Article pubs.acs.org/journal/abseba
Cite This: ACS Biomater. Sci. Eng. XXXX, XXX, XXX−XXX
Engineering the Infrared Luminescence and Photothermal Properties of Double-Shelled Rare-Earth-Doped Nanoparticles for Biomedical Applications Zhenghuan Zhao,†,§ Jun Yuan,‡ Xinyu Zhao,† Aishwarya Bandla,‡ Nitish V. Thakor,‡ and Mei Chee Tan*,† †
Engineering Product Development, Singapore University of Technology and Design, 8 Somapah Road, Singapore 487372 Singapore Institute for Neurotechnology (SINAPSE), National University of Singapore, 28 Medical Drive, #05-COR, Singapore 117456 § College of Pharmaceutical Sciences, Southwest University, Chongqing 400716, China
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S Supporting Information *
ABSTRACT: The nascent field of theranostics, which couples targeted therapy with diagnostics, has catalyzed efforts toward improved nanoprobe designs that facilitate both localized treatment and diagnostic imaging. Rare-earthdoped nanoparticles (RENPs) have emerged as a leading candidate for theranostics because of their versatile synthesis and modification chemistries, photostability, and relative safety. Furthermore, their bright, tunable fluorescence using near-infrared (NIR) excitation enables multispectral imaging with high signal-to-background ratios. In this work, we have synthesized double-shelled RENPs with tunable properties for optimal fluorescent imaging, photoacoustic imaging, and photothermal therapy. The properties of the double-shelled RENPs were tailored by controlling the density of rare-earth ions (i.e., activator or sensitizer) by using either a functional amorphous organic or a crystalline outermost shell. This study systematically analyzes the effects of the functional organic or inorganic outermost shell on the imaging and photothermal conversion properties of our RENPs. Despite the weaker infrared absorption enhancement, the functional organic outermost shell impregnated with a low density of rare-earth ions led to minimal reduction of fluorescence emissions. In contrast, the higher density of rare-earth ions in the inorganic shell led to higher infrared absorption and consequently significant reduction in emissions arising from the undesired optical attenuation. Inorganic shell thickness was therefore modified to reduce the deleterious attenuation, leading to brighter emissions that also enabled the in vitro SWIR detection of ∼2500 cells/cluster. Using the enhanced infrared properties that arise from this functional inorganic layer, which could be engineered to respond to either NIR or SWIR, we demonstrated that (1) bright SWIR emissions allowed detection of small cell clusters; (2) strong PA signals allowed clear visualization of particle distribution within tumors; and (3) strong photothermal effects resulted in localized elevated temperatures. Collectively, these results highlight the utility of these double-shelled RENPs as theranostic agents that are compatible with both photoacoustic or fluorescent imaging platforms. KEYWORDS: infrared nanoparticles, imaging, photothermal, photoacoustic, theranostic perfect fluorescence properties, including adjustable, nonphotobleaching, atom-like, and nonblinking emission, can be excited by the near-infrared (NIR) source to emit shortwave infrared (SWIR) light.16−23 Since SWIR light with the wavelength of 1000−2500 nm shows deeper tissue penetration and high spatial resolution, RENP has been chosen as a favorable platform to design biomedical probes for highly
1. INTRODUCTION Multifunctional nanomaterials that serve as both diagnostic probes and therapeutic agents could potentially improve treatment outcomes by simultaneously imaging and identifying specific targets for timely monitoring of treatment response while minimizing undesired damage to the surrounding normal tissue.1−8 A variety of contrast agents have been constructed for different diagnostic platforms, among which fluorescent imaging has received special attention because of its high sensitivity, rapid imaging, portability, and low cost.9−15 Ceramic rare-earth-doped nanoparticles (RENPs) that exhibit © XXXX American Chemical Society
Received: April 15, 2019 Accepted: June 21, 2019 Published: June 21, 2019 A
DOI: 10.1021/acsbiomaterials.9b00526 ACS Biomater. Sci. Eng. XXXX, XXX, XXX−XXX
Article
ACS Biomaterials Science & Engineering
Scheme 1. Schematic Illustration for the Design of a Theranostic Nanoprobe for Dual Modality Shortwave Infrared (SWIR) Fluorescence and Photoacoustic Imaging as well as Targeted Photothermal Therapy using Double-Shelled Rare-Earth-Doped Nanoparticles with a Functional Outermost Organic or Inorganic Shella
a
PEI denotes polyethyleneimine, IOS denotes inorganic shell, and OS denotes organic shell.
sensitive fluorescent imaging.22−24 Furthermore, since RENPs also simultaneously convert the absorbed NIR photon energy to thermal energy via the nonradiative relaxation process, these RENPs have the added ability to act as a multifunctional agent for photoacoustic (PA) imaging and targeted photothermal (PT) therapy as well. 25−29 PT therapy enables the minimization of damage to surrounding healthy tissues as the photothermal effect is produced only in the presence of both the NIR source and nanoprobe.30−36 Fluorescence and PT (or PA) signals are complementary signal forms which result from radiative and nonradiative relaxations of electrons, respectively. Therefore, it is usually expected that materials exhibiting bright emissions would have weak PT (or PA) effects, while weak emissions would be accompanied by strong PT (or PA) effects. Since the competing fluorescence and PT effects are achieved at different concentration ranges of the rare-earth dopants, designing RENP-based theranostic agents that simultaneously exhibit bright fluorescence and strong PT effects is exceedingly challenging. In this work, we proposed to design a probe that spatially separates the fluorescence and PT domains into different layers within one nanoparticle to create a RENP-based theranostic probe that simultaneously exhibits both a bright fluorescence and strong PT. An intermediate inert layer is needed to effectively separate the fluorescence and PT domains to prevent the diffusion and undesired mixing of rare-earth dopants during the high-temperature synthesis process. Our previous work has shown that RENPs with a doped core and undoped shell structure (β-NaY0.78F4:Yb0.20Er0.02@NaYF4) served as excellent probes for lesion detection using an SWIR imaging platform.22,23 Yb and Er are codoped within the RENP’s core to serve as the sensitizer and emitting (or activator) centers, respectively, to enable optimal absorption at 975 nm and emissions in the visible and SWIR region that are characteristic of Er. The undoped shell served to protect the emitting Er ions within the core from nonradiative decay caused by surface defects, and vibrational losses due to
quenching by organic functional groups from solvents or surface ligands. Therefore, by coating an additional shell on the β-NaY0.78F4:Yb0.20Er0.02@NaYF4 core−shell nanoparticles to increase light absorption and enhance PT effects, a theranostic probe with bright fluorescence emissions and strong PT effects could be created. There are two possible types of coatings to be considered: (1) adsorbing active rare-earth (RE) ions within an amorphous organic outermost shell and (2) introducing active RE ions within a crystalline inorganic outermost shell (Scheme 1). Using the functional organic shell (OS) approach offers the option of increasing the absorption characteristics with insignificant changes in the overall particle size (
