Kinetic modeling of multiplexed SERS nanoparticles for quantitative molecular phenotyping (QMP) of breast cancer Approximately 200,000 women are diagnosed with early-stage invasive breast cancer or carcinoma in situ each year, for which breast-conserving surgery (BCS), or lumpectomy, is the standard surgical treatment. A major challenge for BCS is to ensure that tumors are completely resected, as this is highly correlated with the rate of local recurrence. Unfortunately, many surgeries result in incomplete tumor removal, and re-excision rates range from 20 to 60%. Re-excision surgeries are costly, inconvenient for patients, increases the risk of iatrogenic injury, and can result in delayed adjuvant therapies with inferior patient outcomes. In this study, we aim to develop a wide-area quantitative molecular phenotyping (QMP) strategy to comprehensively image the final surgical margin surface of biopsy shavings routinely obtained during breast conserving surgeries. QMP utilizes surface-enhanced Raman scattering (SERS) nanoparticles (NPs) that are available in multiple ?flavors,? each of which emits a characteristic Raman fingerprint spectrum that allows for the quantification of large multiplexed mixtures of NPs with low-power laser illumination at a single wavelength. In preliminary studies, the QMP technology developed by PI Dr. Liu has been shown to enable the visualization of up to 4 tumor biomarkers at the surfaces of fresh breast tissues following a rapid topical staining (5-min) and rinse removal (20-s) protocol. While these previous studies utilized a ratiometric paired-agent imaging method to mitigate nonspecific effects and to quantify the relative expression of biomarker targets, the specific focus of this R21 proposal is to develop and validate a new kinetic-imaging method to enable absolute quantification of cell-surface receptor expression levels. The accurate quantification of receptor densities will provide a clinical advantage for the identification of receptor-positive tumors in women with diverse stromal characteristics, and for patients whose normal breast tissues express low levels of certain tumor biomarkers, albeit at a differential level compared to tumors. This exploratory study will develop an automated device that enables multi-stage staining, rinsing, and imaging of tissue specimens (Aim 1) in order to visualize temporal binding kinetics, and to model these kinetics (Aim 2) such that receptor expression levels can be accurately quantified. Validation studies will utilize freshly excised tissues from mice implanted with well-characterized biomarker-positive cell lines, as well as fresh human tissue specimens, and will demonstrate that our QMP method enables more-accurate quantitative imaging of biomarker expression compared with a single-time-point ratiometric imaging method. The technologies developed in this exploratory study will pave the way for future clinical studies to examine the accuracy (sensitivity and specificity) of tumor detection for intraoperative lumpectomy guidance. !

Public Health Relevance

topublichealth Weproposetodevelopastrategytoquantitativelyimageapanelofproteinbiomarkersofbreastcancerduring lumpectomy surgeries in order to guide these procedures. This intraoperative quantitative molecular phenotypingtechnologyhasthepotentialtoimprovethecompletenessofbreast-conservingsurgeriesandto reducetheneedforre-excisionsurgeries.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA215561-02
Application #
9462789
Study Section
Biomedical Imaging Technology Study Section (BMIT)
Program Officer
Farahani, Keyvan
Project Start
2017-04-01
Project End
2019-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Washington
Department
Engineering (All Types)
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Kang, Soyoung; Wang, Yu Winston; Xu, Xiaochun et al. (2018) Microscopic investigation of"" topically applied nanoparticles for molecular imaging of fresh tissue surfaces. J Biophotonics 11:e201700246
Wang, Yu Winston; Reder, Nicholas P; Kang, Soyoung et al. (2017) Multiplexed Optical Imaging of Tumor-Directed Nanoparticles: A Review of Imaging Systems and Approaches. Nanotheranostics 1:369-388
Wang, Yu Winston; Reder, Nicholas P; Kang, Soyoung et al. (2017) Raman-Encoded Molecular Imaging with Topically Applied SERS Nanoparticles for Intraoperative Guidance of Lumpectomy. Cancer Res 77:4506-4516
Xu, Xiaochun; Wang, Yu; Xiang, Jialing et al. (2017) Rinsing paired-agent model (RPAM) to quantify cell-surface receptor concentrations in topical staining applications of thick tissues. Phys Med Biol 62:5098-5113