3 research outputs found
Ultrasensitive Detection of α‑Fetoprotein by Total Internal Reflection Scattering-Based Super-Resolution Microscopy for Superlocalization of Nano-Immunoplasmonics
Superlocalization
of immunoplasmonic nanotags on antibody-bound
gold-nanoislands (GNIs) along the <i>x</i> and <i>y</i> coordinates was determined using total internal reflection scattering-based
super-resolution microscopy (TIRS-SRM) at subdiffraction limit resolution.
Individual immunoplasmonic nanotags (20 nm silver nanoparticles) and
100 nm GNIs were selectively acquired in the evanescent field layer
by wavelength-dependent plasmonic scattering using two illumination
lasers (405 and 635 nm, respectively). α-Fetoprotein (AFP),
a liver cancer-related model protein, was immobilized as a target
molecule on the GNI arrays. The centroid position of a localized immunoplasmonic
nanotag on the GNI was resolved at less than 10 nm of spatial resolution
by applying 2D Gaussian fitting to its point spread function. This
method showed enhanced sensitive quantification with a limit of detection
(LOD) of 7.04 zM (1–2 molecules of AFP/GNI), which was 100–5000000000
times lower than detection limits obtained with previous AFP detection
methods. Furthermore, the method was also successfully applied to
quantify AFP molecules at the single-molecule level in human serum
samples. The wavelength-dependent TIRS-SRM method was demonstrated
to be an effective tool for superlocalizing individual protein molecules
and interactions in nanoscale regions and was a reliable method for
the ultrasensitive quantitative detection of disease-related protein
molecules as a nanosensor and for diagnosis at the single-molecule
level
Ultrasensitive Detection of α‑Fetoprotein by Total Internal Reflection Scattering-Based Super-Resolution Microscopy for Superlocalization of Nano-Immunoplasmonics
Superlocalization
of immunoplasmonic nanotags on antibody-bound
gold-nanoislands (GNIs) along the <i>x</i> and <i>y</i> coordinates was determined using total internal reflection scattering-based
super-resolution microscopy (TIRS-SRM) at subdiffraction limit resolution.
Individual immunoplasmonic nanotags (20 nm silver nanoparticles) and
100 nm GNIs were selectively acquired in the evanescent field layer
by wavelength-dependent plasmonic scattering using two illumination
lasers (405 and 635 nm, respectively). α-Fetoprotein (AFP),
a liver cancer-related model protein, was immobilized as a target
molecule on the GNI arrays. The centroid position of a localized immunoplasmonic
nanotag on the GNI was resolved at less than 10 nm of spatial resolution
by applying 2D Gaussian fitting to its point spread function. This
method showed enhanced sensitive quantification with a limit of detection
(LOD) of 7.04 zM (1–2 molecules of AFP/GNI), which was 100–5000000000
times lower than detection limits obtained with previous AFP detection
methods. Furthermore, the method was also successfully applied to
quantify AFP molecules at the single-molecule level in human serum
samples. The wavelength-dependent TIRS-SRM method was demonstrated
to be an effective tool for superlocalizing individual protein molecules
and interactions in nanoscale regions and was a reliable method for
the ultrasensitive quantitative detection of disease-related protein
molecules as a nanosensor and for diagnosis at the single-molecule
level
Lead Optimization of a Novel Series of Imidazo[1,2‑<i>a</i>]pyridine Amides Leading to a Clinical Candidate (Q203) as a Multi- and Extensively-Drug-Resistant Anti-tuberculosis Agent
A critical
unmet clinical need to combat the global tuberculosis
epidemic is the development of potent agents capable of reducing the
time of multi-drug-resistant (MDR) and extensively-drug-resistant
(XDR) tuberculosis therapy. In this paper, we report on the optimization
of imidazoÂ[1,2-<i>a</i>]Âpyridine amide (IPA) lead compound <b>1</b>, which led to the design and synthesis of Q203 (<b>50</b>). We found that the amide linker with IPA core is very important
for activity against Mycobacterium tuberculosis H37Rv. Linearity and lipophilicity of the amine part in the IPA
series play a critical role in improving in vitro and in vivo efficacy
and pharmacokinetic profile. The optimized IPAs <b>49</b> and <b>50</b> showed not only excellent oral bioavailability (80.2% and
90.7%, respectively) with high exposure of the area under curve (AUC)
but also displayed significant colony-forming unit (CFU) reduction
(1.52 and 3.13 log<sub>10</sub> reduction at 10 mg/kg dosing level,
respectively) in mouse lung