Drug Targeting Organ-Specific Strategies

With the development of more advanced drugs such as therapeutic proteins, antisense
molecules and genes, not only controllable release, but also controllable delivery in the target
cells becomes desirable. As a consequence, targeting modalities need to be incorporated
into the vehicles. Although drugs and drug formulation based on proteins were first considered
unfeasible, nowadays practice has proven this not to be the case. Since 1994, on average
more than seven FDA approvals per year have been issued for protein-based therapies. It is
furthermore believed that the increasing yield of protein molecules produced by recombinant
techniques will boost application of protein drugs in the near future [50].
In recent years, various reviews have been published in which the current status of liposome
[2] and antibody [6] based drug targeting strategies have been summarized. Similarly,
the current status of gene therapy in both pre-clinical and clinical settings have been recently
reviewed [51,52].Without trying to be complete, the next sections will give an overview on
recently published studies with drug targeting formulations in a clinical setting.
1.4.1 Liposome Based Therapies in the Clinic
Several liposomal formulations are either under investigation in phase I/II/III clinical trials
or have been approved by the US Food and Drug Administration or cleared for empiric therapy
(see also Chapter 8 for FDA approved formulations in cancer therapy). They are in use
for the treatment of cancer or fungal infections and, consisting of non-targeted liposomes,
aim at slow release of the encapsulated drugs over a prolonged period of time to circumvent
dose-limiting (cardiac) toxicity. Recently reported clinical studies with liposome formulations
are summarized in Table 1.1. The reader is also referred to references [4] and [53] for a
more detailed description of these liposome-based therapeutic strategies.
The general outcome of these studies was that the liposomal drugs were well tolerated and
exerted a clinical effect, although larger studies need to be carried out to demonstrate the extent
of the effects. Furthermore, in the various studies of liposome-incorporated drugs, it was
observed that cardiotoxicity was either absent or only limited, in contrast to studies with nonliposomally
formulated drugs.
1.4.2 Monoclonal Antibody Therapies in the Clinic
1.4 Drug Targeting Strategies in the Clinic 11
Clinical studies on cancer therapy with antibodies have been elegantly summarized by Farah
et al. [6] and more recently by Glennie and Johnson [54]. The majority of antibody-based
therapies in the clinic have exploited the activity of the antibody per se. In the therapy of cancer,
the highest response rates have been observed in patients with haematological malignancies
that are easily accessible to antibodies. In recent years, numerous clinical studies with
antibodies directed against the B cell non-Hodgkin lymphoma-associated epitope CD20
(Rituximab, Rituxan) and the breast carcinoma antigen Her-2 (also known as neu or erbB2)
have been carried out. The mechanisms of action of these antibodies are believed to consist
of complement-mediated lysis, antibody-dependent cellular cytotoxicity by macrophages and
natural killer cells, and signal transduction leading to apoptosis or growth arrest [55]. Novel