Hyperthermie zur tumorgerichteten Therapie mit Liposomen und Gentransferkomlexen im Tiermodell

Despite various approaches of cancer treatment, side effects due to
the missing tumour selectivity are still dose limiting and result
in inefficient therapy outcome. Local hyperthermia of tumour tissue
is crucial to increase the efficiency of common therapies and
already made its way to clinical application. To further increase
efficiency and specificity of antitumoural treatments and to
decrease toxicity, thermosensitive carriers with a phase transition
temperature designed for hyperthermic applications were developed.
After systemic application of thermosensitive PVP-polyplexes in
Neuo2A tumour bearing mice combined with hyperhermia treatment a
significantly higher and more selective gene expression was found
in hyperthermia treated tumours. Combination of PVP10-polyplexes
and hyperthermia showed a high specifity on tumours whereas the
treatment was less efficent compared to systemic application of
PVP10 without hyperthermia. Furthermore, efficiency and specificity
correlated with tumor size, showing higher but less specific
reporter gene expression in larger tumours. Histology showed that
PVP-polyplexes are associated to tumour endothelium which probably
decreased the uptake into the tumour tissue and resulted in lower
efficiency. In conclusion, despite established non viral gene
transfer polyplexes the evaluated PVP-polyplexes are remarkably
specific when combined with hyperthermia. Further experiments are
on their way to enlighten the mechanism of thermosensitive
polyplexes and to optimise efficiency of treatment. To determine
the effect of hyperthermia on clinically used chemotherapeutics
BFS-1 tumour bearing mice were treated with liposomal and free
doxorubicin at hyperthermic and normothermic conditions. No effect
on tumour growth was observed by hyperthermia alone. The
combination of free doxorubicin with hyperthermia showed a
synergistic effect and resulted in a significant tumour growth
delay compared to chemotherapy alone or controls. Hyperthermia
increases the efficiency of free doxorubicin via changing the
physiological properties of tumour tissue. However, liposomal
doxorubicin out rated the hyperthermia effect due to increased
plasma circulation time. Nevertheless hyperthermia is a promising
approach to increase the efficiency of chemotherapeutic drugs. An
in vivo toxicity study of liposomal HePC did not show any side
effects. Because of HePC integration into the lipid membrane a
systemic application of the usually haemolytic drug is possible.
After the treatment with HePC-TSL and hyperthermia a significant
increase of HePC concentration was found in hyperthermia treated
tumours. However, due to low drug levels or study design no effect
on tumour growth was detected. Further studies will focus on the
addition of hydrophilic drugs within the core of HePC-TSL and
therefore enrich two synergistic drugs in hyperthermia treated
tumor tissue. The development of thermosensitive carriers might be
a very promising improvement of cancer treatment. Combined with
hyperthermia those carriers result in a specific, local enrichment
of drugs in targeted tissues.