Carbon Dots as a New Class of Diamagnetic Chemical Exchange Saturation Transfer (diaCEST) MRI Contrast Agents

Abstract

While carbon dots (C-dots) have been extensively investigated pertaining to their fluorescent, phosphorescent, electrochemiluminescent, optoelectronic,and catalytic features, their inherent chemical exchange saturation transfer magnetic resonance imaging (CEST MRI) properties are unknown. By virtue of their hydrophilicity and abundant exchangeable protons of hydroxyl, amine,a nd amide anchored on the surface,wereport here that C-dots can be adapted as effective diamagnetic CEST (diaCEST) MRI contrast agents.A s ap roof-of-concept demonstration, human glioma cells were labeled with liposomes with or without encapsulated C-dots and implanted in mouse brain. In vivo CEST MRI was able to clearly differentiate labeled cells from non-labeled cells.T he present findings may encourage new applications of C-dots for in vivo imaging in deep tissues,whichiscurrently not possible using conventional fluorescent (near-infrared) C-dots.Carbon dots (C-dots), [1] defined as discrete quasi-spherical carbogenic nanoparticles of several nm in size, [2] are an ew type of organic materials composed primarily of carbon, oxygen, and hydrogen. C-dots are considered to be more biocompatible than the more widely used heavy metal-based quantum dots, [3] with both displaying favorable distinctive properties pertaining to electrochemiluminescence, [4] optoelectronics, [5] catalysis, [6] and size-dependent fluorescence behavior. [7] Consequently,numerous nanosystems integrating C-dots with functional groups have been designed for pH imaging, [8] sensing of metal ions and molecules, [9] drug delivery, [10] and monitoring of hydrogel degradation, [11] all of which used fluorescence intensity as readout. However, noninvasive in vivo fluorescence imaging using C-dots or quantum dots is hampered by the limited light penetration depth (approximately 1-2 cm) even in the near-infrared spectrum. [12] Unlike fluorescence imaging,magnetic resonance imaging (MRI) is able to acquire images of deeply seated organs.T wo strategies have been pursued to adapt carbon dots for MRI contrast enhancement:1 )toi ncorporate Gd III or Mn II in Cdots for T 1 contrast enhancing, [13] and 2) to hybridize with iron oxide nanoparticles for T 2 /T 2 *c ontrast enhancing. [14] Doping with paramagnetic metals,h owever,r aises toxicity concerns, [15] while the C-dots/iron oxide hybrid produces an unfavorable negative contrast. Herein we propose to take advantage of the natural chemical exchange saturation transfer (CEST) MRI contrast properties of metal-free C-dots to generate contrast without the need for (super)paramagnetic labels.CEST is arelatively new powerful MRI technique that can detect diamagnetic agents by their water exchangeable protons. [16] In aC EST study,e xchangeable protons are magnetically tagged using ar adiofrequencys aturation pulse irradiated at their specific resonance frequencies,followed by exchange of the tagged protons with surrounding water to decrease the water MRI signal. As proton exchange occurs many times when al ong saturation pulse is applie...

A multifunctional chemical toolbox to engineer carbon dots for biomedical and energy applications

“…Recent work demonstrated that the abundant exchangeable protons from the surface functional groups of g-N-CDs are inherently CEST-MRI-detectable. 134 g-N-CDs exhibited appreciable CEST-MRI contrast, which was attributed to the abundant exchangeable hydroxyl and guanidinium protons on the CD surface derived from the glucose and arginine precursors. This example points to further advances of CDs as CEST-MRI contrast agents because the variety of functional groups commonly found on the CD surface usually contains exchangeable protons, and the nature of these groups can also be easily controlled through pre-synthetic design.…”

Construction of nanomaterials as contrast agents or probes for glioma imaging

“…Copyright 2016, American Chemical Society. d Schematic illustration of the cellular uptake of AC-dots following liposome encapsulation (Reprint with permission [ 95 ]. Copyright 2019, WILEY–VCH) …”

“…3 c). In addition to organic nano Cas, hydrophilic carbon dots were also demonstrated to produce CEST signals due to the abundance of exchangeable protons on the surface [ 95 ]. The carbon dots were obtained through a microwave-assisted synthesis method with glucose as the carbon source and arginine as the hydrophilic modification molecules.…”

Recent advances and prospects of carbon dots in cancer nanotheranostics

“…8a). 105 They encapsulated AC-dots with liposomes (Lipo-AC-dots) to increase the cellular uptake of AC-dots (Fig. 8b).…”