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

TL;DR

This study uses mathematical modeling to reveal how bacterial proteolytic activity enhances tumor drug delivery by degrading extracellular matrix, reducing pressure, and increasing vessel density, especially when combined with liposomal chemotherapy.

Contribution

It provides a mechanistic understanding of how bacterial activity improves drug penetration in tumors, highlighting size and binding affinity dependencies.

Findings

Bacterial proteolytic activity doubles doxorubicin concentration in tumors.

Collagen degradation reduces interstitial pressure and increases vessel density.

Enhanced drug delivery is specific to liposomal doxorubicin, not free doxorubicin.

Abstract

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.