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Rare-earth-doped biological composites as in vivo shortwave infrared reporters

Identifieur interne : 000399 ( Pmc/Curation ); précédent : 000398; suivant : 000400

Rare-earth-doped biological composites as in vivo shortwave infrared reporters

Auteurs : D. J. Naczynski ; M. C. Tan ; M. Zevon ; B. Wall ; J. Kohl ; A. Kulesa ; S. Chen ; C. M. Roth ; R. E. Riman ; P. V. Moghe

Source :

RBID : PMC:3736359

Abstract

The extension of in vivo optical imaging for disease screening and image-guided surgical interventions requires brightly-emitting, tissue-specific materials that optically transmit through living tissue and can be imaged with portable systems that display data in real-time. Recent work suggests that a new window across the short wavelength infrared region can improve in vivo imaging sensitivity over near infrared light. Here we report on the first evidence of multispectral, real-time short wavelength infrared imaging offering anatomical resolution using brightly-emitting rare-earth nanomaterials and demonstrate their applicability toward disease-targeted imaging. Inorganic-protein nanocomposites of rare-earth nanomaterials with human serum albumin facilitated systemic biodistribution of the rare-earth nanomaterials resulting in the increased accumulation and retention in tumor tissue that was visualized by the localized enhancement of infrared signal intensity. Our findings lay the groundwork for a new generation of versatile, biomedical nanomaterials that can advance disease monitoring based on a pioneering infrared imaging technique.


Url:
DOI: 10.1038/ncomms3199
PubMed: 23873342
PubMed Central: 3736359

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PMC:3736359

Le document en format XML

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</contrib>
<contrib contrib-type="author">
<name>
<surname>Riman</surname>
<given-names>R.E.</given-names>
</name>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Moghe</surname>
<given-names>P.V.</given-names>
</name>
</contrib>
</contrib-group>
<pub-date pub-type="nihms-submitted">
<day>29</day>
<month>7</month>
<year>2013</year>
</pub-date>
<pub-date pub-type="ppub">
<year>2013</year>
</pub-date>
<pub-date pub-type="pmc-release">
<day>19</day>
<month>1</month>
<year>2014</year>
</pub-date>
<volume>4</volume>
<fpage>2199</fpage>
<lpage>2199</lpage>
<pmc-comment>elocation-id from pubmed: 10.1038/ncomms3199</pmc-comment>
<permissions>
<license>
<license-p>Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
<uri xlink:type="simple" xlink:href="http://www.nature.com/authors/editorial_policies/license.html#terms">http://www.nature.com/authors/editorial_policies/license.html#terms</uri>
</license-p>
</license>
</permissions>
<abstract>
<p id="P1">The extension of
<italic>in vivo</italic>
optical imaging for disease screening and image-guided surgical interventions requires brightly-emitting, tissue-specific materials that optically transmit through living tissue and can be imaged with portable systems that display data in real-time. Recent work suggests that a new window across the short wavelength infrared region can improve
<italic>in vivo</italic>
imaging sensitivity over near infrared light. Here we report on the first evidence of multispectral, real-time short wavelength infrared imaging offering anatomical resolution using brightly-emitting rare-earth nanomaterials and demonstrate their applicability toward disease-targeted imaging. Inorganic-protein nanocomposites of rare-earth nanomaterials with human serum albumin facilitated systemic biodistribution of the rare-earth nanomaterials resulting in the increased accumulation and retention in tumor tissue that was visualized by the localized enhancement of infrared signal intensity. Our findings lay the groundwork for a new generation of versatile, biomedical nanomaterials that can advance disease monitoring based on a pioneering infrared imaging technique.</p>
</abstract>
</article-meta>
</front>
<floats-group>
<fig id="F1" orientation="portrait" position="float">
<label>Figure 1</label>
<caption>
<title>Properties of the rare-earth-doped nanoprobes</title>
<p id="P45">
<bold>(a)</bold>
Rare earth nanoprobes consist of a NaYF4 Yb:Ln doped core (Ln: Er, Ho, Tm or Pr) surrounded by an undoped shell of NaYF4. TEM images of nanoprobes
<bold>(b)</bold>
show uniform 10 nm spherical particles (scale bar = 10 nm). SWIR emissions can be tuned
<bold>(c)</bold>
by selecting suitable rare earth ion emitting centers. Probes consisting of a NaYF4 host doped with ytterbium (Yb) and one or more elements selected from holmium (Ho), praseodymium (Pr), thulium (Tm) and erbium (Er) enable emissions at 1185, 1310, 1475 and 1525 nm, respectively. The 1185, 1310, 1475 and 1525 nm emissions of Ho-, Pr-, Tm- and Er-doped samples are attributed to the
<sup>5</sup>
I
<sub>6</sub>
<sup>5</sup>
I
<sub>8</sub>
,
<sup>1</sup>
G
<sub>4</sub>
<sup>3</sup>
H
<sub>5</sub>
,
<sup>3</sup>
H
<sub>4</sub>
<sup>3</sup>
F
<sub>4</sub>
, and
<sup>4</sup>
I
<sub>13/2</sub>
<sup>4</sup>
I
<sub>15/2</sub>
transitions, respectively
<bold>(d)</bold>
. X-ray crystallography (XRD) plot
<bold>(e)</bold>
of nanoprobes confirm a predominately hexagonal phase crystalline structure. The ranking for the optical efficiencies
<bold>(f)</bold>
of the differently doped systems is: Er- > Ho- > Tm- > Pr-, where the relative ratios are 688:12:5:1, respectively. Bar graph data are expressed as mean values ± standard deviation (s.d.); n=3.</p>
</caption>
<graphic xlink:href="nihms499736f1"></graphic>
</fig>
<fig id="F2" orientation="portrait" position="float">
<label>Figure 2</label>
<caption>
<title>RE nanoprobe SWIR tissue transmission is superior to that of NIR and visible light</title>
<p id="P46">SWIR light (1525 nm) emitted from Er-doped REs is significantly more effective at transmitting through blood and pigmented tumor tissue
<bold>(a)</bold>
than visible light at 550 nm. Bar graph data in
<bold>(a)</bold>
are expressed as mean values ± standard error (s.e.m.); n=3 (†, P < 0.01) determined by Student's t-test. Transmission spectra
<bold>(b)</bold>
of visible (white region), NIR (gray region) and SWIR (blue region) light reveal that SWIR wavelengths exhibit lower absorbance and improved transmission through strong tissue absorbers such as blood and pigmented tumor tissue. Note the break in the spectra from 800 to 900 nm is due to the spectrometer's detector change. The SWIR emissions from REs patterned into the shape of an "R" and irradiated with 980 nm light ("low" − 0.14 W cm
<sup>−2</sup>
; "high" − 0.5 W cm
<sup>−2</sup>
) were more clearly visualized through a mouse body
<bold>(c)</bold>
and at lower power densities than visible emissions due to reduced scattering and absorbance. Tissue phantom studies
<bold>(d)</bold>
comparing scattering from 808 nm NIR to 1525 nm SWIR light demonstrate improved resolution quality of SWIR signals. The intensities of both the SWIR and NIR light were measured to be identical prior to the application of the tissue phantoms. Signal intensity of SWIR and NIR light as a function of tissue phantom depth
<bold>(e)</bold>
shows complete attenuation of NIR light by 5 mm while SWIR light is able to be detected through 10 mm of phantom tissues
<bold>(f)</bold>
. Data in
<bold>(f)</bold>
are expressed as mean values ± s.d.; n=3. The power outputs from the SWIR and NIR sources were adjusted to be identical (~30 µW) before tissue phantoms were applied.</p>
</caption>
<graphic xlink:href="nihms499736f2"></graphic>
</fig>
<fig id="F3" orientation="portrait" position="float">
<label>Figure 3</label>
<caption>
<title>RE nanoprobes enable real-time and multispectral imaging
<italic>in vivo</italic>
</title>
<p id="P47">Schematic of our portable SWIR-imaging prototype
<bold>(a)</bold>
. The prototype consists of a room temperature cooled InGaAs camera operating at a typical exposure time of 50 ms, adjustable filter mounts, a collimated laser with an output power density of 0.14 W cm
<sup>−2</sup>
, and a neoprene rubber imaging surface. Real-time, video-rate biodistribution of intravenously injected REs captured in hairless mice using the imaging system prototype from both ventral
<bold>(b)</bold>
and left lateral
<bold>(c)</bold>
aspects. Nude mice bearing melanoma xenografts were intravenously injected with REs and imaged near surrounding tumor regions before dissection
<bold>(d)</bold>
from the ventral aspect. Proof-of-concept multiplexed SWIR imaging performed from the dorsal aspect in mouse xenografts
<bold>(e)</bold>
after Er- and Ho-doped rare-earth probes were separately injected into tumor sites on either flank of the animal. Representative images (n=3) are shown in all instances.</p>
</caption>
<graphic xlink:href="nihms499736f3"></graphic>
</fig>
<fig id="F4" orientation="portrait" position="float">
<label>Figure 4</label>
<caption>
<title>Biologically permissive nanocomposites of REs exhibit SWIR emission</title>
<p id="P48">Rare-earth encapsulated albumin nanocarriers (RE(ANC)s)
<bold>(a)</bold>
consist of REs encapsulated by a coating of HSA to form an inorganic-organic nanocomposite, which can be tuned in size. SEM images
<bold>(b)</bold>
of (RE)ANCs show uniform sub-100 nm spherical particles (scale bar = 200 nm). (RE)ANCs retain the SWIR emission of the encapsulated REs
<bold>(c)</bold>
, exhibiting peak emission between 1550–1600 nm following 980 nm excitation. DLS measurements
<bold>(d)</bold>
confirm a low polydispersity and heterogeneity of size. (RE)ANCs exhibit negative zeta potentials in PBS (pH 7.4) and contain approximately 30 REs per particle. Data in
<bold>(d)</bold>
are expressed as mean values ± s.d.; n=5.</p>
</caption>
<graphic xlink:href="nihms499736f4"></graphic>
</fig>
<fig id="F5" orientation="portrait" position="float">
<label>Figure 5</label>
<caption>
<title>RE biologic nanocomposites profile disease progression
<italic>in vivo</italic>
</title>
<p id="P49">SWIR imaging of REs and (RE)ANCs after IP injection
<bold>(a)</bold>
into a transgenic orthotopic murine melanoma model ("TGS") over 72 h. SWIR emission of non-encapsulated REs is observed localized in the abdominal cavity 0.5 h through 72 h post-injection (white arrows). Blood concentration (% ID g
<sup>−1</sup>
) of yttrium
<bold>(b)</bold>
after RE and (RE)ANC IP injection. Data in
<bold>(b)</bold>
are expressed as mean values ± s.e.m.; n = 3. Tumor accumulation over time
<bold>(c)</bold>
of REs and (RE)ANCs in the ears of TGS mice after IP injection. Bright SWIR signal around the tumors was observed with (RE)ANCs (yellow arrows). Representative images (n=3) viewed from the ventral aspect are shown in all instances. The accumulation and clearance of SWIR fluorescence
<bold>(d)</bold>
in the tumors was described by a third-order polynomial fit for (RE)ANCs (R
<sup>2</sup>
=0.99) but could not be detected for REs. Data in
<bold>(d)</bold>
are expressed as mean values ± s.d.; n = 3. ICP-MS was performed
<bold>(e)</bold>
to detect the presence of yttrium in the tumors and quantify the imaging results observed in
<bold>(c)</bold>
. Bar graph data are expressed as mean values ± s.e.m.; n=10 for 12 h and 24 h, n=5 for 48 h and 72 h. *P < 0.10; **P < 0.05; ***P < 0.02, determined by one-way ANOVA, Tukey post-hoc. Data in
<bold>(e)</bold>
are presented as a fold increase compared to REs.</p>
</caption>
<graphic xlink:href="nihms499736f5"></graphic>
</fig>
</floats-group>
</pmc>
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