Bio

Professional Education


  • Bachelor of Arts, Trinity University (2002)
  • Bachelor of Science, Trinity University (2002)
  • Doctor of Philosophy, University of Missouri Columbia (2014)

Stanford Advisors


Publications

All Publications


  • An activatable NIR fluorescent rosol for selectively imaging nitroreductase activity SENSORS AND ACTUATORS B-CHEMICAL Klockow, J. L., Hettie, K. S., LaGory, E. L., Moon, E., Giaccia, A. J., Graves, E. E., Chin, F. T. 2020; 306
  • Multiplexed NIR-II Probes for Lymph Node-Invaded Cancer Detection and Imaging-Guided Surgery. Advanced materials (Deerfield Beach, Fla.) Tian, R., Ma, H., Zhu, S., Lau, J., Ma, R., Liu, Y., Lin, L., Chandra, S., Wang, S., Zhu, X., Deng, H., Niu, G., Zhang, M., Antaris, A. L., Hettie, K. S., Yang, B., Liang, Y., Chen, X. 2020: e1907365

    Abstract

    Tumor-lymph node (LN) metastasis is the dominant prognostic factor for tumor staging and therapeutic decision-making. However, concurrently visualizing metastasis and performing imaging-guided lymph node surgery is challenging. Here, a multiplexed-near-infrared-II (NIR-II) is reported in vivo imaging system using nonoverlapping NIR-II probes with markedly suppressed photon scattering and zero-autofluorescence, enabling visualization of the metastatic tumor and the tumor metastatic proximal LNs resection. A bright and tumor-seeking donor-acceptor-donor (D-A-D) dye, IR-FD, is screened for primary/metastatic tumor imaging in the NIR-IIa (1100-1300 nm) window. This optimized D-A-D dye exhibits greatly improved quantum yield of organic D-A-D fluorophores in aqueous solutions (6.0%) and good in vivo performance. Ultrabright PbS/CdS core/shell quantum dots (QDs) with dense polymer coating are used to visualize cancer-invaded sentinel LNs in the NIR-IIb (>1500 nm) window. Compared to clinically used indocyanine green, the QDs show superior brightness and photostability (no obvious bleaching even after continuous laser irradiation for 5 h); thus, only a picomolar dose is required for sentinel LNs detection. This combination of dual-NIR-II image-guided surgery can be performed under bright light, adding to its convenience and appeal in clinical use.

    View details for DOI 10.1002/adma.201907365

    View details for PubMedID 32022975

  • An Activatable NIR Fluorescent Rosol for Selectively Imaging Nitroreductase Activity. Sensors and actuators. B, Chemical Klockow, J. L., Hettie, K. S., LaGory, E. L., Moon, E. J., Giaccia, A. J., Graves, E. E., Chin, F. T. 2020; 306

    Abstract

    Hypoxia (pO2 ≤ ~1.5%) is an important characteristic of tumor microenvironments that directly correlates with resistance against first-line therapies and tumor proliferation/infiltration. The ability to accurately identify hypoxic tumor cells/tissue could afford tailored therapeutic regimens for personalized treatment, development of more-effective therapies, and discerning the mechanisms underlying disease progression. Fluorogenic constructs identifying aforesaid cells/tissue operate by targeting the bioreductive activity of primarily nitroreductases (NTRs), but collectively present photophysical and/or physicochemical shortcomings that could limit effectiveness. To overcome these limitations, we present the rational design, development, and evaluation of the first activatable ultracompact xanthene core-based molecular probe (NO 2 -Rosol) for selectively imaging NTR activity that affords an "OFF-ON" near-infrared (NIR) fluorescence response (> 700 nm) alongside a remarkable Stokes shift (> 150 nm) via NTR activity-facilitated modulation to its energetics whose resultant interplay discontinues an intramolecular d-PET fluorescence-quenching mechanism transpiring between directly-linked electronically-uncoupled π-systems comprising its components. DFT calculations guided selection of a suitable fluorogenic scaffold and nitroaromatic moiety candidate that when adjoined could (i) afford such photophysical response upon bioreduction by upregulated NTR activity in hypoxic tumor cells/tissue and (ii) employ a retention mechanism strategy that capitalizes on an inherent physical property of the NIR fluorogenic scaffold for achieving signal amplification. NO 2 -Rosol demonstrated 705 nm NIR fluorescence emission and 157 nm Stokes shift, selectivity for NTR over relevant bioanalytes, and a 28-/12-fold fluorescence enhancement in solution and between cells cultured under different oxic conditions, respectively. In establishing feasibility for NO 2 -Rosol to provide favorable contrast levels in solutio/vitro, we anticipate NO 2 -Rosol doing so in preclinical studies.

    View details for DOI 10.1016/j.snb.2019.127446

    View details for PubMedID 32265579

    View details for PubMedCentralID PMC7138224

  • Near-Infrared Fluorescent Rosol Dye Tailored toward Lymphatic Mapping Applications ANALYTICAL CHEMISTRY Hettie, K. S., Klockow, J. L., Glass, T. E., Chin, F. T. 2019; 91 (4): 3110–17

    Abstract

    An optical molecular imaging contrast agent that is tailored toward lymphatic mapping techniques implementing near-infrared (NIR) fluorescence image-guided navigation in the planning and surgical treatment of cancers would significantly aid in enabling the real-time visualization of the potential metastatic tumor-draining lymph node(s) for their needed surgical biopsy and/or removal, thereby ensuring unmissed disease to prevent recurrence and improve patient survival rates. Here, the development of the first NIR fluorescent rosol dye (THQ-Rosol) tailored to overcome the limitations arising from the suboptimal properties of the generic molecular fluorescent dyes commonly used for such applications is described. In developing THQ-Rosol, we prepared a progressive series of torsionally restrictive N-substituted non-NIR fluorescent rosol dyes based on density functional theory (DFT) calculations, wherein we discerned high correlations amongst their calculated energetics, modeled N-C3' torsion angles, and evaluated properties. We leveraged these strong relationships to rationally design THQ-Rosol, wherein DFT calculations inspired an innovative approach and synthetic strategy to afford an uncharged xanthene core-based scaffold/molecular platform with an aptly elevated p Ka value alongside NIR fluorescence emission (ca.700-900 nm). THQ-Rosol exhibited 710 nm NIR fluorescence emission, a 160 nm Stokes shift, robust photostability, and an aptly elevated p Ka value (5.85) for affording pH-insensitivity and optimal contrast upon designed use. We demonstrated the efficacy of THQ-Rosol for lymphatic mapping with in vitro and in vivo studies, wherein it revealed timely tumor drainage and afforded definitive lymph node visualization upon its administration and accumulation. THQ-Rosol serves as a proof-of-concept for the effective tailoring of an uncharged xanthene core-based scaffold/molecular platform toward a specific imaging application using rational design.

    View details for PubMedID 30669835

  • Albumin-chaperoned cyanine dye yields superbright NIR-II fluorophore with enhanced pharmacokinetics. Science advances Tian, R., Zeng, Q., Zhu, S., Lau, J., Chandra, S., Ertsey, R., Hettie, K. S., Teraphongphom, T., Hu, Z., Niu, G., Kiesewetter, D. O., Sun, H., Zhang, X., Antaris, A. L., Brooks, B. R., Chen, X. 2019; 5 (9): eaaw0672

    Abstract

    NIR-II fluorescence imaging greatly reduces scattering coefficients for nearly all tissue types at long wavelengths, benefiting deep tissue imaging. However, most of the NIR-II fluorophores suffer from low quantum yields and/or short circulation time that limit the quality of NIR-II imaging. Here, we engineered a supramolecular assembly of protein complex with lodged cyanine dyes to produce a brilliant NIR-II fluorophore, providing a NIR-II quantum yield of 21.2% with prolonged circulation time. Computational modeling revealed the mechanism for fluorescence enhancement and identified key parameters governing albumin complex for NIR-II fluorophores. Our complex afforded high-resolution microvessel imaging, with a 3-hour imaging window compared to 2 min for free dye alone. Furthermore, the complexation strategy was applied to an antibody-derived assembly, offering high-contrast tumor imaging without affecting the targeting ability of the antibody. This study provides a facile strategy for producing high-performance NIR-II fluorophores by chaperoning cyanine dyes with functional proteins.

    View details for DOI 10.1126/sciadv.aaw0672

    View details for PubMedID 31548981

    View details for PubMedCentralID PMC6744268

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