Gd(III)-Grafted Detonation Nanodiamonds for MRI Contrast

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C: Physical Processes in Nanomaterials and Nanostructures

Gd(III)-Grafted Detonation Nanodiamonds for MRI Contrast Enhancement Alexander M. Panich, Moti Salti, Shaul D. Goren, Elena B. Yudina, Aleksandr E. Aleksenskii, Alexander Ya. Vul, and Alexander I. Shames J. Phys. Chem. C, Just Accepted Manuscript • DOI: 10.1021/acs.jpcc.8b11655 • Publication Date (Web): 10 Jan 2019 Downloaded from http://pubs.acs.org on January 16, 2019

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The Journal of Physical Chemistry

Gd(III)-Grafted Detonation Nanodiamonds for MRI Contrast Enhancement

A. M. Panich,*a M. Salti,b S. D. Goren,a E. B. Yudina,c A. E. Aleksenskii,c A. Ya. Vul',c and A. I. Shamesa

a

Physics Department, Ben-Gurion University of the Negev, 8410501 Be'er Sheva, Israel,

b

Brain Imaging Research Center, Ben-Gurion University of the Negev, 8410501 Be'er Sheva,

Israel c

Ioffe Institute, St. Petersburg 194021, Russia

* Corresponding author: e-mail [email protected], Phone: +972 8 6472458, Fax: +972 8 6472904

Abstract We report on the first 1H NMR relaxation and magnetic resonance imaging (MRI) study of aqueous suspensions of detonation nanodiamonds (DND) grafted by Gd(III) ions. In contrast to Gd(III)-ND conjugates implemented via organic species, Gd(III) ions were directly grafted to the surface of DND particles. Such Gd(III)-grafted DND particles significantly shorten spinlattice (T1) and spin-spin (T2) relaxation times of water protons providing relaxivities of r1 = 33.4 and r2 = 332 mM-1 s-1, which considerably exceed the most of those reported in the literature. It makes the Gd(III)-grafted DND complexes attractive for use as novel MRI contrast agents.

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1. Introduction Due to a small primary particle size (4 to 5 nm) with narrow size distribution, facile surface functionalization and high biocompatibility and non-toxicity, detonation nanodiamond (DND) particles are promising nanomaterials for biomedical and bioengineering applications such as drug delivery

1-5

and medical imaging.

6-9

The chemically active DND surface with

negative zeta-potential is mainly functionalized by carboxyl groups that enable its grafting by metal cations.10-15 DND particles grafted by various transition and rare-earth elements are promising materials for advanced applications such as magnetic resonance imaging (MRI) contrast agents, since they reduce the relaxation time of water protons in tissues under examination. Although there are some manganese- and iron-based contrast agents approved for clinical use, the vast majority of contrast enhanced clinical exams are performed with gadolinium complexes since Gd(III) ions have a large unpaired electron spin of S = 7/2 and large magnetic moment of 7.9  B (here  B is the Bohr magneton). To this end, synthesis of amine-functionalized Gd(III) contrast agents conjugated to the ND surface,6,7 of ND particles modified with an organo-gadolinium (diethylenetriaminepentaacetic acid, DTPA) moiety

16

and of a DND-

polyglycerol-Gd(III) (ND-PG-Gd(III)) conjugate system17 were reported. Such agents consist of the paramagnetic metal species with one or more coordination sites available for water to interact with the unpaired electrons of the Gd(III) ion, resulting in a decrease of the proton spin-lattice and spin-spin relaxation times. The (ND-PG-Gd(III)) conjugate system demonstrated good dispersibility together with relatively high water proton relaxivity of this complex in aqueous solution, making it a promising contrast agent for MR imaging.17 We note that conjugation of organo-gadolinium moieties to the ND surface enlarges the particle size. E.g., the thickness of PG layer on the ND was calculated to be 10–15 nm.17 Such an increase of the contrast agent particles’ size may limit their medical applications. We have recently reported on preparation and investigation of Cu-, Co- and Gd-grafted DND, in which the paramagnetic transition and rare-earth metal ions are directly conjugated to the DND surface via exchange with protons of surface carboxyl (–COOH) groups in a mixture of 2 ACS Paragon Plus Environment

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aqueous DND suspension with aqueous solutions of metal nitrates.10-14,18,19 To evidence the ion grafting to the surface, we developed an effective approach based on the analysis of nuclear spinlattice relaxation data combined with direct EPR observations of surface transition metal ions. The grafting was proved by noticeable acceleration of the spin-lattice relaxation of

13C

and 1H

nuclear spins of the diamond obtained, revealing interaction of these spins with grafted paramagnetic Cu(II), Co(II) and Gd(III) ions and thus their binding to the DND surface. This approach allows calculating distances between the ions and surface. The complexes are stable up to at least 550 oC. We note that all these compounds were studied in the solid state. However, MRI applications require dispersing such substances in aqueous solutions and measuring spinlattice and spin-spin relaxation rates of water protons of the solution. In the present paper we report on the first 1H nuclear magnetic resonance (NMR) measurements of spin-spin and spin-lattice relaxation rates of the water protons in suspensions of highly purified disaggregated DND particles and those with chemically grafted gadolinium ions, as well as MR imaging of the aqueous suspensions under study. We found that both intrinsic paramagnetic defects in DND and particularly grafted gadolinium ions noticeably reduce the aforementioned relaxation rates of 1H spins in the surrounding water solution. Our results obtained are compared with the literature data on Gd(III) conjugated NDs and other Gd(III)based organic complexes. The relaxivities of our compounds were found to be much larger than most of those discussed in the literature. It makes Gd(III)-grafted DND particles promising contrast agents for magnetic resonance imaging.

2. Experimental section Aqueous suspensions of highly purified and de-agglomerated DND particles were prepared using previously developed method.20 Average particle size determined by the dynamic light scattering (DLS) was 4.9 nm. Most of the particles in suspension exist in the monodisperse form and show negative zeta potential. Grafting of Gd(III) ions to the DND surface was performed by mixing of 0.04 mM DND aqueous suspension with an aqueous solution of ACS Paragon Plus Environment

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gadolinium nitrate hexahydrate Gd(NO3)3⋅6H2O.14 Dissociated Gd(III) cations in this mixture undergo ion exchange with the hydrogen atoms of surface carboxyl groups and chemical bonding to the nanoparticle surface14 (see details in Supplementary Information). We studied (i) aqueous suspensions with DND concentration of 0.0754, 0.1939 and 0.4431 mM and (ii) aqueous 0.04 mM DND suspensions when DND particles being grafted by Gd in concentrations 0.0802, 0.1604 and 0.2005 mM, which correspond to the Gd contents of 2, 4 and 5 ions per particle, respectively. The resulting hydrosols are very stable and did not undergo noticeable changes or precipitation for several years of storage. 1H

NMR measurements of the nanodiamond hydrosols were carried out at temperature of

310.1 K (37 oC) in the external magnetic field B0 = 8.0 T. 1H spin-lattice relaxation times T1 were measured using inversion recovery pulse sequence, while spin-spin relaxation times T2 – using Carr-Purcell-Meiboom-Gill (CPMG) pulse sequence.21 NMR parameters of the medium were measured as well. The duration of the π/2 pulse was 1.6 μs. Repetition time was chosen as 5T1 for each measurement. MR imaging of aqueous suspensions of DND and Gd(III)-grafted DND samples was performed on a clinical 3 T MRI instrument. Contrast-to-noise (CNR) values were calculated against pure water sample #1, i.e. CNR(sample#**) = SNR(sample#**) – SNR(sample#1), where SNR = Mean Signal/Standard Deviation of Background Noise. 3. Results and Discussion Our experimental nuclear spin relaxation and relaxivity data are shown in Table 1 and Figures 1 and 2, respectively. DND particles reveal intrinsic localized paramagnetic defects: 22,23 (i) P1 nitrogen paramagnetic centers distributed throughout the diamond core and (ii) unpaired electron spins of dangling bonds positioned mainly in the near-surface layer. The overall defect density in the DND particle measured by EPR is ~6×1019 spin/g. The contributions of these paramagnetic defects in DND to the spin-lattice and spin-spin relaxation rates R1DND and R2DND of water protons (Figure 1) are


4

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R1DND 

1 DND

T1



1 exp 1

T



1 H 2O

T1

 r1DND [ DND] ,

R2DND 

1 DND 2

T



1 exp 2

T



1 H 2O 2

T

 r2DND [ DND]

(1)

where T1DND and T2DND are the 1H spin-lattice and spin-spin relaxation times caused by paramagnetic defects of nanodiamond particles, T1H 2 O and T2H 2O are relaxation times of de-ionized water, and [DND] is the DND concentration. Relaxivities r1 and r2, defined as the slopes of the concentration dependences of

1 DND

T1

and

1 DND 2

T

, were determined as r1 = 2.1±0.3 and r2 = 15.8±1

mM-1s-1, respectively. Note that spin-spin relaxivity is 7 times larger than the spin-lattice one. Thus we find that even DND particles which are not grafted by Gd affect relaxation rates of the water protons in the suspension.

Table 1. Concentrations of DND and grafted Gd ions in the studied suspensions and corresponding proton spin-lattice (T1) and spin-spin (T2) relaxation times. Sample

DND (mM)

Gd(III) (mM)

T1 (ms) a

T2 (ms) a

1

0

0

3884

2421

2

0.0754

0

1730

473

3

0.1939

0

1450

298

4

0.4431

0

805

131

5

0.04

0.0802

343.5

38.2

6

0.04

0.1604

173.4

17.8

7

0.04

0.2005

143

15.1

a Errors

in determination of T1 and T2 do not exceed ± 5%


5


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Figure 1. 1H spin-lattice (R1) (a) and spin-spin (R2) (b) relaxation rates of water protons caused by intrinsic paramagnetic defects in DND plotted against the DND concentration in aqueous DND suspension measured at T = 37oC.

The main results of our study are presented in Figure 2, which shows the contributions of the paramagnetic gadolinium ions grafted to the DND surface to spin-lattice and spin-spin relaxations of water protons: R1Gd 

1 1 1 1 1 1 1 1  exp  DND  H 2 O  r1Gd [Gd ] , R2Gd  Gd  exp  DND  H 2 O  r2Gd [Gd ] Gd T1 T1 T1 T1 T2 T2 T2 T2

(2)

Here [Gd] is the Gd(III) ions concentration.


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Figure 2. 1H spin-lattice (R1) (a) and spin-spin (R2) (b) relaxation rates of water proton caused by paramagnetic Gd(III) ions grafted to the DND surface against the Gd concentration in the aqueous Gd-DND suspension measured at T = 37oC.

In accordance with the theory,24 both relaxation rates R1Gd and R2Gd are proportional to the resulting paramagnetic Gd(III) ion concentration. Herewith the relaxivities r1 and r2 are 33.4±0.6 and 332±13 mM-1 s-1, respectively. These data reveal that Gd grafting to DND causes dramatic increase of proton relaxivities, both r1 and especially, r2. These values exceed almost all known data (Table 2) and reveals high efficiency of these materials as MRI contrast agents. Here it is worth mentioning that relaxivities of pure DND and Gd(III)-grafted DND have been measured using different ways of changing the contrast agents’ content. Indeed, for getting the Gd(III)-grafted DND relaxivity, the concentration of the contrast agent in the aqueous suspension had been changed by variation of the number of Gd ions per DND particle keeping the concentration of the DND particles fixed. This approach answers several questions within the ACS Paragon Plus Environment

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frame of a single experiment. First, it demonstrates dependence of proton relaxation on the Gdion loading. Second, it shows efficacy of working with low concentrations of the paramagnetic ions’ carriers (i.e. Gd-grafted DND particle). And last but not least, in contrast to Gd-conjugated DND, where each DND particle carries a single Gd ion, it demonstrates flexibility in a choice of proper contrasting setup in real MRI experiments.

Table 2. Water proton relaxivities in aqueous solutions of Gd complexes. Compound

r1. mM-1s-1 r2. mM-1s-1 Notes

Ref.

Magnevist, C28H54GdN5O20

3.7 / 3.4

-

B0 = 1.5 T / 7.0 T

[17]

Gd-DTPA, C14H18GdN3O10

3.8

4.7

B0= 0.47 T

[27]

Gd-DOTA, C16H24GdN4O8

3.56

4.75

B0 = 0.47 T

[27, 28]

ND-PG-Gd(III) a

19.4 / 8.2

-

B0 = 1.5 T / 7.0 T

[17]

C20H36GdN5O6 in H2O-TFA b

58.8

-

B0 = 1.5 T

[6]

ND-C20H36GdN5O6 in H2O

5.42

-

B0 = 1.5 T

[6]

K[C20H32GdN4O8]·5H2O

11.5

15.5

B0 = 7.0 T

[7]

Gd-BOPTA, C22H28GdN3O11

4.39

5.56

B0 = 0.47 T

[25]

Gd-BOPTA, C22H28GdN3O11

4.8

5.7

B0 = 8.0 T

This work

coated 13.9

15.0

B0 = 0.47 T

[26]

33.4

332

B0 = 8.0 T

This work

PGP/dextran

(dextran

GdPO4) Gd(III)-grafted DND a

PG is the polyglycerol, b TFA is the triethylsilane, other abbreviations are done above.

Figure 3 represents coronal plane T1-weighted MR images of seven square spectrophotometer cells containing suspensions under study. It is clearly seen that images of Gd(III)-free DND-containing suspensions (Figure 3, samples 2 - 4) have been already demonstrating higher brightness than water (Figure 3, sample 1): the contrast-to-noise ratios (CNRs) versus water are found to be 105, 145 and 366 for samples 2, 3 and 4, respectively. 8 ACS Paragon Plus Environment

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However, the Gd(III)-grafted DND-containing suspensions shows the most dramatic contrasting effect (Figure 3, samples 5 -7). Here CNRs versus water are 589, 587 and 545 for samples 5, 6 and 7, respectively.

Figure 3. T1-weighted MR images of seven square spectrophotometer cells containing doubly deionized water (sample 1), aqueous DND suspensions in concentrations of 0.0754, 0.1939 and 0.4431 mM, respectively (samples 24) and 0.04 mM aqueous suspensions of DND particles grafted by Gd(III) ions in concentrations of 0.0802, 0.1604 and 0.2005 mM, respectively (samples 5-7).

The lack of the CNR dependence on Gd concentration (or even its reduction for the highest Gd content) for the Gd(III)-grafted DND samples may be explained by a drastic shortening of proton T2 relaxation times found for high Gd-contents suspensions – see Figure 2. Since the T2 values for samples 6 and 7 (17.8 and 15.1 ms, respectively) become to be comparable with the shortest TE delay available in our MRI machine for obtaining of T1weighted images (TE = 7 ms, see Supplementary Information) it causes obvious reduction of the intensity of nuclear spin echo signals, recorded using the same pulse sequence as for Gd(III) free or low Gd(III) containing samples.


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Summary Summarizing, we report on the first study of NMR relaxivities and MR images of suspensions of DND in which Gd(III) ions are directly grafted to the detonation nanodiamond surface. The proton relaxivities provided by these novel nanoparticles are found to be much larger than the most of those reported in the literature. This opens new perspectives for using the Gd(III)-grafted DND complexes as novel MRI contrast agents.

Supporting Information Samples preparation, nanodiamond size histogram, electron and rotational correlation times, details of 1H NMR relaxivity and MRI measurements.

Acknowledgement We thank Prof. S. P. Babailov for useful discussion. A. E. Alexenskii, E. B. Yudina and A. Ya. Vul thank for support of the Russian Scientific Fund (project N 14-13-00795).

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Gd(III)-Grafted Detonation Nanodiamonds for MRI Contrast

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