27 research outputs found
APPLIED PHOTOPROPERTIES OF PHENYLENE ETHYNYLENES
Light-absorbing molecules can be used as powerful tools to perturb and understand biological systems by fluorescence, sensitization, or photochemical reactions. A thorough understanding of the delivery of dyes to specific biochemical targets and the processes that control the fate of excited-state energy is needed to engineer useful technology out of organic photochemistry. This thesis presents four projects investigating different aspects of pathogen destruction and biochemical sensing in a variety of systems, using the properties of p-phenylene ethynylenes (PEs), an especially flexible and well-studied class of conjugated molecules. Of particular relevance, some PEs are found to be effective dyes for amyloid protein aggregates both in solution and in mouse and human brain tissue. As well, control of the solvent microenvironment can be used to tune accessibility of the triplet state, which has implications for targeted photodynamic inactivation of both pathogens and cancer cells
Discriminating radiation injury from recurrent tumor with [18F]PARPi and amino acid PET in mouse models
Background
Radiation injury can be indistinguishable from recurrent tumor on standard imaging. Current protocols for this differential diagnosis require one or more follow-up imaging studies, long dynamic acquisitions, or complex image post-processing; despite much research, the inability to confidently distinguish between these two entities continues to pose a significant dilemma for the treating clinician. Using mouse models of both glioblastoma and radiation necrosis, we tested the potential of poly(ADP-ribose) polymerase (PARP)-targeted PET imaging with [18F]PARPi to better discriminate radiation injury from tumor. Results
In mice with experimental radiation necrosis, lesion uptake on [18F]PARPi-PET was similar to contralateral uptake (1.02 ± 0.26 lesion/contralateral %IA/ccmax ratio), while [18F]FET-PET clearly delineated the contrast-enhancing region on MR (2.12 ± 0.16 lesion/contralateral %IA/ccmax ratio). In mice with focal intracranial U251 xenografts, tumor visualization on PARPi-PET was superior to FET-PET, and lesion-to-contralateral activity ratios (max/max, p = 0.034) were higher on PARPi-PET than on FET-PET. Conclusions
A murine model of radiation necrosis does not demonstrate [18F]PARPi avidity, and [18F]PARPi-PET is better than [18F]FET-PET in distinguishing radiation injury from brain tumor. [18F]PARPi-PET can be used for discrimination between recurrent tumor and radiation injury within a single, static imaging session, which may be of value to resolve a common dilemma in neuro-oncology
Substituent, Charge, and Size Effects on the Fluorogenic Performance of Amyloid Ligands: A Small-Library Screening Study
Exterior, general vie
Oligo(<i>p</i>‑phenylene ethynylene) Electrolytes: A Novel Molecular Scaffold for Optical Tracking of Amyloids
Finding new optical probes to detect
and track amyloid protein
aggregates is key to understanding and defeating the myriad of neurodegenerative
and other diseases associated with these misfolded proteins. Herein
we report that a series of fluorescent, soluble oligoÂ(<i>p</i>-phenylene ethynylene)Âs (OPEs) are able to detect amyloids <i>in vitro</i> by massive binding-activated superluminescence,
with low micromolar affinity and high selectivity for the amyloid
conformer. The OPEs track the kinetics of amyloid fibril formation
from native hen egg white lysozyme (HEWL) similarly to thioflavin
T (ThT), and the dependence of binding affinity on OPE length supports
the theory of a linear binding groove. We hypothesize, based on spectral
properties, induced circular dichroism, and previous work in analogous
systems, that the fluorescence turn-on mechanism is a combination
of the reduction of static solvent-mediated quenching at the ethyl
ester end groups of the phenylene ethynylene fluorophore and the formation
of chiral J-type aggregates templated on the amyloid fibril surface
Substituent, Charge, and Size Effects on the Fluorogenic Performance of Amyloid Ligands: A Small-Library Screening Study
Developing new molecular ligands
for the direct detection and tracking
of amyloid protein aggregates is key to understanding and defeating
myriad neurodegenerative and other disorders including Alzheimer’s
and Parkinson’s diseases. A crucial factor in the performance
of an amyloid dye is its ability to detect the amyloid structural
motif independent of the sequence of the amyloid-forming protomer.
The current study investigates structure–function relationships
of a class of novel phenyleneethynylene (PPE)-based dyes and fluorescent
polymers using amyloid fibrils formed by two model proteins: lysozyme
and insulin. A small library of 18 PPE compounds that vary in molecular
weights, charge densities, water solubilities, and types and geometries
of functional groups was tested. One compound, the small anionic oligoÂ(<i>p</i>-phenylene ethynylene) electrolyte OPE1, was identified
as a selective sensor for the amyloid conformation of both lysozyme
and insulin. On the basis of protein binding and photophysical changes
observed in the dye from this set of PPE compounds, keys to the selective
detection of the amyloid protein conformation include moderate size,
negative charge, and substituents that provide high microenvironment
sensitivity to the fluorescence yield. These principles can serve
as a guide for the further refinement of the effective amyloid-sensing
molecules
Discriminating radiation injury from recurrent tumor with [18F]PARPi and amino acid PET in mouse models
Abstract Background Radiation injury can be indistinguishable from recurrent tumor on standard imaging. Current protocols for this differential diagnosis require one or more follow-up imaging studies, long dynamic acquisitions, or complex image post-processing; despite much research, the inability to confidently distinguish between these two entities continues to pose a significant dilemma for the treating clinician. Using mouse models of both glioblastoma and radiation necrosis, we tested the potential of poly(ADP-ribose) polymerase (PARP)-targeted PET imaging with [18F]PARPi to better discriminate radiation injury from tumor. Results In mice with experimental radiation necrosis, lesion uptake on [18F]PARPi-PET was similar to contralateral uptake (1.02 ± 0.26 lesion/contralateral %IA/ccmax ratio), while [18F]FET-PET clearly delineated the contrast-enhancing region on MR (2.12 ± 0.16 lesion/contralateral %IA/ccmax ratio). In mice with focal intracranial U251 xenografts, tumor visualization on PARPi-PET was superior to FET-PET, and lesion-to-contralateral activity ratios (max/max, p = 0.034) were higher on PARPi-PET than on FET-PET. Conclusions A murine model of radiation necrosis does not demonstrate [18F]PARPi avidity, and [18F]PARPi-PET is better than [18F]FET-PET in distinguishing radiation injury from brain tumor. [18F]PARPi-PET can be used for discrimination between recurrent tumor and radiation injury within a single, static imaging session, which may be of value to resolve a common dilemma in neuro-oncology