(171c) Characterization of the Transport of Live Autonomous Drug Particles (DrugBots) in Tumor Spheroids Interstitium

Limited efficacy of the existing chemotherapeutic treatments of primary cancer tumors is partially attributed to the limited diffusion distance of the drug particles which prevents successful treatment of the quiescent tumor cells. For an anticancer drug to be effective against a solid primary tumor, it must be able to reach all cancerous cells within the tumor to prevent clonogenic tumor stem cells from regeneration. Current chemotherapeutic drugs have limited penetration within the tumor. The low selectivity of anti-cancer drugs with respect to cancerous tissue is also problematic due to the exposure of healthy cells to anti-cancer drugs. Thus, chemotherapy can be enhanced through both better anti-cancer drug cargo targeting towards cancerous cells. Several strains of attenuated bacteria have been identified to possess the innate ability to target and preferentially colonize tumor tissues. In this work, we demonstrate that the tumor targeting E. coli bacteria can be coupled with therapeutic nanoparticles to form intelligent autonomous drug carriers (DrugBots). DrugBots consists of an engineered abiotic body (i.e. drug-laden particles) and a living component (i.e. bacteria) for sensing and actuation purposes. The use of innate sensing and propulsion capabilities in DrugBots can dramatically improve delivery of chemotherapeutic to solid primary tumors. DrugBots actively sense and target tumors and utilize chemotaxis to carry drug nanoparticles deep into the tumor^1,2.  In this work, we demonstrate that DrugBots can penetrate deeper within the tumor tissue when compared to the commonly used passively diffusing chemotherapeutic nanoparticles.

For this study, tumor spheroids were grown in-vitro using human colon carcinoma cells (HT-29) in low adhesion round bottom 96-well plates³. To quantify the extravascular transport of the DrugBots, DrugBots suspended in DMEM culture media were incubated with the tumor spheroids and imaged using confocal microscopy.

The distribution of the DrugBots as well as passively diffusing nanoparticles was quantified by measuring the fluorescence intensity within the tumor spheroid. Our preliminary results indicate that DrugBots have the capability to transport loads significantly deeper within the tumor tissue. This study demonstrates that bio-hybrid tumor targeting systems (drug loaded nanoparticles self-assembled with tumor-targeting bacteria) can be used as live autonomous drug delivery agents with enhanced selectivity and penetration of solid tumors. As illustrated in this work, bacteria carrying particles can penetrate a solid tumor past the proliferating ring into the quiescent and necrotic core with a fairly homogeneous distribution in the tumor.

References:

1. K. Low et al. Nature biotech., 17:37-41, 1999
2. R. Kasinskas et al. Biotechnol and Bioeng., 94: 710-721, 2006
3. A. Ivascu et al. J Biomol Screen., 11: 922-932, 2006