Drug Targeting Organ-Specific Strategies

homing potential if the antigen recognition domain is affected. To circumvent this problem,
dextran and poly-glutamic acid (PGA) polymers have been used as bridging molecules for
the conjugation of cytostatic drugs (Figure 11.3j–k) [92,93].These polymers were loaded with
the drug and subsequently reacted with amino groups or carbohydrate residues of the carrier.
This technique enabled the conjugation of about 80 doxorubicin molecules per protein in
the case of the dextran bridge, and up to 100 doxorubicin molecules as a result of the PGA
linkage. Efficacy studies with tumour cell lines and in vivo tumour xenograft models in mice
demonstrated the potential of the above-described conjugates [93].
11.5.2 Extracellular Degradation
11.5 The Linkage Between Drug and Carrier 291
In addition to targeting constructs which are endocytosed and which release the active drug
substance intracellularly, other constructs are activated outside the target cell. The latter approach
is not appropriate for target tissues in which the extracellular fluid is rapidly removed
by perfusion, since this would result in a reduction of the time that the drug remained at the
target site and consequently systemic redistribution of the drug would occur. Thus, extracellular
drug release is preferred for use in compartments or tissues where the rate of perfusion
is low. Conditions of slow perfusion are associated with most solid tumours due to their poor
lymphatic drainage. In addition, many tumour cells secrete proteolytic enzymes that are capable
of degrading extracellular matrix in the process of tumour growth and metastasis. If
such enzymes are present in the tumour and in minimal amounts in the extracellular fluid of
other tissues, their presence can be exploited for the selective release of the drug in the tumour
tissue. Examples of such enzymes include cathepsins, that are normally only present in
the lysosomes, and matrix-degrading enzymes such as collagenase or plasminogen activators
[67]. These enzymes are all peptidases, and therefore peptide linkers are feasible spacers for
use with this approach. In the case of a secreted lysosomal enzyme, the same spacer sequences
shown in Table 11.3 can be used for the linkers.
An attractive approach to drug targeting is the delivery of the drug-regenerating enzyme
instead of the actual drug substance to the target site. This approach, also referred to as
ADEPT (antibody directed enzyme pro-drug therapy), is based on a two-step targeting principle.
In the first step, an enzyme is selectively delivered to the target site by means of an antibody–enzyme
conjugate. In the second step, small-molecule pro-drugs are administered,
which will subsequently be activated by the targeted enzyme [94,95].
A point to be noted regarding ADEPT relates to the plasma half-life of the enzyme–antibody
construct. Generally, antibody–enzyme conjugates, are slowly cleared from the central
circulation.Their sustained presence in the bloodstream will lead to non-target site activation
of the pro-drug.Thus, the enzyme and pro-drug should be consecutively administered after a
well-chosen time interval when the concentration of the antibody-enzyme conjugate is still
high in the target tissue while being low in the central circulation and non-target tissues.