Abstract:
Contemporary chemotherapy is limited by disseminated,
resistant cancer. Targeting nanoparticulate drug delivery
systems that encapsulate synergistic drug combinations
are a rational means to increase the therapeutic index of chemotherapeutics.
A lipopolymeric micelle co-encapsulating an
in vitro optimized, synergistic fixed-ratio combination of paclitaxel
(PTX) and clofazimine (B663) has been developed and
called Riminocelles™. The present pre-clinical study investigated
the acute toxicity, systemic exposure, repeat dose toxicity
and efficacy of Riminocelles in parallel to Taxol® at an
equivalent PTX dose of 10 mg/kg. Daily and weekly dosing
schedules were evaluated against Pgp-expressing human colon
adenocarcinoma (HCT-15) xenografts implanted subcutaneously
in athymic mice. Riminocelles produced statistically
significant (p<0.05) tumor growth delays of 3.2 and 2.7 days
for the respective schedules in contrast to Taxol delaying
growth by 0.5 and 0.6 days. Using the control tumor doubling
time of 4.2 days, tumor-cell-kill values of 0.23 for
Riminocelles and 0.04 for Taxol following daily schedules
were calculated. A significant weight loss of 5.7 % after
14 days (p<0.05) relative to the control group (n=8) was
observed for the daily Taxol group whereas Riminocelles
did not incur significant weight loss neither were blood
markers of toxicity elevated after acute administration (n=
3). The safety and efficacy of Riminocelles is statistically superior
to Taxol. However, passive tumor targeting was not
achieved and the tumor burden progressed quickly. Prior to
further animal studies, the in vivo thermodynamic instability of the simple lipopolymeric micellular delivery system requires
improvement so as to maintain and selectively deliver
the fixed-ratio drug combination.