Translating a Low‐Molecular‐Weight MRI Probe Sensitive to Amino Acid Neurotransmitters into a PAMAM Dendrimer Conjugate: The Impact of Conjugation

Abstract

A novel nano‐sized MRI probe sensitive to zwitterionic amino acid neurotransmitters (ZNTs) was prepared by the conjugation of bismacrocyclic ZNT‐responsive units to a generation 4 (G4) polyamidoamine (PAMAM) dendrimer. In vitro evaluation through 1H NMR relaxometric titrations provided binding profiles revealing a surface morphology‐dependent interaction with the ZNTs. The positively charged dendrimeric periphery gave higher initial relaxivities and a milder decrease upon interaction with the target molecules. To improve solubility under physiologically relevant conditions, polyethylene glycol (PEG) units were additionally conjugated to the dendrimeric surface. The PEGylated conjugate displayed discrimination towards acetylcholine and a slightly increased binding affinity towards glutamate over the massively abundant competitive metabolite hydrogencarbonate.

How to Develop Bioresponsive MRI Probes Based on Paramagnetic Gd(III) for in vivo Applications

“…[48e] Additionally, an analog of 28 was used as a monomeric unit to prepare the first ZNT-sensitive nanosized probe based on the G4 PAMAM dendrimer. [49] The great potential of these MR sensors was demonstrated using probe 21 to monitor the release of ZNTs in acute mouse brain slices using MRI. [48a] Neuronal activity was provoked by adding KCl, which induced the membrane potential depolarization and neurotransmitter release.…”

“…Importantly, probe 28 , comprising a formanilide derivative as the pendant arm on the crown ether could effectively discriminate ZNTs from bicarbonate and displayed a considerably stronger affinity toward Glu and Gly [48e] . Additionally, an analog of 28 was used as a monomeric unit to prepare the first ZNT‐sensitive nanosized probe based on the G4 PAMAM dendrimer [49] …”

Nanotheranostics for Image-Guided Cancer Treatment

“…For example, when constructing radiolabeled PAMAM targeting to prostate cancer, Wojciech et al first attached the DOTA chelators to the PAMAM, to allow subsequent 64 Cu chelating [ 60 ]. A similar chelator-based approach can also be used to chelate Gd 3+ ions to endow MRI-detectability to PAMAM [ 64 ]. As PAMAM and PEI are also commonly used to coat the surface of other NPs, image-detectability of the resultant nanoDDS can be generated using iron-oxide NPs as the core for MRI [ 65 ] or gold NPs as the core for CT [ 66 ].…”