5.3 Renal Delivery Using Macromolecular Carriers: The Low Molecular Weight Protein Approach 137
5.3.2 Renal uptake of LMWP Conjugates
5.3.2.1 Renal Uptake of Native LMWPs
Comparison of the kinetic features of different LMWPs revealed that all LMWPs tested so
far (such as lysozyme, cytochrome-c and aprotinin) are quickly cleared from the circulation
and accumulate rapidly in the kidney [38]. The fractions of the injected LMWP that are reported
to be taken up by the kidney vary between 40–80 % of the injected dose. In our studies,
using external counting of radioactivity, at least 80 % of the intravenously injected LMW-
Ps was finally taken up by the kidneys, which is in agreement with renal extraction studies
[69,70]. However, studies in which the actual amount of LMWP in the kidney was measured
directly in the tissue, indicated a lower, but still substantial accumulation of 40% of the injected
dose [71,72]. Apart from the kidney, LMWPs do not seem to accumulate elsewhere in
the body (Figure 5.8).
From this we concluded that LMWPs are potentially suitable to serve as renal-specific
drug carriers: a drug–LMWP conjugate will be rapidly removed from the circulation and the
drug can be intra-renally released. Consequently, major distribution to extra-renal tissue and
related unwanted effects elsewhere in the body can, in principle, be avoided. It is assumed
that secondary redistribution of the generated drug from the kidney is relatively slow so that
systemic concentrations remain below the therapeutic window for extra-renal effects.
Figure 5.8. Renal specificity of a radiolabelled LMWP. Gamma-camera imaging after an intravenous
injection of a radiolabelled low molecular weight protein (LMWP) in the rat, showing the predominant
uptake of the LMWP by the kidneys.
5.3.2.2 Renal Delivery of Naproxen–Lysozyme
Targeting of nonsteroidal anti-inflammatory drugs (NSAIDs) such as naproxen could be of
interest for the treatment of proteinuria and tubular defects such as Fanconi syndrome and
Bartter’s syndrome [73,74]. Although a conjugate with an ester spacer is preferred to a conjugate
with a direct peptide linkage [66,67], we continued our research using naproxen di-