Drug Targeting Organ-Specific Strategies

8.5 Strategies to Deliver Drugs to Targets within the Tumour (Cells) 205
these drugs are excreted through the kidneys and liver at least partially by the P-gp systems
[19].
The use of so-called reversal agents to block P-gp in order to decrease multi-drug resistance,
will therefore also affect the elimination rate of those anti-cancer agents that are substrates
for this transport system [19].
The pharmacokinetic processing of macromolecules used as targeting devices or drug carrier
systems is different from that of conventional cytotoxic drugs and plays an important
role in e.g. the targeting efficiency of these cytotoxic agents coupled to the macromolecules.
8.5 Strategies to Deliver Drugs to Targets within the Tumour
(Cells)
As discussed above there are several hurdles to overcome in attempting to enhance the delivery
of the drug to the tumour cell. In addition to the use of high dose chemotherapy with
concomitant protection of normal tissues, a number of other approaches have been developed.
Local perfusion is used with significant benefit in some cancers. This technique is however
limited to cancers localized to a single site, e.g. to one of the extremities. This approach
will not be discussed here.
Other approaches have been exploited in attempting to increase the therapeutic index by
improving the specificity and efficacy of the drug and reducing the toxicity. One example of
this is to target the cytotoxic agent to the tumour cells.To increase specificity and reduce toxicity,
trigger mechanisms have been designed to activate cytotoxic agents synthesized in their
pro-drug/inactive forms, in a site selective manner.Triggering signals can be either exogenous
factors such as light or chemicals or endogenous (cellular) factors such as enzymes. The inherent
features of cancer cells can also be used in the development of targeting agents for tumour
cells. Cancer cells often over-express specific (tumour) antigens, carbohydrate structures,
or growth factor receptors on their cell surface. In addition to tumour cell membranespecific
antigens, some cells also express unique proteases. Based on the above concepts, various
strategies for targeting cytotoxic agents are under development and are currently being
tested in pre-clinical and/or clinical settings. These include:
(1) Monoclonal antibodies (MAb) against tumour-associated antigens or growth factors using
their intrinsic activity or used as carriers to target cytotoxic drugs, radionuclides and
toxins (Section 8.5.1).
(2) Bispecific monoclonal antibodies (BsMAb) which combine the specificity of two different
antibodies within one molecule and cross-link an effector cell or a toxic molecule with
the target cell (Section 8.5.2).
(3) Pro-drugs in conjunction with enzymes or enzyme–MAb conjugates (Section 8.5.3).
(4) Synthetic copolymers as drug carriers (Section 8.5.4);
(5) Liposomes as carriers for drug delivery (Section 8.5.5).
The following sections will discuss these different approaches in more detail. Only those approaches
which are of interest for potential development into clinical strategies will be discussed.