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The use of bacteria has been attractive to cancer researchers as drugdelivery vehicle because motile bacteria are able to penetrate in tumors. Inparticular, the combination of therapeutic bacteria and conventionalchemotherapy leads to dramatically high anti-tumor efficay. However, themechanisms of the synergy, in part, remain unclear. To aim for understandingthe mechanisms of the synergy of the combination therapy, simultaneous deliveryof C. novyi-NT and chemotherapeutic agents in tumors is mathematically modeledfrom porous media approach. Simulated doxorubicin concentration in tumors afterDoxil administration with or without bacteria agreed reasonably well withexperimental literature. The simulated doxorubicin concentration in tumors bythe combination of Doxil and C. novyi-NT is over twice higher than that ofDoxil alone, as observed in previous experimental literature. This enhancedconcentration is because of the degradation of extracellular matrix of collagenby bacterial proteolytic activity, which reduced interstitial fluid pressure intumors by increasing hydraulic conductivity of interstitium, and thus increasesconvection through vessel walls. Additionally, solid stress alleviation causedby collagen degradation increases vessel density by decompressing bloodvessels. On the other hand, the simulated doxorubicin concentration in tumorsfor non-liposomal doxorubicin is not enhanced by C. novyi-NT because vascularpermeability of free-doxorubicin is larger than Doxil, and thus, increased butrelatively small convection across vessel walls is outweighed by the efflux dueto increased interstitial flow. A strategy to further enhance this combinationtherapy is discussed with sensitivity analysis.

Drug delivery in tumors is enhanced by bacterial proteolytic activity in a size and binding affinity dependent manner -A mechanistic understanding