Noninvasive Antemortem Detection of Retinal Prions by a Fluorescent Tracer.

BACKGROUND: Neurodegenerative diseases are widespread yet challenging to diagnose and stage antemortem. As an extension of the central nervous system, the eye harbors retina ganglion cells vulnerable to degeneration, and visual symptoms are often an early manifestation of neurodegenerative disease. OBJECTIVE: Here we test whether prion protein aggregates could be detected in the eyes of live mice using an amyloid-binding fluorescent probe and high-resolution retinal microscopy. METHODS: We performed retinal imaging on an experimental mouse model of prion-associated cerebral amyloid angiopathy in a longitudinal study. An amyloid-binding fluorophore was intravenously administered, and retinal imaging was performed at timepoints corresponding to early, mid-, and terminal prion disease. Retinal amyloid deposits were quantified and compared to the amyloid load in the brain. RESULTS: We report that by early prion disease (50% timepoint), discrete fluorescent foci appeared adjacent to the optic disc. By later timepoints, the fluorescent foci surrounded the optic disc and tracked along retinal vasculature. CONCLUSION: The progression of perivascular amyloid can be directly monitored in the eye by live imaging, illustrating the utility of this technology for diagnosing and monitoring the progression of cerebral amyloid angiopathy.

Polymeric Gd-DOTA amphiphiles form spherical and fibril-shaped nanoparticle MRI contrast agents.

A Gd3+-coordinated polymerizable analogue of the MRI contrast agent Gd-DOTA was used to prepare amphiphilic block copolymers, with hydrophilic blocks composed entirely of the polymerized contrast agent. The resulting amphiphilic block copolymers assemble into nanoparticles (NPs) of spherical- or fibril-shape, each demonstrating enhanced relaxivity over Gd-DOTA. As an initial examination of their behavior in vivo, intraperitoneal (IP) injection of NPs into live mice was performed, showing long IP residence times, observed by MRI. Extended residence times for particles of well-defined morphology may represent a valuable design paradigm for treatment or diagnosis of peritoneal malignances.

Labelling Polymers and Micellar Nanoparticles via Initiation, Propagation and Termination with ROMP.

In this paper we compare and contrast three approaches for labelling polymers with functional groups via ring-opening metathesis polymerization (ROMP). We explored the incorporation of functionality via initiation, termination and propagation employing an array of novel initiators, termination agents and monomers. The goal was to allow the generation of selectively labelled and well-defined polymers that would in turn lead to the formation of labelled nanomaterials. Norbornene analogues, prepared as functionalized monomers for ROMP, included fluorescent dyes (rhodamine, fluorescein, EDANS, and coumarin), quenchers (DABCYL), conjugatable moieties (NHS esters, pentafluorophenyl esters), and protected amines. In addition, a set of symmetrical olefins for terminally labelling polymers, and for the generation of initiators in situ is described.

Polymerization of a peptide-based enzyme substrate.

Polymers of norbornenyl-modified peptide-based enzyme substrates have been prepared via ring-opening metathesis polymerization (ROMP). Peptides displayed on water-soluble homopolymers retain the ability to be enzymatically processed by a disease-associated enzyme. In contrast, when the peptides are densely arrayed on a nanoparticle derived from a self-assembled amphiphilic block-copolymer, they function with reduced activity as enzymatic substrates.

Biological stimuli and biomolecules in the assembly and manipulation of nanoscale polymeric particles.

Living systems are replete with complex, stimuli-responsive nanoscale materials and molecular self-assemblies. There is an ever increasing and intense interest within the chemical sciences to understand, mimic and interface with these biological systems utilizing synthetic and/or semi-synthetic tools. Our aim in this review is to give perspective on this emerging field of research by highlighting examples of polymeric nanoparticles and micelles that are prepared utilizing biopolymers together with synthetic polymers for the purpose of developing nanomaterials capable of interacting and responding to biologically relevant stimuli. It is expected that with the merging of evolved biological molecules with synthetic materials, will come the ability to prepare complex, functional devices. A variety of applications will become accessible including self-healing materials, self-replicating systems, biodiagnostic tools, drug targeting materials and autonomous, adaptive sensors. Most importantly, the success of this type of strategy will impact how biomolecules are stabilized and incorporated into synthetic devices and at the same time, will influence how synthetic materials are utilized within biomedical applications.