Drug Targeting Organ-Specific Strategies

were physically entrapped inside the neutral liposomes rather than being complexed on the
surface of cationic liposomes. Gene expression was demonstrated in brain cells beyond the
BBB, indicating both penetration of the liposomes through the BBB in vivo and escape from
the endosomal compartment by an as yet unidentified mechanism.
In conclusion, the use of an immunoliposome-based drug delivery system allows for targeted
delivery of a small molecule such as daunomycin or plasmids to the rat brain in vivo.
Further experiments will be needed to clarify the subcellular routes and compartments involved
in the transcytosis mechanism, as well as the eventual release mechanism in the target
cell.
2.5 Conclusions
2.5 Conclusions 49
Table 2.3. Pharmacokinetics of different formulations of [ 3 H]-daunomycin after i.v. administration to
rats.
Cl (ml min -1 kg -1 ) PS (µl min -1 g -1 tissue) %ID g -1 tissue
Daunomycin 44.7 ± 6.8 1.63 ± 0.20 0.009 ± 0.001
Liposomes 12.6 ± 6.3 0.21 ± 0.06 0.009 ± 0.004
PEG–liposomes 0.19 ± 0.01 0.001 ± 0.005 0.001 ± 0.003
29 OX26 0.91 ± 0.11 0.144 ± 0.038 0.029 ± 0.011
IgG2a 0.37 ± 0.04 0.001 ± 0.006 0.001 ± 0.001
Plasma clearance (Cl), blood–brain barrier permeability surface area product (PS) and accumulation
as % injected dose detected in brain tissue (%ID g -1 tissue) at 1 h after administration. Results show
free [ 3 H]-daunomycin (Daunomycin), [ 3 H]-daunomycin encapsulated in conventional liposomes (Liposomes),
sterically stabilized liposomes (PEG–liposomes), immunoliposomes (29 OX26, where 29 designates
the number of OX26 mAb conjugated per liposome) and control immunoliposomes where the
OX26 mAb was replaced by a non-specific isotype control antibody (IgG 2a). Values are means ± SEM
of n = 3 experiments.
Various strategies to circumvent or to overcome the BBB for brain-directed drug therapies
are under evaluation. It can be predicted that for broad clinical application noninvasive
methods will be required, in particular for chronic diseases where long-term treatment is necessary.
The utilization of physiological transport mechanisms at the BBB in experimental
models generated evidence that pharmacological effects can be achieved with this approach.
In order to be useful as drug delivery systems in humans, several steps are necessary. The
transport capacity must be increased, which is possible through improved vectors and optimized
coupling strategies. In order to avoid potential immunogenicity of antibody-based vectors
from murine sources, humanization techniques are now being applied [117]. Further developments
may include specific targeting to neuronal or non-neuronal cells, and efficient intracellular
release mechanisms.