Nano Today
Volume 34, October 2020, 100905
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Engineering NIR-IIb fluorescence of Er-based lanthanide nanoparticles for through-skull targeted imaging and imaging-guided surgery of orthotopic glioma

https://doi.org/10.1016/j.nantod.2020.100905Get rights and content

Highlights

  • Fine modulation of the second near-infrared-IIb (NIR IIb, 1500−1700 nm) emission of Er-based lanthanide nanoparticles.

  • Significant enhancement of NIR IIb fluorescence of Er-based lanthanide nanoparticles by 675 folds.

  • Efficient delivery of NIR IIb nanoparticles to tumor by using focused ultrasound sonication and active targeting strategy.

  • NIR IIb fluorescence imaging-guided surgery of orthotopic glioma.

Abstract

Highly sensitive and specific discrimination of brain tumor margins from the surrounding parenchyma remains a formidable challenge. Limited by the short of photostable probes with deep tissue penetration and high efficiency of crossing the blood-brain-barrier (BBB), the development of fluorescence-guided surgery (FGS) of brain tumors was markedly constrained. Herein, we report the capability of the strong second near-infrared-IIb (NIR IIb, 1500−1700 nm) fluorescence from Er-based lanthanide nanoparticles in imaging-guided surgery of orthotopic glioma. We designed an energy-cascaded Er3+-Ce3+-A3+ (A = Yb, Ho, Tm) system and prepared a series of NaErF4:Ce@NaAF4@NaLuF4 down-conversion nanoparticles (DCNPs) for optimizing the influence of NaAF4 interlayer and Ce3+ dopants. We modified the optimal NaErF4:2.5 %Ce@NaYbF4(0.9 nm)@NaLuF4 DCNPs with Dye-brush polymer (Dye-BP) to facilitate 4I13/24I15/2 transition, which leads to an impressive 675-fold enhancement of 1525 nm fluorescence in aqueous solution under 808 nm excitation due to the excellent energy-cascaded downconversion (ECD), in comparison with that of NaErF4 nanoparticles. We further modified these highly bright nanoparticles with tumor-targeting angiopep-2 peptide, and efficiently delivered them to the glioma by using the focused ultrasound sonication (FUS) to temporarily open the BBB. We obtained the highest tumor-to-background ratio (TBR = 12.5) ever reported in the targeted NIR IIb fluorescence imaging of small orthotopic glioma (size < 3 mm, depth> 3 mm) through intact skull and scalp, which was drastically improved to ∼150 after cardiac perfusion and craniotomy to ensure the precise resection of tumor. More importantly, the size of glioma measured from the width of fluorescence profile is very close to that from T2-weighted MRI images. Our work provides the insights into engineering NIR IIb fluorescence of lanthanide nanoparticles, and demonstrates the great potential of NIR IIb fluorescence imaging-guided surgery of tumor.

Introduction

Finely and clearly visualizing the margins of brain tumors, especially for glioblastoma (GBM), which is the most common malignant brain tumor, from the surrounding parenchyma is the lynchpin for their precise diagnosis and surgery [[1], [2], [3]]. Although the typical use of visual inspection and imaging guidance can provide valuable information for clinicians, the intrinsic limitations of currently available imaging methods, such as low sensitivity, non-dynamical inspection, and hazardous ionizing radiation, can cause intraoperative failure in completely resecting tumor tissues [1,[4], [5], [6]]. In addition, for fluorescence-guided surgery (FGS) of brain tumors, photostable probes with strong capability of crossing the blood-brain-barrier (BBB) are crucial for precise delineation glioma margin and the subsequent curative resection. The intrinsic drawbacks of clinically used probes (5-aminolevulinic acid (5-ALA) [7,8] and indocyanine green (ICG) [9,10]), such as insufficient photostability [11] and short excitation/emission wavelength-induced low tissue penetration depth, are driving the development of alternative probes for FGS of brain tumors.

Recently, much effort has been devoted to developing the second near-infrared (NIR II, 1000−1700 nm) fluorescence imaging favoring for reduced tissue absorption, scattering and minimized auto-fluorescence [12,13]. In particular, the fluorescence in the range of 1500−1700 nm (NIR IIb) has attracted considerable interests, because it offers the lowest photon scattering effect, according to the Mie theory (μs'∝λ−α, μs' represents the reduced scattering coefficient, λ is the wavelength of incident light, α = 0.2–4 for different tissues) [14], and the negligible autofluorescence under laser irradiation in this window [15,16]. Currently, the NIR IIb fluorescent probes, such as single-walled carbon nanotubes [16], PbS@CdS quantum dots [17], organic dyes [18], have been applied for imaging mouse brain vasculature through intact skull and scalp. Despite of their advances, some other limitations drive the research of complementary nanoprobes [19,20]. Alternatively, Er-based rare-earth nanoparticles are well-known for up-conversion (UC) and down-conversion (DC) fluorescence from visible to NIR II region with controllable size, shape and functionality [[21], [22], [23], [24]]. Typical Yb3+-Er3+ co-doped lanthanide nanoparticles could emit NIR IIb fluorescence under 980 nm light excitation, but the water in tissues would inevitably attenuate 980 nm light to produce local heat and reduce penetration depth [25]. Although introducing Nd3+ sensitizers into Yb3+-Er3+ co-doped nanoparticles makes the feasibility of excitation with ∼800 nm light [26], precise control of core and shell is demanded for optimizing NIR IIb emission.

Unlike other lanthanide ions serving as either sensitizers or activators, Er3+ ions can act as both the sensitizers and activators to render effective UC and DC processes [22]. To increase near-infrared absorption as much as possible, high concentration of sensitizers is usually required [27], which can inevitably cause non-radiative cross-relaxation and energy migration loss of Er3+-heavily doped nanoparticles. To reduce the negative effects caused by activators (Er3+ ions), various energy trapping centers (Yb3+, Tm3+, Ho3+, etc) were introduced to confine the excitation energy to enhance the UC process [28,29]. However, there is rare report on boosting DC process of Er3+-heavily doped lanthanide nanoparticles, which are facing the challenge of weak NIR IIb fluorescence.

To significantly improve NIR IIb emission of Er3+-heavily doped nanoparticles under 808 nm excitation, maximally increasing absorption and optimizing the energy transfer to 4I13/2 are crucial. Herein, we report an energy-cascaded strategy to boost NIR IIb emission of Er-based core-shell-shell down-conversion nanoparticles (DCNPs), and a cooperative tactic to deliver them to orthotopic glioma for targeted imaging and imaging-guided surgery. The resulting nanoparticles exhibit 675-fold enhancement of emission at 1525 nm in aqueous solution in comparison with core nanoparticles. Their strong NIR IIb fluorescence and low background make them very useful in imaging and imaging-guided surgery of deep-seated tumor.

Section snippets

Modulating NIR IIb emission of Er-based DCNPs via energy-cascaded process

We designed core-shell-shell NaErF4:Ce@NaYbF4@NaLuF4 DCNPs by using excitation energy trapping and non-radiative cross-relaxation approaches (Fig. 1a) [20,29,30]. In this energy-cascaded Er3+-Ce3+-Yb3+ system, NaYbF4 interlayer can bounce back the radiative energy from 4I11/2 of Er3+, and sequentially drive cross-relaxation to 4I13/2 of Er3+ via Ce3+ ions to maximize 4I13/24I15/2 transition (Fig. 1b). Although other self-sensitized activators, such as Er3+, Ho3+, and Tm3+ ions, could promote

Materials

ErCl3·6H2O, CeCl3·7H2O, YbCl3·6H2O, TmCl3·6H2O, HoCl3·6H2O, LuCl3·6H2O, sodium fluoride (NaF, 99.99 %), oleic acid (OA, 85 %), 1-octadecene (ODE, 90 %), 4-mercaptobenzoic acid (90 %), 2-aminoethyl methacrylate hydrochloride (AMA, 90 %), N,N′-dicyclohexylcarbodiimide (DCC, 99.0 %), 4-cyano-4-(phenylcarbonothioylthio)pentanoic acid (CTA, >97 %), 2,2′-azobis(2-methylpropionitrile) (AIBN, 99 %), and tris(2-carboxyethyl)phosphine (TCEP, 98 %) were purchased from Aladdin Co. Ltd. Sodium hydroxide

Author statement

F. R. performed the preparation, modification, and characterization of nanoprobes, and drafted the manuscript. H. L., H. Z., and Z. J. performed the cell and animal experiments. B. X. and T. H. synthesized and characterized the block polymers. C. G. and M. A. performed the TEM analysis of samples. Z. L., Q. S., and M. G. did the critical revisions of the manuscript.

Declaration of Competing Interest

The authors declare no conflict of interest.

Acknowledgements

Z. Li acknowledges support from the National Natural Science Foundation of China (81971671, 81527901), National Key Research and Development Program of China (2018YFA0208800), Jiangsu Provincial Key Research and Development Program (BE2019660). The authors also are grateful for support from the Jiangsu Provincial Key Laboratory of Radiation Medicine and Protection, the Priority Academic Development Program of Jiangsu Higher Education Institutions (PAPD). The authors would like to thank Dr.

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