Hyperpolarization of Silicon Nanoparticles with TEMPO Radicals - The

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C: Physical Processes in Nanomaterials and Nanostructures

Hyperpolarization of Silicon Nanoparticles with TEMPO Radicals Jingzhe Hu, Nicholas Whiting, and Pratip K Bhattacharya J. Phys. Chem. C, Just Accepted Manuscript • DOI: 10.1021/acs.jpcc.8b00911 • Publication Date (Web): 24 Apr 2018 Downloaded from http://pubs.acs.org on April 25, 2018

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The Journal of Physical Chemistry

Hyperpolarization of Silicon Nanoparticles with TEMPO Radicals Jingzhe Hu1,2, ‡, Nicholas Whiting1,†,‡, and Pratip Bhattacharya1*. 1

Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center,

Houston, TX 77054, United States 2

Department of Bioengineering, Rice University, Houston TX, 77045, United States

*

Corresponding author: [email protected]; (phone): 1-713-745-0769; (fax): 1-713-794-5456 ‡

These authors contributed equally to the work.

†

Current affiliation: Departments of Physics & Astronomy and Molecular & Cellular Biosciences, Rowan University, Glassboro, NJ 08028

KEYWORDS: Silicon nanoparticles, dynamic nuclear polarization, hyperpolarization, MRI, TEMPO radical, in vivo imaging

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ABSTRACT: 29

Silicon-based particles can be hyperpolarized via dynamic nuclear polarization to enhance

Si

magnetic resonance signals. Application of this technique to nanoscale silicon particles has been limited because of the low signal enhancements achieved; it is hypothesized that this is due to the low number of endogenous electronic defects inherent to the particles. We introduce a method of incorporating exogenous radicals into silicon nanoparticle suspensions in order to improve the hyperpolarization of 29Si nuclear spins to levels sufficient for in vivo MR imaging. Calibration of radical concentrations and polarization times are reported for a variety of silicon particle sizes (30-200 nm in diameter), with optimal radical concentrations of 30-60 mM. Addition of the radical slightly affects the T relaxation of the nanoparticles; however, these losses in T are 1

1

overcome by the overall improvement in 29Si magnetization. With optimal amounts of the added radical, 29Si T times are ~20 minutes, and MR images in phantoms can be achieved over an hour 1

after hyperpolarization. Co-registered 1H/29Si MR imaging of nanoparticles administered to a mouse model is also presented.


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INTRODUCTION Due to their biocompatibility and simple surface chemistry, silicon-based nanomaterials have potential utility for applications in biomedicine,1,2 ranging from targeted molecular imaging3,4 to serving as drug delivery vehicles.5,6 Because the nonradioactive

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Si isotope (~4.6% naturally

abundant) is detectable using magnetic resonance (MR) methods, silicon nanoparticles are interesting candidates for development as MRI-based targeted contrast agents. Unfortunately, the acquisition of in vivo

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Si MRI for nanoparticles at thermal equilibrium is exceedingly

unrealistic, due to their low natural abundance, small gyromagnetic ratio (~20% of 1H), and the relatively low physiological concentration of exogenous particles administered to the body. Recently, the hyperpolarization of demonstrated to temporarily increase

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Si nuclear spins in silicon particles has been

Si MR signals by several orders of magnitude7 through

enhanced nuclear spin alignment. This technique utilizes solid-state dynamic nuclear polarization (DNP)8-9—a process that uses low temperatures (typically 3.5x T1; see Supplemental Figure S2 for similar

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Si signal data for the 100 nm particles); at the end of the decay study

(featuring 14 signal acquisitions), a high contrast MR image of the particles in the sample tube can still be obtained (Figure 3a inset). These T1 values are significantly longer than most other contrast agents hyperpolarized via DNP; for example, the T1 of the most-characterized

13

C-

labelled small molecule metabolite (pyruvate) is on the order of 60 seconds.27 As a comparison, room temperature T1 values of hyperpolarized

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C in nanodiamonds have ranged from ~55

seconds28 to ~250 s.29 Also, while mostly larger in size, the room temperature HP 29Si T1’s of the SiNPs examined here compare favorably to previous studies of smaller (~10 nm) SiNPs that were synthesized in a laboratory environment (T1: 5-10 minutes).23 This ability to monitor hyperpolarized

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Si MR signals in nanoscale silicon particles over such long time durations (>1

hr) further incentivizes their development for use as in vivo targeted biomedical imaging agents. Previous studies11, 21 have demonstrated that hyperpolarized 29Si MR images could be attained in vivo using micro-scale silicon particles. However, due their large size and limited mobility, micro-scale silicon is poorly equipped to function as an MRI-based targeted molecular imaging agent. Because of the low number of endogenous electronic defects, previous DNP studies utilizing nano-scale silicon21, 23, 30 have not demonstrated the ability to perform in vivo imaging due to the relatively lower

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Si MR signal (compared to microparticles). In the current study,

optimization of DNP for nano-scale silicon particles through the addition of exogenous radicals has allowed high resolution in vivo

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Si MRI of silicon nanoparticles administered to mice

(Figure 4). Following DNP, an aliquot of 70 nm SiNPs (with 30 mM TEMPO) was suspended in 300 µL phosphate buffered saline (PBS) and administered through the rectum of a normal mouse


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(i.e., enema). The

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Si image was acquired 5 minutes after administration of the particles, and

utilized a ‘rapid acquisition of refocused echoes’ (RARE; α = 90°) imaging sequence that took advantage of the silicon particles’ long T2. Following the

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Si imaging sequence, a 1H MRI-

generated anatomical overlay was produced using the same (dual-tuned) detection coil. In this high contrast image, the SiNPs are shown to trace the lower portion of the large intestines, between the rectum and the cecum. It should also be noted that, given the spatial delocalization of particles following administration to the animal and subsequent wait period, a significant amount of

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Si magnetization is required in order to provide sufficient signal in each pixel to

generate a 29Si MR image, especially after several minutes.

Figure 4: In vivo hyperpolarized 29Si MRI. 29Si MRI (color) of hyperpolarized silicon nanoparticles (70 nm / 30 mM TEMPO) taken 5 minutes after rectal administration of the particles via an enema procedure. Silicon particles are shown to occupy portions of the large intestines between the rectum and cecum. Silicon image co-registered with a 1H anatomical image (greyscale).

This demonstrated ability to achieve HP

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Si MRI in vivo for nano-scale silicon particles

potentially opens the door to a variety of biomedical applications, ranging from targeted


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molecular imaging of different disease systems to theranostics. The advantages over micro-scale silicon includes improved solubility and mobility, advantageous binding kinetics, improved circulation and cell uptake, and ease of physiological administration. The smaller particle size reduces the reticuloendothelial (RES) clearance,31 enhances the blood circulation time, and allows improved biodistribution.32,33 The minimal RES capture may also prevent the long term accumulation of nanoparticles, as well as assuage potential toxicity concerns. While robust toxicity studies were beyond the remit of the present study, there were no apparent ill-effects to the mice that were administered the silicon nanoparticle/TEMPO suspensions. It is possible that this was due to the method of administration (directly into the colon, as opposed to vascular delivery). The effects of shorter T1 values (from the addition of TEMPO) are overcome by the improvement in 29Si signal, such that it is advantageous to use SiNPs with an optimal amount of TEMPO at any time point following DNP. Also, the room temperature 29Si MR signal compared favorably to the previously-characterized microparticles upon transfer to the MR scanner. Because of their robust surface chemistry, the addition of various targeting agents (such as antibodies, aptamers, and peptides) is relatively straightforward using a simple amination pathway. Previous studies34 of silicon microparticles have shown that the addition of targeting moieties does not hamper the hyperpolarization characteristics of the particles; also, the nonbiological conditions of DNP did not affect the targeting ability of antibodies coupled to the particle surface. Translating these favorable effects from the micro-scale to the nano-scale will greatly increase the impact of silicon particles in biomedicine; this current study sets the stage for the continued development of hyperpolarized silicon nanoparticles for MRI-based biomedical imaging applications. Given the recent developments incorporating solid and mesoporous silicon


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nanoparticles into clinical trials as drug delivery vehicles,35 the work presented here may assist in furthering their progression into clinically-relevant theranostic nano-agents. While the nanoparticles were probe sonicated immediately prior to DNP, it is possible that the particles may re-aggregate following hyperpolarization. This may be combatted by lowering the concentration of particles that are administered to the animal, as well as augmenting the surface charge to discourage aggregation. The addition of polyethylene glycol (for biostability), or other surface moieties, may also assist with this, as would alterations to the surface charge. Furthermore, in-depth toxicity studies for the silicon nanoparticles will be pursued both in vitro and in vivo, along with temporal biodistribution studies in mice. While silicon particles are widely considered safe for in vivo applications, TEMPO is often removed from the hyperpolarization mixture prior to injection in studies using

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C DNP of metabolites. Future

toxicity studies will determine if the added radicals will need to be removed from the nanoparticle solutions prior to administration into mice; one benefit of silicon particles (compared to

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C-labelled small molecules) is their contrasting size to the radicals, so that

separation via filtration should be relatively straightforward and less time-sensitive (given the long T1 of the particles). There were no detrimental effects noticed in the mice used in the present study; however, larger-scale interrogation of radical toxicity is warranted. Ongoing studies are focused on examining how the mechanism of the DNP process for silicon nanoparticles is altered when employing exogenous radicals (as opposed to utilizing endogenous defects); these will look to couple the electron spin dynamics with the buildup of nuclear spin polarization within the particles. Future studies will also determine the effects of changes to the nanoparticle surface morphology (i.e., porosity), as well as how the addition of targeting groups


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(antibodies, aptamers, etc.) affects the biodistribution of the particles, and how they interact with the 29Si hyperpolarization efficiency.

CONCLUSIONS The ability to improve 29Si hyperpolarization in nano-scale silicon particles through the addition of a radical species is demonstrated, and the effects to the overall 29Si MR signal enhancement and T1 relaxation are characterized for a variety of particle sizes and radical concentrations. This ability to improve DNP of silicon particles allowed for the demonstration of in vivo 29Si MR imaging in mice to whom the particles were administered. The ability to suitably hyperpolarize nano-scale silicon particles for in vivo MRI should further their ability to function as targeted molecular imaging agents, as they exhibit preferred mobility compared to larger micro-scale silicon particles. Furthermore, once functionalized with targeting ligands, the nanoparticles are anticipated to possess favorable binding kinetics to expressed biomarkers of disease systems, in contrast to the microparticles. With continued development, hyperpolarized silicon nanoparticles may be utilized as dual-mode vehicles for targeted drug delivery and molecular imaging.

ASSOCIATED CONTENT Supporting Information. The following files are available free of charge: single PDF file containing additional figures that detail the hyperpolarization dynamics and decay, as well as the calibration of TEMPO concentration for a given silicon particle size.

AUTHOR INFORMATION


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Corresponding Author *Pratip Bhattacharya: [email protected]; (phone): 1-713-745-0769; (fax): 1-713-794-5456 Present Addresses † Current affiliation: Departments of Physics & Astronomy and Molecular & Cellular Biosciences, Rowan University, Glassboro, NJ 08028 Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. ‡ JH & NW contributed equally. Funding Sources This work was funded by the MDACC Odyssey Postdoctoral Fellowship, NCI R25T CA057730, DoD PC131680, CPRIT grant RP150701, MDACC Institutional Research Grants, MDACC Institutional Startup, NCI U54 CA151668, P50 CA083639, NCI R21 CA185536, John S. Dunn Foundation Collaborative Research Award administered by the Gulf Coast Consortia, and NCI Cancer Center Support Grant CA016672.

ACKNOWLEDGMENT The authors would like to thank J. Liu, P. Constantinou & D. Carson (Rice University), P. Dutta, N.Z. Millward, J. Davis & D. Menter (UT MD Anderson), and K. Gellci (Wayne State) for helpful discussions, as well as L. Bitner (UT MD Anderson) for assistance with the animal imaging, and K. Mueller & Z. Xie (UT Austin) for assistance with the ESR spectroscopy.


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ABBREVIATIONS MRI, magnetic resonance imaging; DNP, dynamic nuclear polarization; HP, hyperpolarization; SiNP, silicon nanoparticle; TEM, transmission electron microscopy; ESR, electron spin resonance; TEMPO, (2,2,6,6-tetramethyl-1-piperidinyloxy); PBS, phosphate-buffered saline; D2O, deuterium oxide; DMSO, dimethyl sulfoxide; NMR, nuclear magnetic resonance; RARE, rapid acquisition of refocused echoes. REFERENCES [1] O'Farrell, N.; Houlton, A.; Horrocks, B., Silicon Nanoparticles: Applications in Cell Biology and Medicine. International Journal of Nanomedicine 2006, 1 (4), 451-472. [2] Mann, A. P.; Tanaka, T.; Somasunderam, A.; Liu, X.; Gorenstein, D. G.; Ferrari, M., ESelectin-Targeted Porous Silicon Particle for Nanoparticle Delivery to the Bone Marrow. Advanced. Materials 2011, 23 (36), H278-H282. [3] Erogbogbo, F.; Yong, K.-T.; Roy, I.; Xu, G.; Prasa, P.; Swihar, M., Biocompatible Luminsescent Silicon Quantum Dots for Imaging of Cancer Cells. ACS Nano 2008, 2 (5), 873878. [4] Osminkina, L. A.; Tamarov, K. P.; Sviridov, A. P.; Galkin, R. A.; Gongalsky, M. B.; Solovyev, V. V.; Kudryavtsev, A. A.; Timoshenko, V. Y., Photoluminescent biocompatible silicon nanoparticles for cancer theranostic applications. Journal of Biophotonics 2012, 3 (7), 529-535. [5] Park, J.-H.; Gu, L.; von Maltzahn, G.; Ruoslahti, E.; Bhatia, S. N.; Sailor, M. J., Biodegradable luminescent porous silicon nanoparticles for in vivo applications. Nature Materials 2009, 8, 331-336. [6] Tasciotti, E., et al., Mesoporous Silicon Particles as a Multistage Delivery System for Imaging and Therapeutic Applications. Nature Nanotechnology 2008, 3, 151-157. [7] Dementyev, A. E.; Cory, D. G.; Ramanathan, C., Dynamic Nuclear Polarization in Silicon Microparticles. Physical Review Letters 2008, 100, 127601. [8] Lee, D.; Hediger, S.; Paepe, G. D., Is Solid-State NMR Enhanced by Dynamic Nuclear Polarization? Solid State Nuclear Magnetic Resonance 2015, 66 (20), 6-20.


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Hyperpolarization of Silicon Nanoparticles with TEMPO Radicals - The

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