  The use of bacteria has been attractive to cancer researchers as drug
delivery vehicle because motile bacteria are able to penetrate in tumors. In
particular, the combination of therapeutic bacteria and conventional
chemotherapy leads to dramatically high anti-tumor efficay. However, the
mechanisms of the synergy, in part, remain unclear. To aim for understanding
the mechanisms of the synergy of the combination therapy, simultaneous delivery
of C. novyi-NT and chemotherapeutic agents in tumors is mathematically modeled
from porous media approach. Simulated doxorubicin concentration in tumors after
Doxil administration with or without bacteria agreed reasonably well with
experimental literature. The simulated doxorubicin concentration in tumors by
the combination of Doxil and C. novyi-NT is over twice higher than that of
Doxil alone, as observed in previous experimental literature. This enhanced
concentration is because of the degradation of extracellular matrix of collagen
by bacterial proteolytic activity, which reduced interstitial fluid pressure in
tumors by increasing hydraulic conductivity of interstitium, and thus increases
convection through vessel walls. Additionally, solid stress alleviation caused
by collagen degradation increases vessel density by decompressing blood
vessels. On the other hand, the simulated doxorubicin concentration in tumors
for non-liposomal doxorubicin is not enhanced by C. novyi-NT because vascular
permeability of free-doxorubicin is larger than Doxil, and thus, increased but
relatively small convection across vessel walls is outweighed by the efflux due
to increased interstitial flow. A strategy to further enhance this combination
therapy is discussed with sensitivity analysis.
