Drug Targeting Organ-Specific Strategies

136 5 Delivery of Drugs and Antisense Oligonunucleotides to the Proximal Tubular Cell
Figure 5.7. Schematic representation of the mechanism by which drug targeting to the proximal tubular
cell of the kidney might be achieved using a low molecular weight protein (LMWP) as a carrier.
drolysis of the bond, have been tested in renal cortex homogenates and lysosomal lysates as
well as in in vivo studies. It was found that lysosmal proteases can cleave the peptide bond between
the carboxylic acid group of a drug and an α-amino group of an amino acid. However,
the bond between the carboxylic acid group of the drug and the ε-amino group of lysine
could not be cleaved. Since the conjugation of drugs to amino groups of a protein will predominantly
occur at the ε-lysine residues and only to a small extent at the N-terminal
α-amino group, direct conjugation of a drug via its carboxylic acid group will not result in the
quantitative regeneration of the parent compound [66]. Drugs with a terminal carboxyl
group, such as naproxen [67], can be released as the parent drug from LMWP conjugates using
ester spacers such as L-lactic acid. Increasing spacer length by intercalating a tetra (L-lactic
acid) moiety between the drug and the protein further increases the rate of drug release,
indicating increased accessibility of the bond to the enzymes.
Drugs that have primary amino groups available for conjugation, for instance dopamine
and doxorubicin, can in principle be coupled to LMWPs via oligopeptides. In contrast to the
carboxypeptidases, the aminopeptidases appear to possess a broader specificity. To allow the
release of terminal amino group-containing drugs in the acid environment of the lysosomes
without the requirement of enzymes, an acid-sensitive spacer can be used.
Drugs coupled via a disulfide bond like, captopril, are rapidly released from the proteinspacer
moiety of the conjugate, enzymatically by β-lyase and/or non-enzymatically by thioldisulfide
exchange with endogenous thiols [68].
The different aspects of drug targeting using LMWPs that have been studied to date are
discussed below. As an example, we use the data of two conjugates, naproxen–lysozyme and
captopril–lysozyme.