Heterogeneous delivery of oxygen to tissues plays a crucial role in many biological processes and the treatment of many diseases. This proposal describes the use of a novel oxygen microelectrode device to measure the effect of localized oxygen delivery on tumor necrosis. The specific goals are to: 1) develop an oxygen microgradient chip that allows measurement and control of the oxygen environment in a tissue with microscale spatio-temporal resolution; 2) precisely deliver oxygen to tumor tissue, measure individual cell death, and determine the extent that poor oxygenation causes tumor necrosis; and 3) demonstrate that a HIF1-alpha response is critical for cell survival in hypoxic tumor tissue. Tumor hypoxia and necrosis are both caused by poor oxygen supply and are both correlated with poor patient prognosis. Hypoxia inducible factor1-alpha (HIF1-alpha) is a promising therapeutic target because it promotes cell survival in hypoxic conditions, which may lead to tumor growth. No technology currently exists that allows control of the oxygen microenvironment of tissues with cellular resolution. The proposed device will generate stable microgradient gas profiles that are responsive to transient experimental conditions. This device will be useful with a wide range of tissues and applications including tissue engineering and stem cell differentiation. In this proposal, oxygen will be delivered to HIF1-a-containing and null in vitro tumors while preserving other concentration gradients (glucose, acidic waste products, etc.). By measuring the extent of cell death, the effect of oxygen gradients on cell survival will be independently discerned. Many promising therapeutics are being designed to target the unique microenvironments of tumors. Here, precisely controlled experiments will evaluate the therapeutic potential of targeting both hypoxia and HIF1-alpha. In summary, microelectrodes will be used to deliver oxygen to three-dimensional tumor tissue to measure the effect of oxygen on cell survival and HIF1-alpha expression.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA112335-02
Application #
7140137
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Knowlton, John R
Project Start
2005-09-22
Project End
2007-08-31
Budget Start
2006-09-01
Budget End
2007-08-31
Support Year
2
Fiscal Year
2006
Total Cost
$139,168
Indirect Cost
Name
University of Massachusetts Amherst
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
153926712
City
Amherst
State
MA
Country
United States
Zip Code
01003
Kasinskas, Rachel W; Venkatasubramanian, Raja; Forbes, Neil S (2014) Rapid uptake of glucose and lactate, and not hypoxia, induces apoptosis in three-dimensional tumor tissue culture. Integr Biol (Camb) 6:399-410
Toley, Bhushan J; Tropeano Lovatt, Zachary G; Harrington, Josephine L et al. (2013) Microfluidic technique to measure intratumoral transport and calculate drug efficacy shows that binding is essential for doxorubicin and release hampers Doxil. Integr Biol (Camb) 5:1184-96
Toley, Bhushan J; Forbes, Neil S (2012) Motility is critical for effective distribution and accumulation of bacteria in tumor tissue. Integr Biol (Camb) 4:165-76
Toley, Bhushan J; Park, Jaehyun; Kim, Byoung-Jin et al. (2012) Micrometer-scale oxygen delivery rearranges cells and prevents necrosis in tumor tissue in vitro. Biotechnol Prog 28:515-25
Kim, Byoungjin; Han, Gang; Toley, Bhushan J et al. (2010) Tuning payload delivery in tumour cylindroids using gold nanoparticles. Nat Nanotechnol 5:465-72
Venkatasubramanian, R; Arenas, R B; Henson, M A et al. (2010) Mechanistic modelling of dynamic MRI data predicts that tumour heterogeneity decreases therapeutic response. Br J Cancer 103:486-97
Hunnewell, Michael G; Forbes, Neil S (2010) Active and inactive metabolic pathways in tumor spheroids: determination by GC-MS. Biotechnol Prog 26:789-96
Walsh, Colin L; Babin, Brett M; Kasinskas, Rachel W et al. (2009) A multipurpose microfluidic device designed to mimic microenvironment gradients and develop targeted cancer therapeutics. Lab Chip 9:545-54
Venkatasubramanian, Raja; Henson, Michael A; Forbes, Neil S (2008) Integrating cell-cycle progression, drug penetration and energy metabolism to identify improved cancer therapeutic strategies. J Theor Biol 253:98-117
Kim, Byoung-Jin; Forbes, Neil S (2008) Single-cell analysis demonstrates how nutrient deprivation creates apoptotic and quiescent cell populations in tumor cylindroids. Biotechnol Bioeng 101:797-810

Showing the most recent 10 out of 11 publications