Hydrophilic Quantum Dots Functionalized with Gd(III)-DO3A Monoamide Chelates as Bright and Effective T1-weighted Bimodal Nanoprobes

Maria I A Pereira,Goreti Pereira,Carlos L Cesar,Beate S Santos,André A De Thomaz,Giovannia A L Pereira,Carlos F G C Geraldes,Paulo E Cabral Filho,Adriana Fontes,Camila A P Monteiro

doi:10.1038/s41598-019-38772-8

Abstract

Magnetic resonance imaging (MRI) is a powerful non-invasive diagnostic tool that enables distinguishing healthy from pathological tissues, with high anatomical detail. Nevertheless, MRI is quite limited in the investigation of molecular/cellular biochemical events, which can be reached by fluorescence-based techniques. Thus, we developed bimodal nanosystems consisting in hydrophilic quantum dots (QDs) directly conjugated to Gd(III)-DO3A monoamide chelates, a Gd(III)-DOTA derivative, allowing for the combination of the advantages of both MRI and fluorescence-based tools. These nanoparticulate systems can also improve MRI contrast, by increasing the local concentration of paramagnetic chelates. Transmetallation assays, optical characterization, and relaxometric analyses, showed that the developed bimodal nanoprobes have great chemical stability, bright fluorescence, and high relaxivities. Moreover, fluorescence correlation spectroscopy (FCS) analysis allowed us to distinguish nanosystems containing different amounts of chelates/QD. Also, inductively coupled plasma optical emission spectrometry (ICP – OES) indicated a conjugation yield higher than 75%. Our nanosystems showed effective longitudinal relaxivities per QD and per paramagnetic ion, at least 5 times [per Gd(III)] and 100 times (per QD) higher than the r1 for Gd(III)-DOTA chelates, suitable for T1-weighted imaging. Additionally, the bimodal nanoparticles presented negligible cytotoxicity, and efficiently labeled HeLa cells as shown by fluorescence. Thus, the developed nanosystems show potential as strategic probes for fluorescence analyses and MRI, being useful for investigating a variety of biological processes.

Highlights

The longitudinal (T1) and transverse (T2) relaxation time measurements of bulk water protons in the presence of the bimodal nanosystems quantum dots (QDs)-Gd(III) chelates are shown in Tables 1 and 2, respectively
We report the development of a new fluorescent/paramagnetic nanoparticulate bimodal system based on hydrophilic Cadmium Telluride (CdTe) quantum dots (QDs) directly conjugated by covalent bonds to Gd(III)-DO3A monoamide chelates
According to the calibration curve (r2 = 0.99), we found an amount of 0.29 μM of free Gd(III) in the aliquot of the solution of chelates added to the xylenol solution, which corresponds to only 3% of the total Gd(III) added (9.4 μM)

Summary

Introduction

The longitudinal (T1) and transverse (T2) relaxation time measurements of bulk water protons in the presence of the bimodal nanosystems QDs-Gd(III) chelates are shown in Tables 1 and 2, respectively. We obtained r1 values up to 42 mM−1·s−1 per gadolinium ion (at 20 MHz and 37 °C), which are equivalently efficient, using more stable cyclic Gd(III)-DOTA-type chelates and hydrophilic QDs, prepared by a simple route that did not require post-synthesis procedures to reach the hydrophilicity necessary to work with biological systems.

Results

Conclusion