Engineering Tumor-Targeted Therapies

Forbes Research Group

at the University of Massachusetts Amherst


Rachel W. Kasinskas



155 Goessmann Hall
413 577-0132
413 545-1647 (fax)
rkasinsk@ecs.umass.edu

 

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The current blood-borne therapeutics, which rely on diffusion and convection for delivery have physical limitations that prevent the chemotherapeutics from affecting all the cells in the tumor.  The limitations come from chaotic and irregular tumor vasculature and high interstitial pressure, which prevent chemotherapeutics from diffusing equally throughout all tumor regions.  Additionally, non-proliferating cells distant from vasculature survive chemotherapeutic therapies specifically targeted to proliferating cells.  Between treatments surviving cells proliferate and re-grow as tumors and metastases.  Motile bacteria have the potential to overcome the diffusion and pressure gradients and it could potentially be used individually or in combination with other therapies to destroy tumors.

The two mechanisms that control Salmonella typhimurium accumulation in tumors are preferential growth in and chemotaxis toward specific tumor microenvironments. To quantify the relative contributions of these two mechanisms with florescence microscopy a three definitional tumor model it used in vivo.   Colon carcinoma cells are grown in suspension forming spheroids, which are comparable to tumors.  If the tumor spheroid was used for imaging, though, the only part that would be seen is the external proliferating layer.  This would be trivial because the objective is to visualize how bacteria segregate in all the internal and external layers of the tumor.  A cylindroid is used instead to model the tumor because it allows for visualization in every layer of the tumor model by holding the third dimension constant.  The cylindroids are made by placing spheroids of similar size and shape on the ends of specialized pegs, which are then inserted into a well plate.  The length and depth of the pegs and wells are precisely measured so that the gap formed between them is exactly 150 mm.  The cylindroids are then allowed to equilibrate so that the proliferating region is growing only in one direction.

 

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