Stanford Advisors


All Publications


  • Pre-targeted Imaging of Protease Activity Via In Situ Assembly of Nanoparticles. Angewandte Chemie (International ed. in English) Rao, J., Chen, Z., Chen, M., Zhou, K. 2020

    Abstract

    Pre-targeted strategies combine high specificity of macromolecules such as antibodies for target binding and rapid clearance of small molecular ligands to image target molecules. However, pre-targeted imaging of the activity of enzymes has not been described likely due to the lack of a mechanism to retain the injected substrate in the first step for subsequent labeling. Here we report the use of  two   bioorthogonal reactions-the condensation reaction of aromatic nitriles and aminothiols, and the  inverse-electron demand Deals-Alder reaction (IEDDA) between tetrazine and trans-cyclooctene (TCO) -to develop a novel strategy for pre-targeted imaging of the activity of proteases.  The substrate  probe bearing TCO (TCO-C-SNAT4) can be selectively activated by an enzyme target (e.g. caspase-3/7), which triggers macrocyclization and subsequent in situ self-assembly into nanoaggregates retained at the target site. Our results show that tetrazine-imaging tag conjugate is able to label TCO in the nanoaggregates to generate selective signal retention for imaging in vitro, in cells and in mice. Due to the decoupling of enzyme activation and imaging tag immobilization, TCO-C-SNAT4 can be repetitively injected to generate and accumulate more TCO-nanoaggregates for click labeling. This strategy should be particularly attractive for imaging the activity of enzymes with slow kinetics using short-lived radioisotopes.

    View details for DOI 10.1002/anie.201916352

    View details for PubMedID 32056345

  • Dual-functional red-emitting fluorescent probes for imaging beta-amyloid plaques and viscosity SENSORS AND ACTUATORS B-CHEMICAL Tan, H., Zhou, K., Yan, J., Sun, H., Pistolozzi, M., Cui, M., Zhang, L. 2019; 298
  • Environment-Sensitive Near-Infrared Probe for Fluorescent Discrimination of A beta and Tau Fibrils in AD Brain JOURNAL OF MEDICINAL CHEMISTRY Zhou, K., Yuan, C., Dai, B., Wang, K., Chen, Y., Ma, D., Dai, J., Liang, Y., Tan, H., Cui, M. 2019; 62 (14): 6694–6704

    Abstract

    The early noninvasive diagnosis of Alzheimer's disease targeted β-amyloid (Aβ) plaques or Tau tangles is a major challenge because of the coshared β-sheet structure of the target. In contrast to tailoring probes to specific amyloids, here, we showed that near-infrared (NIR) environment-sensitive probe 18 could fluorescently discriminate Aβ and Tau from artificial aggregates to pathological change in the brain tissue. The biological evaluation demonstrated that the substantial fluorescence enhancement, large blueshift in the emission upon interactions with the aggregates, and the high binding affinity significantly contributed to the fluorescent discrimination. A simplified Ooshika-Lippert-Mataga equation provided an effective means of correlating 18 with the static relative permittivity (ε0) of proteins, elucidating the origin of the distinction capabilities, and quantitatively estimating the dielectric properties of proteins. Moreover, 18 possessed high bioavailability, including sufficient blood-brain barrier penetration, in vivo NIR imaging, and ex vivo histology in living mice.

    View details for DOI 10.1021/acs.jmedchem.9b00672

    View details for Web of Science ID 000477785400017

    View details for PubMedID 31274302

  • Structure-Property Relationships of Polyethylene Glycol Modified Fluorophore as Near-Infrared A beta Imaging Probes ANALYTICAL CHEMISTRY Zhou, K., Li, Y., Peng, Y., Cui, X., Dai, J., Cui, M. 2018; 90 (14): 8576–82

    Abstract

    To optimize the lipophilicity and improve in vivo pharmacokinetics of near-infrared probes targeted Aβ plaques, we designed, synthesized, and evaluated a series of polyethylene glycol modified probes with hydroxyl and methoxyl terminals. The relationships between chemical structure and optical, biological properties were systemically elucidated. The results indicated that a desired Aβ probe should keep a balance among molecular rigidity, size, and lipophilicity. Probe 12d displayed improved properties including intense and selective response to Aβ1-42 aggregates ( Kd = 7.3 nM, 22-fold fluorescence enhancement and emission maxima at 715 nm upon interaction with Aβ1-42 aggregates), sufficient blood-brain barrier penetration (3.04% ID/g), and fast wash out from the brain (brain2 min/brain60 min = 10.1). Clear fluorescence signals retention in transgenic mice than control mice in in vivo near-infrared imaging. Hence, polyethylene glycol modified probes retained favorable optical properties but displayed great improvement of biological properties for Aβ detection.

    View details for DOI 10.1021/acs.analchem.8b01712

    View details for Web of Science ID 000439397700041

    View details for PubMedID 29902376

  • Smart D-pi-A Type Near-Infrared A beta Probes: Effects of a Marked pi Bridge on Optical and Biological Properties ANALYTICAL CHEMISTRY Zhou, K., Bai, H., Feng, L., Dai, J., Cui, M. 2017; 89 (17): 9432–37

    Abstract

    To expand the scope of D-π-A based near-infrared (NIR) probes for detecting β-amyloid (Aβ) plaques and to systematically explore the relationship among their structural characteristics, optical properties, and biological properties, three series of smart NIR probes with different aromatic rings and up to seven trans double bonds were synthesized and evaluated. Marked correlations between the conjugated π system and properties of these probes, such as optical data, binding ability, and brain uptake, were observed. One probe, PHC-4, displayed improved properties as a NIR probe for the in vivo detection of Aβ plaques.

    View details for DOI 10.1021/acs.analchem.7b02246

    View details for Web of Science ID 000410014900117

    View details for PubMedID 28758731

  • The synthesis and evaluation of near-infrared probes with barbituric acid acceptors for in vivo detection of amyloid plaques CHEMICAL COMMUNICATIONS Zhou, K., Fu, H., Feng, L., Cui, M., Dai, J., Liu, B. 2015; 51 (58): 11665–68

    Abstract

    A new array of near-infrared probes containing barbituric acid acceptors has been developed as Aβ imaging agents. These probes displayed long-emission wavelengths and large Stokes shifts, as well as high affinities for Aβ aggregates. In vivo and ex vivo studies demonstrated that BBTOM-3 could intensely label Aβ plaques in the brains of transgenic mice.

    View details for DOI 10.1039/c5cc03662c

    View details for Web of Science ID 000357618200030

    View details for PubMedID 26103205