Abstract
Alzheimer’s disease (AD) is a neurodegenerative disorder characterised by brain accumulation of
toxic protein aggregates, including extracellular amyloid beta (Aβ) plaques, inflammation, neuronal
death and progressive cognitive dysfunction. Current diagnostic modalities, based on cognitive tests,
fail to detect early AD onset, thus emphasising the need to develop improved methods for
pre-symptomatic disease detection.
Building on the properties of the Pittsburgh Compound B (PiB), an Aβ-binding molecule suitable to
use as positron emission tomography (PET) imaging agent, and aiming at using a more clinically available modality (like magnetic ressonance imaging, MRI), PiB derivatives have been conjugated to the macrocyclic chelator 1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane (DO3A) monoamide. However, these derivatives do not readily cross the highly selective blood-brain
barrier (BBB). Taking advantage of the capacity of functionalised carbon nanotubes (f-CNTs) to cross biological barriers, including the BBB, this manuscript reports on the conjugation of two PiB derivative Gd3+ complexes – Gd(L2) and Gd(L3) – to multi-walled f-CNTs (f-MWNTs) and assessment of their in vivo biodistribution and brain uptake. It is shown that Gd(L2) and Gd(L3) can be efficiently loaded onto different f-MWNTs, with significant improvement in brain accumulation of the conjugates compared to the free metal complexes.
Overall, this study demonstrates that f-MWNTs have potential to be used as carriers in theranostic applications involving brain delivery of BBB impermeable compounds
toxic protein aggregates, including extracellular amyloid beta (Aβ) plaques, inflammation, neuronal
death and progressive cognitive dysfunction. Current diagnostic modalities, based on cognitive tests,
fail to detect early AD onset, thus emphasising the need to develop improved methods for
pre-symptomatic disease detection.
Building on the properties of the Pittsburgh Compound B (PiB), an Aβ-binding molecule suitable to
use as positron emission tomography (PET) imaging agent, and aiming at using a more clinically available modality (like magnetic ressonance imaging, MRI), PiB derivatives have been conjugated to the macrocyclic chelator 1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane (DO3A) monoamide. However, these derivatives do not readily cross the highly selective blood-brain
barrier (BBB). Taking advantage of the capacity of functionalised carbon nanotubes (f-CNTs) to cross biological barriers, including the BBB, this manuscript reports on the conjugation of two PiB derivative Gd3+ complexes – Gd(L2) and Gd(L3) – to multi-walled f-CNTs (f-MWNTs) and assessment of their in vivo biodistribution and brain uptake. It is shown that Gd(L2) and Gd(L3) can be efficiently loaded onto different f-MWNTs, with significant improvement in brain accumulation of the conjugates compared to the free metal complexes.
Overall, this study demonstrates that f-MWNTs have potential to be used as carriers in theranostic applications involving brain delivery of BBB impermeable compounds
| Original language | English |
|---|---|
| Pages (from-to) | 168-183 |
| Journal | Nanotheranostics |
| Volume | 2 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - 5 Feb 2018 |