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Quantum Yield‐Engineered Biocompatible Probes Illuminate Lung Tumor Based on Viscosity Confinement‐Mediated Antiaggregation

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Advanced Functional Materials
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Kun Zhang at Xavier University of Louisiana
Kun Zhang
Hong‐Yan Li
Hong‐Yan Li
Hong‐Yan Li
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Jinyi Lang at Sichuan University
Jinyi Lang
Xiao‐Tong Li
Xiao‐Tong Li
Xiao‐Tong Li
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Abstract and Figures

Low quantum yield and aggregation‐mediated quenching are two concerns for fluorescence imaging. However, there are not yet general means available for addressing these issues. Herein, a viscosity confinement‐mediated antiaggregation strategy is established to enable the improved fluorescence properties of entrapped fluorophores in dye‐encapsulation nanotechnology including quantum yield, fluorescence lifetime, and photostability. To instantiate this strategy, solid DL‐menthol (DLM) is introduced to disperse entrapped indocyanine green (ICG) fluorophores when coencapsulating DLM and ICG molecules in organic poly(lactic‐co‐glycolic acid) carriers. Depending on the robust ability of highly viscous DLM to augment the migration barrier and diminish diffusion coefficient, ICG aggregation and aggregation‐mediated quenching are demonstrated to be theoretically and experimentally inhibited, resulting in prolonged fluorescence lifetime, increased quantum yield, and facilitated radiative process. Consequently, the fluorescence imaging ability and photostability are significantly improved, enabling the in vitro, cellular‐level, and in vivo fluorescence imaging. More significantly, this solid DLM‐mediated antiaggregation strategy can act as a general method to extend to the intermolecular fluorescence resonance energy transfer (FRET) process and improve FRET efficiency via inhibiting the aggregation‐mediated quenching. Solid DL‐menthol is introduced into poly(lactic‐co‐glycolic acid) carriers to disperse entrapped fluorophores and established viscosity confinement‐mediated antiaggregation strategy for inhibiting quenching and improving fluorescence imaging properties associated with quantum yield, fluorescence lifetime, and photostability via the high viscosity‐mediated migration barrier elevation, which provides a new avenue to improving fluorescence imaging of entrapped fluorophores in dye‐encapsulation nanotechnology.
Characterizations of DLM/ICG@PLGA and other counterparts (ICG@PLGA, PFH/ICG@PLGA). a1) Low‐fold and a2) high‐fold TEM images of ICG@PLGA nanoparticles; b1) Low‐fold and b2) high‐fold TEM images of PFH/ICG@PLGA nanoparticles; c1) Low‐fold and c2) high‐foldTEM images of DLM/ICG@PLGA nanoparticles; d1) Particle size distributions of ICG@PLGA, d2) PFH/ICG@PLGA, and d3) DLM/ICG@PLGA nanoparticles that were determined by dynamic light scattering (DLS) technology with PDI = 0.105, 0.126, and 0.068, respectively, and their average particle sizes were 522.4, 518.7, and 528.3 nm, respectively.
Characterizations of DLM/ICG@PLGA and other counterparts (ICG@PLGA, PFH/ICG@PLGA). a1) Low‐fold and a2) high‐fold TEM images of ICG@PLGA nanoparticles; b1) Low‐fold and b2) high‐fold TEM images of PFH/ICG@PLGA nanoparticles; c1) Low‐fold and c2) high‐foldTEM images of DLM/ICG@PLGA nanoparticles; d1) Particle size distributions of ICG@PLGA, d2) PFH/ICG@PLGA, and d3) DLM/ICG@PLGA nanoparticles that were determined by dynamic light scattering (DLS) technology with PDI = 0.105, 0.126, and 0.068, respectively, and their average particle sizes were 522.4, 518.7, and 528.3 nm, respectively.
… 
Experimental and theoretical validations of such a migration barrier elevation‐ or viscosity confinement‐mediated antiaggregation strategy for repressing quenching and improving fluorescence imaging property. a) UV–vis spectra and b) photoluminescence (PL) emission spectra of different samples, i.e., free ICG in water, ICG@PLGA, PFH/ICG@PLGA, and DLM/ICG@PLGA; c1) In vitro fluorescence images of DLM/ICG@PLGA, c2) PFH/ICG@PLGA, c3) ICG@PLGA, and c4) free ICG in water; λex = 740 nm and λem = 820 nm. d1) ICG molecule configurations of free ICG molecules in deionized water and d2) entrapped ICG in ICG@PLGA, d3) PFH/ICG@PLGA, and d4) DLM/ICG@PLGA. Notes: these samples share identical L = 28 nm between two ICG molecules corresponding to 1 × 10⁻⁴ mol L⁻¹ in per particle or free water, and to guarantee identical ICG content with that in free water, the particle concentration of each sample was 2.4 mg mL⁻¹. e) Migration barriers of different surrounding environments, i.e., free ICG deionized water and entrapped ICG molecules in ICG@PLGA, PFH/ICG@PLGA, and DLM/ICG@PLGA.
Experimental and theoretical validations of such a migration barrier elevation‐ or viscosity confinement‐mediated antiaggregation strategy for repressing quenching and improving fluorescence imaging property. a) UV–vis spectra and b) photoluminescence (PL) emission spectra of different samples, i.e., free ICG in water, ICG@PLGA, PFH/ICG@PLGA, and DLM/ICG@PLGA; c1) In vitro fluorescence images of DLM/ICG@PLGA, c2) PFH/ICG@PLGA, c3) ICG@PLGA, and c4) free ICG in water; λex = 740 nm and λem = 820 nm. d1) ICG molecule configurations of free ICG molecules in deionized water and d2) entrapped ICG in ICG@PLGA, d3) PFH/ICG@PLGA, and d4) DLM/ICG@PLGA. Notes: these samples share identical L = 28 nm between two ICG molecules corresponding to 1 × 10⁻⁴ mol L⁻¹ in per particle or free water, and to guarantee identical ICG content with that in free water, the particle concentration of each sample was 2.4 mg mL⁻¹. e) Migration barriers of different surrounding environments, i.e., free ICG deionized water and entrapped ICG molecules in ICG@PLGA, PFH/ICG@PLGA, and DLM/ICG@PLGA.
… 
Principle explorations of such a viscosity confinement‐mediated antiaggregation strategy for improving fluorescence imaging based on DLM‐mediated migration barrier elevation. a) Fluorescence quantum yield, b) fluorescence lifetime, c) and radiative decay rate of different samples from 1 to 4 that share identical L = 28 nm between two ICG molecules, and 1–4 represent free ICG in water solvent, ICG@PLGA, PFH/ICG@PLGA, and DLM/ICG@PLGA, respectively, wherein, “*,” “**,” and “***” represent P <0.05, 0.01, and 0.001, respectively. Note: the used particle concentration was 0.1 mg mL⁻¹. d) UV–vis spectra of aqueous DLM/ICG@PLGA after treatment with different temperatures (25, 37, and 45 °C) for 2 h; e) PL emission spectra of DLM/ICG@PLGA after treatment with different temperatures (25, 37, and 45 °C) for 2 h and free ICG at 25 °C; Notes: λex = 740 nm; In vitro fluorescence images of DLM/ICG@PLGA after treatment with different temperatures, i.e., f1) 25 °C, f2) 37 °C, and f3) 45 °C for 2 h, and f4) free ICG at 25 °C; Notes: λex = 740 nm and λem = 820 nm. These samples share identical L = 28 nm between two ICG molecules corresponding to 1 × 10⁻⁴ mol L⁻¹ in per particle or free water. To guarantee identical ICG content with that in free water, the used particle concentration of ICG@PLGA, PFH/ICG@PLGA, and DLM/ICG@PLGA were 2.4 mg mL⁻¹.
Principle explorations of such a viscosity confinement‐mediated antiaggregation strategy for improving fluorescence imaging based on DLM‐mediated migration barrier elevation. a) Fluorescence quantum yield, b) fluorescence lifetime, c) and radiative decay rate of different samples from 1 to 4 that share identical L = 28 nm between two ICG molecules, and 1–4 represent free ICG in water solvent, ICG@PLGA, PFH/ICG@PLGA, and DLM/ICG@PLGA, respectively, wherein, “*,” “**,” and “***” represent P <0.05, 0.01, and 0.001, respectively. Note: the used particle concentration was 0.1 mg mL⁻¹. d) UV–vis spectra of aqueous DLM/ICG@PLGA after treatment with different temperatures (25, 37, and 45 °C) for 2 h; e) PL emission spectra of DLM/ICG@PLGA after treatment with different temperatures (25, 37, and 45 °C) for 2 h and free ICG at 25 °C; Notes: λex = 740 nm; In vitro fluorescence images of DLM/ICG@PLGA after treatment with different temperatures, i.e., f1) 25 °C, f2) 37 °C, and f3) 45 °C for 2 h, and f4) free ICG at 25 °C; Notes: λex = 740 nm and λem = 820 nm. These samples share identical L = 28 nm between two ICG molecules corresponding to 1 × 10⁻⁴ mol L⁻¹ in per particle or free water. To guarantee identical ICG content with that in free water, the used particle concentration of ICG@PLGA, PFH/ICG@PLGA, and DLM/ICG@PLGA were 2.4 mg mL⁻¹.
… 
In vivo evaluations using such a viscosity confinement‐mediated antiaggregation strategy for improving fluorescence imaging of SPC‐A‐1 lung tumor subsequently implanted on nude mice. a1–d1) In vivo fluorescence images and a2–d2) signal intensities of nude mice bearing SPC‐A‐1 lung tumor as a function of time before and after intravenously administering different samples, i.e., a1,a2) free ICG, b1,b2) ICG@PLGA, c1,c2) PFH/ICG@PLGA, and d1,d2) DLM/ICG@PLGA in PBS; Notes: λex = 740 nm and λem = 820 nm, and the used particle concentration was 2.4 mg mL⁻¹.
In vivo evaluations using such a viscosity confinement‐mediated antiaggregation strategy for improving fluorescence imaging of SPC‐A‐1 lung tumor subsequently implanted on nude mice. a1–d1) In vivo fluorescence images and a2–d2) signal intensities of nude mice bearing SPC‐A‐1 lung tumor as a function of time before and after intravenously administering different samples, i.e., a1,a2) free ICG, b1,b2) ICG@PLGA, c1,c2) PFH/ICG@PLGA, and d1,d2) DLM/ICG@PLGA in PBS; Notes: λex = 740 nm and λem = 820 nm, and the used particle concentration was 2.4 mg mL⁻¹.
… 
FRET manipulations in DLM/DiD‐DiR@PLGA by solid DLM‐mediated migration barrier elevation for antiaggregation and inhibited quenching. a) FRET schematic from DiD to DiR in DLM/DiD‐DiR@PLGA; b) UV–vis spectrum of DLM/DiD‐DiR@PLGA. c) Schematic of intermolecular FRET from DiD to DiR determined by their intermolecular distance (L), wherein distance‐dependent FRET under two conditions: L (28 nm) > dc (10 nm) and L (7.7 nm) < dc (10 nm) were set. Notes: dc represents the critical distance of FRET occurrence, beyond which FRET process ceases, and vice versa. d) PL spectra of different samples, i.e., DLM/DiD‐DiR@PLGA (L > dc), PFH/DiD‐DiR@PLGA (L > dc), DLM/DiD‐DiR@PLGA (L < dc) at room temperature (25 °C) and DLM/DiD‐DiR@PLGA (L > dc) at 45 °C. Notes: λex = 640 nm. e) In vitro fluorescence images of different samples, i.e., DLM/DiD‐DiR@PLGA (L > dc), PFH/DiD‐DiR@PLGA (L > dc), DLM/DiD‐DiR@PLGA (L < dc) at room temperature (25 °C), and DLM/DiD‐DiR@PLGA (L > dc) at 45 °C. Notes: λex = 640 nm and λem = 800 nm. f) The FRET efficiency of DLM/DiD‐DiR@PLGA dispersed in PBS as a function of incubation time. The ratio of DiD to DiR was fixed to be 1:1, and L = 28 and 7.7 nm corresponded to 1 × 10⁻⁴ mol L⁻¹ and 4.8 × 10⁻³ mol L⁻¹ molar concentrations of ICG in per particle or free water, respectively. To guarantee identical ICG content with that in free water, the used particle concentrations were 2.4 mg mL⁻¹ for L = 28 nm and 0.05 mg mL⁻¹ for L = 7.7 nm, respectively.
FRET manipulations in DLM/DiD‐DiR@PLGA by solid DLM‐mediated migration barrier elevation for antiaggregation and inhibited quenching. a) FRET schematic from DiD to DiR in DLM/DiD‐DiR@PLGA; b) UV–vis spectrum of DLM/DiD‐DiR@PLGA. c) Schematic of intermolecular FRET from DiD to DiR determined by their intermolecular distance (L), wherein distance‐dependent FRET under two conditions: L (28 nm) > dc (10 nm) and L (7.7 nm) < dc (10 nm) were set. Notes: dc represents the critical distance of FRET occurrence, beyond which FRET process ceases, and vice versa. d) PL spectra of different samples, i.e., DLM/DiD‐DiR@PLGA (L > dc), PFH/DiD‐DiR@PLGA (L > dc), DLM/DiD‐DiR@PLGA (L < dc) at room temperature (25 °C) and DLM/DiD‐DiR@PLGA (L > dc) at 45 °C. Notes: λex = 640 nm. e) In vitro fluorescence images of different samples, i.e., DLM/DiD‐DiR@PLGA (L > dc), PFH/DiD‐DiR@PLGA (L > dc), DLM/DiD‐DiR@PLGA (L < dc) at room temperature (25 °C), and DLM/DiD‐DiR@PLGA (L > dc) at 45 °C. Notes: λex = 640 nm and λem = 800 nm. f) The FRET efficiency of DLM/DiD‐DiR@PLGA dispersed in PBS as a function of incubation time. The ratio of DiD to DiR was fixed to be 1:1, and L = 28 and 7.7 nm corresponded to 1 × 10⁻⁴ mol L⁻¹ and 4.8 × 10⁻³ mol L⁻¹ molar concentrations of ICG in per particle or free water, respectively. To guarantee identical ICG content with that in free water, the used particle concentrations were 2.4 mg mL⁻¹ for L = 28 nm and 0.05 mg mL⁻¹ for L = 7.7 nm, respectively.
… 
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© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1905124 (1 of 12)
Low quantum yield and aggregation-mediated quenching are two concerns
for fluorescence imaging. However, there are not yet general means available
for addressing these issues. Herein, a viscosity confinement-mediated
antiaggregation strategy is established to enable the improved fluorescence
properties of entrapped fluorophores in dye-encapsulation nanotechnology
including quantum yield, fluorescence lifetime, and photostability. To
instantiate this strategy, solid DL-menthol (DLM) is introduced to disperse
entrapped indocyanine green (ICG) fluorophores when coencapsulating DLM
and ICG molecules in organic poly(lactic-co-glycolic acid) carriers. Depending
on the robust ability of highly viscous DLM to augment the migration
barrier and diminish diffusion coefficient, ICG aggregation and aggregation-
mediated quenching are demonstrated to be theoretically and experimentally
inhibited, resulting in prolonged fluorescence lifetime, increased quantum
yield, and facilitated radiative process. Consequently, the fluorescence
imaging ability and photostability are significantly improved, enabling the in
vitro, cellular-level, and in vivo fluorescence imaging. More significantly, this
solid DLM-mediated antiaggregation strategy can act as a general method to
extend to the intermolecular fluorescence resonance energy transfer (FRET)
process and improve FRET efficiency via inhibiting the aggregation-mediated
quenching.
1. Introduction
Fluorescence molecular imaging has
exhibited a widespread application poten-
tial ranging from in vitro noninvasive
detection to in vivo imaging, even to
anatomical pathology, protein or gene
examinations, and biological analysis.[1–5]
Moreover, various organic fluorophores
lay a solid foundation to the advance of
fluorescence imaging technology. Unfor-
tunately, organic fluorophores still suffer
from some inherent drawbacks, e.g., deg-
radation, aggregation, quenching, adsorp-
tion by serum, and short circulation time
caused by rapid clearance, which inevi-
tably impairs the resolution and sensitivity
of fluorescence imaging and even disables
in vivo imaging.[6–8]
In an attempt to develop new means to
protect organic fluorophores, great pro-
gress has been made in employing carriers
to entrap organic fluorescence mole-
cules.[9,10] Especially, dye-encapsulation
nanotechnology that uses some carriers to
Quantum Yield-Engineered Biocompatible
Probes Illuminate Lung Tumor Based on Viscosity
Confinement-Mediated Antiaggregation
Kun Zhang,* Hong-Yan Li, Jin-Yi Lang, Xiao-Tong Li, Wen-Wen Yue,* Yi-Fei Yin,
Dou Du, Yan Fang, Hong Wu, Yong-Xiang Zhao,* and Chuan Xu*
DOI: 10.1002/adfm.201905124
Anti-Aggregation
The ORCID identification number(s) for the author(s) of this article
can be found under https://doi.org/10.1002/adfm.201905124.
Prof. K. Zhang, Dr. H.-Y. Li, Dr. W.-W. Yue, Dr. Y.-F. Yin, Dr. D. Du,
Dr. Y. Fang
Department of Medical Ultrasound
Shanghai Tenth People’s Hospital
Ultrasound Research and Education Institute
Tongji University School of Medicine
301 Yan-chang-zhong Road, Shanghai 200072, P. R. China
E-mail: zhang1986kun@126.com; yuewen0902@163.com
Prof. K. Zhang, Prof. J.-Y. Lang, Dr. H. Wu, Prof. C. Xu
Department of Oncology
Sichuan Provincial People’s Hospital
Sichuan Cancer Hospital & Institute
Sichuan Cancer Center
School of Medicine
University of Electronic Science and Technology of China
No. 55, Section 4, Renmin South Road
Chengdu, Sichuan 610047, P. R. China
E-mail: xuchuan100@163.com
Prof. K. Zhang, Dr. X.-T. Li, Prof. Y.-X. Zhao
National Center for International Research
of Bio-targeting Theranostics
Guangxi Key Laboratory of Bio-targeting Theranostics
Collaborative Innovation Center for Tumor-targeting Theranostics
Guangxi Medical University
22 Shuang-Yong Road, Nanning, Guangxi 530021, P. R. China
E-mail: zhaoyongxiang@gxmu.edu.cn
Adv. Funct. Mater. 2019, 29, 1905124
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  • Nov 2017
  • NAT BIOTECHNOL
Afterglow optical agents, which emit light long after cessation of excitation, hold promise for ultrasensitive in vivo imaging because they eliminate tissue autofluorescence. However, afterglow imaging has been limited by its reliance on inorganic nanoparticles with relatively low brightness and short-near-infrared (NIR) emission. Here we present semiconducting polymer nanoparticles (SPNs) <40 nm in diameter that store photon energy via chemical defects and emit long-NIR afterglow luminescence at 780 nm with a half-life of ~6 min. In vivo, the afterglow intensity of SPNs is more than 100-fold brighter than that of inorganic afterglow agents, and the signal is detectable through the body of a live mouse. High-contrast lymph node and tumor imaging in living mice is demonstrated with a signal-to-background ratio up to 127-times higher than that obtained by NIR fluorescence imaging. Moreover, we developed an afterglow probe, activated only in the presence of biothiols, for early detection of drug-induced hepatotoxicity in living mice.
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Development of organic semiconducting materials for deep-tissue optical imaging, phototherapy and photoactivation
Article
  • Jan 2019
Biophotonics as a highly interdisciplinary frontier often requires the assistance of optical agents to control the light pathways in cells, tissues and living organisms for specific biomedical applications. Organic semiconducting materials (OSMs) composed of π-conjugated building blocks as the optically active components have recently emerged as a promising category of biophotonic agents. OSMs possess common features including excellent optical properties, good photostability and biologically benign composition. This review summarizes the recent progress in the development of OSMs based on small-molecule fluorophores, aggregation-induced emission (AIE) dyes and semiconducting oligomer/polymer nanoparticles (SONs/SPNs) for advanced biophotonic applications. OSMs have been exploited as imaging agents to transduce biomolecular interactions into second near-infrared fluorescence, chemiluminescence, afterglow or photoacoustic signals, enabling deep-tissue ultrasensitive imaging of biological tissues, disease biomarkers and physiological indexes. By fine-tuning the molecular structures, OSMs can also convert light energy into cytotoxic free radicals or heat, allowing for effective cancer phototherapy. Due to their instant light response and efficient light-harvesting properties, precise regulation of biological activities using OSMs as remote transducers has been demonstrated for protein ion channels, gene transcription and protein activation. In addition to highlighting OSMs as a multifunctional platform for a wide range of biomedical applications, current challenges and perspectives of OSMs in biophotonics are discussed.
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Multimodal Biophotonics of Semiconducting Polymer Nanoparticles
Article
  • Aug 2018
Biophotonics as an interdisciplinary frontier plays an increasingly important role in modern biomedical science. Optical agents are generally involved in biophotonics to interpret biomolecular events into readable optical signals for imaging and diagnosis or to convert photons into other forms of energy (such as heat, mechanical force, or chemical radicals) for therapeutic intervention and biological stimulation. Development of new optical agents including metallic nanoparticles, quantum dots, up-conversion nanoparticles, carbon dots, and silica nanoparticles has contributed to the advancement of this field. However, most of these agents have their own merits and demerits, making them less effective as multimodal biophotonic platforms.
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Tailoring Fluorescence Brightness and Switching of Nanoparticles through Dye Organization in the Polymer Matrix
Article
  • Nov 2017
  • ACS APPL MATER INTER
Fluorescent nanoparticles (NPs) help to increase spatial and temporal resolution in bioimaging. Advanced microscopy techniques require very bright NPs that exhibit either stable emission for single-particle tracking or complete on/off switching (blinking) for super-resolution imaging. Here, ultrabright dye-loaded polymer NPs with controlled switching properties are developed. To this aim, the salt of a dye (rhodamine B octadecyl ester) with a hydrophobic counterion (fluorinated tetraphenylborate) is encapsulated at very high concentrations up to 30 wt % in NPs made of poly(lactic-co-glycolic acid) (PLGA), poly(methyl methacrylate) (PMMA), and polycaprolactone (PCL) through nanoprecipitation. The obtained 35 nm NPs are nearly 100 times brighter than quantum dots. The nature of the polymer is found to define the collective behavior of the encapsulated dyes so that NPs containing thousands of dyes exhibit either whole particle blinking, for PLGA, or stable emission, for PMMA and PCL. Fluorescence anisotropy measurements together with small-angle X-ray scattering experiments suggest that in less hydrophobic PLGA, dyes tend to cluster, whereas in more hydrophobic PMMA and PCL, dyes are dispersed within the matrix, thus altering the switching behavior of NPs. Experiments using a perylene diimide derivative show a similar effect of the polymer nature. The resulting fluorescent NPs are suitable for a wide range of imaging applications from tracking to super-resolution imaging. The findings on the organization of the load innside NPs will have impact on the development of materials for applications ranging from photovoltaics to drug delivery.
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Nanoparticle Regrowth Enhances Photoacoustic Signals of Semiconducting Macromolecular Probe for In Vivo Imaging
Article
Smart molecular probes that emit deep-tissue penetrating photoacoustic (PA) signals responsive to the target of interest are imperative to understand disease pathology and develop innovative therapeutics. This study reports a self-assembly approach to develop semiconducting macromolecular activatable probe for in vivo imaging of reactive oxygen species (ROS). This probe comprises a near-infrared absorbing phthalocyanine core and four poly(ethylene glycol) (PEG) arms linked by ROS-responsive self-immolative segments. Such an amphiphilic macromolecular structure allows it to undergo an ROS-specific cleavage process to release hydrophilic PEG and enhance the hydrophobicity of the nanosystem. Consequently, the residual phthalocyanine component self-assembles and regrows into large nanoparticles, leading to ROS-enhanced PA signals. The small size of the intact macromolecular probe is beneficial to penetrate into the tumor tissue of living mice, while the ROS-activated regrowth of nanoparticles prolongs the retention along with enhanced PA signals, permitting imaging of ROS during chemotherapy. This study thus capitalizes on stimuli-controlled self-assembly of macromolecules in conjunction with enhanced heat transfer in large nanoparticles for the development of smart molecular probes for PA imaging.
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Aggregation-Induced Emission Luminogen with Deep-Red Emission for Through-Skull Three-Photon Fluorescence Imaging of Mouse
Article
  • Oct 2017
Imaging the brain with high integrity is of great importance to neuroscience and related applications. X-ray computed tomography (CT) and magnetic resonance imaging (MRI) are two clinically used modalities for deep-penetration brain imaging. However, their spatial resolution is quite limited. Two-photon fluorescence microscopic (2PFM) imaging with its femtosecond (fs) excitation wavelength in the traditional near-infrared (NIR) region (700-1000 nm) is able to realize deep-tissue and high-resolution brain imaging. However, it requires craniotomy and cranial window, or skull-thinning techniques, due to photon scattering of the excitation light. Herein, based on a type of aggregation-induced emission luminogen (AIEgen) DCDPP-2TPA with large three-photon absorption (3PA) cross-section at 1550 nm and deep-red emission, we realized through-skull three-photon fluorescence microscopic (3PFM) imaging of mouse cerebral vasculature without craniotomy and skull-thinning. Reduced photon scattering of 1550 nm fs excitation laser allowed it effectively penetrate skull and tightly focus onto DCDPP-2TPA nanoparticles (NPs) in the cerebral vasculature, generating bright three-photon fluorescence (3PF) signals. In vivo 3PF images of the cerebral vasculature at various vertical depths were obtained, and a vivid 3D reconstruction of the vascular architecture beneath the skull was built. As deep as 300 μm beneath the skull, small blood vessels of 2.4 μm could still be recognized.
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