Oxygenation plays a critical role in health and medicine. Deficits or excesses in cells, tissues and organisms are associated with disease, damage, poor healing, and even death. For example, hypoxia is implicated in cancer progression, metastasis, and resistance to therapies. Hypoxia inducible factor 1 (HIF-1) expression in low oxygen environments accelerates angiogenesis and promotes tumor survival, and radiation and drug treatments can be less effective when reactive oxygen is not present to enhance the tumor damage or when hypoxia-induced changes in the tumor microenvironment otherwise affect drug delivery and action. Despite the importance of oxygen partial pressure (pO2) to biomedicine, its assessment is often limited to oxygen consumption rate (OCR) measurements, invasive probes, or expensive imaging modalities. Often methods provide only average values for whole populations of cells, or are restricted to single point measurements in space or time. The long-term goal of this project is to develop a versatile material set and platform of pO2 imaging technologies that can enhance preclinical studies and aid in diagnosis, treatment and surgery in many medical contexts. Building upon success in proof of concept studies and the strengths of our team in materials synthesis, imaging, and cancer biology, the objective of this application is to develop dualemissive difluoroboron ?-diketonate-poly(lactic acid) (BF2bdkPLA) dye-polymer nanoparticles (BNPs) in conjunction with imaging methodologies for luminescence detection and ratiometric O2 sensing in breast cancer in vitro and in vivo mouse models. This objective will be accomplished by pursuing the following specific aims: 1) BNP dyes will be chemically modified for broad range emission color tuning and oxygen sensitivity modulation;imaging methods will be developed for their use in in vitro ratiometric O2 sensing (i.e. both fluorescence (F) and phosphorescence (P) detection). 2) BNP polymers will be adapted for passive and active targeting for pO2 monitoring with improved spatial specificity;targeted BNPs will be investigated in vitro and in vivo. 3) BNP hypoxia imaging agents will be tested for their ability to detect tumors, and to monitor tumor progression and radiation and chemotherapy response over time in a mouse mammary window model. The proposed cost- effective technology is innovative because it enables dynamic hypoxia imaging with improved combined spatial and temporal resolution compared to existing approaches with a modular, tunable, synthetically accessible materials platform. The expected outcome is a versatile oxygen nanosensor technology in conjunction with common optical imaging modalities to quantify pO2 in cells, tissues and in vivo. BNPs with greater specificity, tissue penetration of light, and multiplexing capability will result. This work will have a positive impact on cancer car because it will better illuminate the relationships between hypoxia, cancer progression, and treatment protocols. Ultimately, BNPs will shed light on many medical challenges by helping to map relationships between oxygenation and biological function. This is already being realized.

Public Health Relevance

Tissue oxygenation plays a critical role in diseases, health, and healing, but it is difficult to measure with good spatial and temporal resolution. We plan to develop oxygen nanosensors and associated optical detection methods for quantitative, high-resolution hypoxia imaging that promises new insight into the relationships between tumor oxygenation and breast cancer biology, detection and treatment protocols.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA167250-02
Application #
8550797
Study Section
Nanotechnology Study Section (NANO)
Program Officer
Zhang, Yantian
Project Start
2012-09-25
Project End
2017-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$315,546
Indirect Cost
$60,862
Name
University of Virginia
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
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Morris, William A; Butler, Tristan; Kolpaczynska, Milena et al. (2017) Stimuli Responsive Furan and Thiophene Substituted Difluoroboron ?-Diketonate Materials. Mater Chem Front 1:158-166
DeRosa, Christopher A; Seaman, Scott A; Mathew, Alexander S et al. (2016) Oxygen Sensing Difluoroboron ?-Diketonate Polylactide Materials with Tunable Dynamic Ranges for Wound Imaging. ACS Sens 1:1366-1373
Kolpaczynska, Milena; DeRosa, Christopher A; Morris, William A et al. (2016) Thienyl Difluoroboron ?-Diketonates in Solution and Polylactide Media. Aust J Chem 69:537-545
Daly, Margaret L; DeRosa, Christopher A; Kerr, Caroline et al. (2016) Blue Thermally Activated Delayed Fluorescence from a Biphenyl Difluoroboron ?-Diketonate. RSC Adv 6:81631-81635
Mathew, Alexander S; DeRosa, Christopher A; Demas, James N et al. (2016) Difluoroboron ?-Diketonate Materials with Long-Lived Phosphorescence Enable Lifetime Based Oxygen Imaging with a Portable Cost Effective Camera. Anal Methods 8:3109-3114
DeRosa, Christopher A; Kerr, Caroline; Fan, Ziyi et al. (2015) Tailoring Oxygen Sensitivity with Halide Substitution in Difluoroboron Dibenzoylmethane Polylactide Materials. ACS Appl Mater Interfaces 7:23633-43
Samonina-Kosicka, Jelena; Weitzel, Douglas H; Hofmann, Christina L et al. (2015) Luminescent difluoroboron ?-diketonate PEG-PLA oxygen nanosensors for tumor imaging. Macromol Rapid Commun 36:694-9
DeRosa, Christopher A; Samonina-Kosicka, Jelena; Fan, Ziyi et al. (2015) Oxygen Sensing Difluoroboron Dinaphthoylmethane Polylactide. Macromolecules 48:2967-2977
Hendargo, Hansford C; Zhao, Yulin; Allenby, Taylor et al. (2015) Snap-shot multispectral imaging of vascular dynamics in a mouse window-chamber model. Opt Lett 40:3292-5

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