Most cancer patients die from metastatic disease as the result of circulating tumor cells (CTCs) spreading from a primary tumor through the blood to distant organs. Clinical studies have demonstrated the tremendous potential of using CTC counts as prognostic or predictive markers of metastatic development and therapeutic efficacy. Despite significant progress in the development of in vitro CTC assays, they still have low sensitivity due to the small samples of blood taken. To overcome these problems, we developed in vivo photoacoustic (PA) flow cytometry (PAFC) and have demonstrated its feasibility in the first pilot trials in melanoma patients. However, these trials revealed the principal limitations nt only of PAFC but most optical diagnostic and therapeutic methods in vivo. These include poor delivery of noninvasive optical radiation to deep tissue, laser safety concerns, and little progres in early cancer diagnosis, prevention metastasis, and overcoming of tumor resistance. Simultaneously, these trials helped identify innovative ways to further significantly improve optical technology in vivo, particularly PAFC, including the safe delivery of a higher level of lasr energy to deeper tissue and more efficient detection of low pigmented CTCs in complex biological backgrounds. The goal of this proposal is to develop innovative approaches to significantly enhance the sensitivity of optical methods in vivo, with a focus on the PAFC platform, and to demonstrate its capabilities in a large cohort of melanoma patients for real-time control of therapeutic efficacy through detection and identification of CTCs, and potentially CTPs. In particular, we propose the concept of fractionated delivery of diagnostic laser energy, nonlinear nanobubble-associated signal amplification in humans, picosecond spectroscopy with switchable wavelength laser, controlling of CTC sizes, and a focused spherical ultrasound transducer array, together with optical skin clearing to reduce light scattering in human skin. To achieve this goal, we will pursue the following Specific Aims: (1) Test the concept of nonlinear, fractionated delivery of laser energy. (2) Optimize the parameters of the nonlinear, fractionated PA detection and PT eradication of CTCs in vitro. (3) Explore the clinical capabilities of in vivo nonlinear, fractionated PA diagnosis and PT therapy of CTCs in melanoma patients during and after conventional treatment. The new clinical prototype of label-free PA-PT theranostic platform will be tested in vivo in humans in three stages: (1) in vivo study of healthy individuals, 2) in vvo PA-PT theranostics in advanced-stage melanoma patients, and 3) controlling CTCs at surgery and during drug administration in melanoma patients. In the course of this study, we will obtain statistically significant data that will demonstrate this innovative technique's unprecedented sensitivity threshold of 1 CTC/500 mL; we will also attempt to achieve a threshold of 1 CTC/1-3 L.

Public Health Relevance

The capability of a painless, noninvasive, labeling-free, photoacoustic flow cytometry for selective, time-resolved detection of photoacoustic signals from different vessels will be assessed in (1) white and black healthy volunteers and (2) melanoma patients at different stages of disease, in whom circulating metastatic melanoma cells will be quantitatively determined. In the course of this study, we will obtain statistically significant data that will demonstrate this innovative technique's unprecedented capability for quantitatively monitoring circulating melanoma cells in vivo without the need for labeling. The benefits to the public health of achieving this goal extend to the routine monitoring of circulatin cells as early markers of micrometastatic development and cancer recurrence in vivo in melanoma patients, as well as to evaluating the efficacy of therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA131164-10
Application #
9666874
Study Section
Biomedical Imaging Technology Study Section (BMIT)
Program Officer
Ossandon, Miguel
Project Start
2007-12-01
Project End
2021-03-31
Budget Start
2019-04-01
Budget End
2021-03-31
Support Year
10
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Arkansas for Medical Sciences
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
122452563
City
Little Rock
State
AR
Country
United States
Zip Code
72205
Jenkins, Samir V; Nedosekin, Dmitry A; Miller, Emily K et al. (2018) Galectin-1-based tumour-targeting for gold nanostructure-mediated photothermal therapy. Int J Hyperthermia 34:19-29
Sarimollaoglu, Mustafa; Stolarz, Amanda J; Nedosekin, Dmitry A et al. (2018) High-speed microscopy for in vivo monitoring of lymph dynamics. J Biophotonics 11:e201700126
Koonce, Nathan A; Juratli, Mazen A; Cai, Chengzhong et al. (2017) Real-time monitoring of circulating tumor cell (CTC) release after nanodrug or tumor radiotherapy using in vivo flow cytometry. Biochem Biophys Res Commun 492:507-512
Nedosekin, Dmitry A; Nolan, Jacqueline; Cai, Chengzhong et al. (2017) In vivo noninvasive analysis of graphene nanomaterial pharmacokinetics using photoacoustic flow cytometry. J Appl Toxicol 37:1297-1304
Galanzha, Ekaterina I; Weingold, Robert; Nedosekin, Dmitry A et al. (2017) Spaser as a biological probe. Nat Commun 8:15528
Nedosekin, Dmitry A; Fahmi, Tariq; Nima, Zeid A et al. (2017) Photoacoustic in vitro flow cytometry for nanomaterial research. Photoacoustics 6:16-25
Menyaev, Yulian A; Carey, Kai A; Nedosekin, Dmitry A et al. (2016) Preclinical photoacoustic models: application for ultrasensitive single cell malaria diagnosis in large vein and artery. Biomed Opt Express 7:3643-3658
Cai, Chengzhong; Nedosekin, Dmitry A; Menyaev, Yulian A et al. (2016) Photoacoustic Flow Cytometry for Single Sickle Cell Detection In Vitro and In Vivo. Anal Cell Pathol (Amst) 2016:2642361
Galanzha, Ekaterina I; Viegas, Mark G; Malinsky, Taras I et al. (2016) In vivo acoustic and photoacoustic focusing of circulating cells. Sci Rep 6:21531
Nolan, Jacqueline; Sarimollaoglu, Mustafa; Nedosekin, Dmitry A et al. (2016) In Vivo Flow Cytometry of Circulating Tumor-Associated Exosomes. Anal Cell Pathol (Amst) 2016:1628057

Showing the most recent 10 out of 51 publications