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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. BRIEF INTRODUCTION OF LANTHANIDE ELEMENTS
  5. LUMINESCENCE CHARACTERISTICS OF LANTHANIDE IONS
  6. FABRICATION STRATEGIES FOR LDHNs
  7. FABRICATION STRATEGIES FOR SINGLE-PHASE LANTHANIDE-DOPED HOLLOW NANOMATERIALS
  8. FABRICATION STRATEGIES FOR LANTHANIDE-DOPED HOLLOW NANOCOMPOSITES
  9. BIOAPPLICATIONS OF LDHNs
  10. BIODETECTION
  11. IMAGING
  12. DRUG/GENE DELIVERY
  13. OTHER THERAPEUTIC APPLICATIONS
  14. CONCLUSION AND OUTLOOK
  15. ACKNOWLEDGMENTS
  16. REFERENCES

The field of theranostics has sprung up to achieve personalized medicine. The theranostics fuses diagnostic and therapeutic functions, empowering early diagnosis, targeted drug delivery, and real-time monitoring of treatment effect into one step. One particularly attractive class of nanomaterials for theranostic application is lanthanide-doped hollow nanomaterials (LDHNs). Because of the existence of lanthanide ions, LDHNs show outstanding fluorescent and paramagnetic properties, enabling them to be used as multimodal bioimaging agents. Synchronously, the huge interior cavities of LDHNs are able to be applied as efficacious tools for storage and delivery of therapeutic agents. The LDHNs can be divided into two types based on difference of component: single-phase lanthanide-doped hollow nanomaterials and lanthanide-doped hollow nanocomposites. We describe the synthesis of first kind of nanomaterials by use of hard template, soft template, template-free, and self-sacrificing template method. For lanthanide-doped hollow nanocomposites, we divide the preparation strategies into three kinds (one-step, two-step, and multistep method) according to the synthetic procedures. Furthermore, we also illustrate the potential bioapplications of these LDHNs, including biodetection, imaging (fluorescent imaging and magnetic resonance imaging), drug/gene delivery, and other therapeutic applications. WIREs Nanomed Nanobiotechnol 2014, 6:80–101. doi: 10.1002/wnan.1251

Conflict of interest: The authors have declared no conflicts of interest for this article.

For further resources related to this article, please visit the WIREs website.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. BRIEF INTRODUCTION OF LANTHANIDE ELEMENTS
  5. LUMINESCENCE CHARACTERISTICS OF LANTHANIDE IONS
  6. FABRICATION STRATEGIES FOR LDHNs
  7. FABRICATION STRATEGIES FOR SINGLE-PHASE LANTHANIDE-DOPED HOLLOW NANOMATERIALS
  8. FABRICATION STRATEGIES FOR LANTHANIDE-DOPED HOLLOW NANOCOMPOSITES
  9. BIOAPPLICATIONS OF LDHNs
  10. BIODETECTION
  11. IMAGING
  12. DRUG/GENE DELIVERY
  13. OTHER THERAPEUTIC APPLICATIONS
  14. CONCLUSION AND OUTLOOK
  15. ACKNOWLEDGMENTS
  16. REFERENCES

The past decade has witnessed enormous advances in engineering lanthanide-doped nanoparticles (NPs) with a good wealth of morphologies.[1] Enormous studies focused on the imaging functions of such NPs. They can act as fluorescent imaging agents for early cancer diagnostics at cellular or molecular levels.[2] They can also function as computed tomography (CT) imaging agents because of their high X-ray attenuation coefficient, and serve as T1 or T2 contrast agents (CAs) for magnetic resonance imaging (MRI).[3], [4] The key feature of lanthanide-doped NPs for enabling a series of biomedical applications is based on their unfilled 4f electronic structures.

The field of theranostics has emerged as an interdisciplinary research area involving chemistry, material science, biology, and medicine. The theranostics, combine diagnositics and therapeutics, enabling early detection, targeted drug delivery and release, and monitoring of therapeutic response with the aid of imaging modalities in a single procedure.[5] The multifunctional NPs will enhance therapeutic efficacy, reduce the frequency of drug administration, and relieve patient discomfort. A convenient strategy in constructing theranostics systems is to apply imaging agents themselves to load therapeutic agents.[6] Among various NPs investigated for this aim, LDHNs can serve as satisfying platform for theranostics. Fluorescent nanoparticle probes including dye-loaded NPs, quantum dots and phosphores were summarized and discussed by Santra's group.[7] Comparatively speaking, LDHNs for imaging of cancer are advantageous. Suitable imaging probes can be used for patients on demand by selecting different lanthanide elements. The porous inorganic materials with high specific surface area are extensively used to store various drugs.[8] Due to the large interior cargo volume, LDHNs can encapsulate considerable amount of drugs with controlled releasing property to obtain higher therapeutic efficiency compared with conventional drug delivery systems such as mesoporous nanomaterials.[9]

This review focuses on recent developments of LDHNs. A short description of lanthanide elements is firstly given, and their luminescent and magnetic characteristics for the bioapplication are introduced. We classify LDHNs into single-phase lanthanide-doped hollow nanomaterials and lanthanide-doped hollow nanocomposites, and explain the fabrication approaches of two types of nanomaterials in details, respectively. Finally, we highlight their biomedical applications in biodetection, imaging (fluorescent imaging and MRI), drug/gene delivery, and other therapeutic applications.

BRIEF INTRODUCTION OF LANTHANIDE ELEMENTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. BRIEF INTRODUCTION OF LANTHANIDE ELEMENTS
  5. LUMINESCENCE CHARACTERISTICS OF LANTHANIDE IONS
  6. FABRICATION STRATEGIES FOR LDHNs
  7. FABRICATION STRATEGIES FOR SINGLE-PHASE LANTHANIDE-DOPED HOLLOW NANOMATERIALS
  8. FABRICATION STRATEGIES FOR LANTHANIDE-DOPED HOLLOW NANOCOMPOSITES
  9. BIOAPPLICATIONS OF LDHNs
  10. BIODETECTION
  11. IMAGING
  12. DRUG/GENE DELIVERY
  13. OTHER THERAPEUTIC APPLICATIONS
  14. CONCLUSION AND OUTLOOK
  15. ACKNOWLEDGMENTS
  16. REFERENCES

The lanthanide elements comprise the fifteen elements with atomic numbers 57 through 71, from lanthanum through lutetium (Table 1). These elements, along with the chemically similar elements scandium and yttrium, are collectively known as the rare earth elements. Luminescence of lanthanide ions essentially orginates from transitions of unfilled 4f electrons.[10] The lanthanide ions have the electronic configuration [Xe]4fn (n = 0–14) generates abundant electronic levels. As a consequence of this, lanthanide-doped NPs are able to emit light that covers ultraviolet (UV)–visible to near infrared (NIR) regions. In the light of emission mechanism, lanthanide-doped luminescent materials could be divided into two categories: down-conversion (DC) and up-conversion (UC). DC refers to the process that absorption of higher-energy photon (short wavelength) results in the emission of light at longer wavelengths than the excitation photons. On the basis of the number of generated lower-energy photon, DC could be further divided into two types: downshifting (DS) and quantum cutting. DS is the phenomenon in which one higher-energy photon is transformed into a longer-wavelength one, and excess energy is lost in the form of heat.[11] The other type is quantum cutting, which represents the process that one higher-energy photon is transformed into two or more lower-energy photons. The DC luminescence involves in this review is the former type. On the contrary, the UC process refers to nonlinear optical phenomenon in which higher-energy photons are emitted after the absorption of lower-energy photons.[12] The excitation sources of lanthanide-doped DC and UC phosphors are generally UV and NIR (e.g., 980 nm) light, respectively. In particular, UC nanophosphors are prequalified for biomedical application. They present several advantages over traditional bioprobes (organic dyes or quantum dots), including high detection sensitivity, high photostability and penetration depth, low toxicity and low photodamage to living organisms.

Table 1. A Summary of Lanthanide Elements
Lanthanide elementLanthanum (La)Cerium (Ce)Praseodymium (Pr)Neodymium (Nd)Promethium (Pm)Samarium (Sm)Europium (Eu)
Atomic number57585960616263
Atomic electron configurationa5d14f15d14f34f44f54f64f7
Lanthanide elementGadolinium (Gd)Terbium (Tb)Dysprosium (Dy)Holmium (Ho)Erbium (Er)Thulium (Tm)Ytterbium (Yb)Lutetium (Lu)
  1. a

    Between initial [Xe] and final 6s2 electronic shells.

Atomic number6465666768697071
Atomic electron configurationa4f75d14f94f104f114f124f134f144f145d1

Some lanthanide-doped NPs can also be applied as MRI CAs, which are introduced to improve imaging sensitivity.[13] Two types of MRI CAs, T1 and T2 MRI CAs, are classified. They are also called positive and negative CAs, because they induce a brightening or a darkening effect on the MR image, respectively. Paramagnetic Gd3+ ions have seven unpaired 4f electrons, which can effectively alter the longitudinal relaxation of protons of nearby waters. Hence, Gd3+-containing NPs generally manifest T1-weighted contrast enhancement. Additionally, the highest magnetic moments (10.4–10.7 B.M.) are exhibited by Dy3+ and Ho3+. Dy3+ ions are suitable as T2 MRI CAs for shortening the transverse relaxation time of water protons.

LUMINESCENCE CHARACTERISTICS OF LANTHANIDE IONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. BRIEF INTRODUCTION OF LANTHANIDE ELEMENTS
  5. LUMINESCENCE CHARACTERISTICS OF LANTHANIDE IONS
  6. FABRICATION STRATEGIES FOR LDHNs
  7. FABRICATION STRATEGIES FOR SINGLE-PHASE LANTHANIDE-DOPED HOLLOW NANOMATERIALS
  8. FABRICATION STRATEGIES FOR LANTHANIDE-DOPED HOLLOW NANOCOMPOSITES
  9. BIOAPPLICATIONS OF LDHNs
  10. BIODETECTION
  11. IMAGING
  12. DRUG/GENE DELIVERY
  13. OTHER THERAPEUTIC APPLICATIONS
  14. CONCLUSION AND OUTLOOK
  15. ACKNOWLEDGMENTS
  16. REFERENCES

One of the most remarkable features of lanthanide ions is photoluminescence. The partially filled 4f shell is shielded from its environment by the closed 5s2 and 5p6 shells, the crystal field effect can only produce faint perturbation to 4f electrons. Hence, the luminescence originated from 4f–4f transitions of lanthanide ions, is generally characterized by sharp emission peaks with relatively long lifetimes.[14] The color of the emitted light mainly depends on the lanthanide ion, not the matrix. For example, Eu3+ emits red light, Tb3+ green light, and Sm3+ orange light. The red emissions originated from 5D0[RIGHTWARDS ARROW]7FJ (J = 0–6) transitions of Eu3+, and the green emissions are ascribed to 5D4[RIGHTWARDS ARROW]7FJ (J = 6, 5, 4, 3) transitions of Tb3+. Ce3+ is a special case because this ion emits intense broadband emission due to allowed f–d transitions. The position of the emission maximum strongly depends on the ligand environment of the Ce3+ ion.[15]

Er3+ and Tm3+ ions are the most commonly used activators to yield efficient visible emissions when excited using a NIR laser.[16] In order to enhance up-conversion luminescent (UCL) efficiency, Yb3+ ions, possessing a much larger NIR absorption cross-section, are often co-doped as sensitizers along with Er3+ to give rise to green and red UC emissions, or together with Tm3+ for blue and NIR UCL. The peaks in the green and red emission region are assigned to the 2H11/2[RIGHTWARDS ARROW]4I15/2, 4S3/2[RIGHTWARDS ARROW]4I15/2 and 4 F9/2[RIGHTWARDS ARROW]4I15/2 transitions of the Er3+ ions. The blue and NIR emission bands of the Tm3+ are ascribed to the 1G4[RIGHTWARDS ARROW]3H6, 1G4[RIGHTWARDS ARROW]3 F4, 3 F3[RIGHTWARDS ARROW]3H6, and 3H4[RIGHTWARDS ARROW]3H6 transitions of Tm3+, respectively.[17]

FABRICATION STRATEGIES FOR LDHNs

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. BRIEF INTRODUCTION OF LANTHANIDE ELEMENTS
  5. LUMINESCENCE CHARACTERISTICS OF LANTHANIDE IONS
  6. FABRICATION STRATEGIES FOR LDHNs
  7. FABRICATION STRATEGIES FOR SINGLE-PHASE LANTHANIDE-DOPED HOLLOW NANOMATERIALS
  8. FABRICATION STRATEGIES FOR LANTHANIDE-DOPED HOLLOW NANOCOMPOSITES
  9. BIOAPPLICATIONS OF LDHNs
  10. BIODETECTION
  11. IMAGING
  12. DRUG/GENE DELIVERY
  13. OTHER THERAPEUTIC APPLICATIONS
  14. CONCLUSION AND OUTLOOK
  15. ACKNOWLEDGMENTS
  16. REFERENCES

Based on difference of the components, the LDHNs can be classified into two types: single-phase lanthanide-doped hollow nanomaterials and lanthanide-doped hollow nanocomposites. Single-phase lanthanide-doped hollow nanomaterials include lanthanide-doped oxides, hydroxides, vanadates, phosphates, and fluorides with various hollow architectures, such as hollow spheres, tubes, and hollow cubes. Lanthanide-doped hollow nanocomposites are comprised of lanthanide-doped NPs and other inorganic or organic components. The fabrication strategies of each kind of nanomaterials are introduced as follows.

FABRICATION STRATEGIES FOR SINGLE-PHASE LANTHANIDE-DOPED HOLLOW NANOMATERIALS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. BRIEF INTRODUCTION OF LANTHANIDE ELEMENTS
  5. LUMINESCENCE CHARACTERISTICS OF LANTHANIDE IONS
  6. FABRICATION STRATEGIES FOR LDHNs
  7. FABRICATION STRATEGIES FOR SINGLE-PHASE LANTHANIDE-DOPED HOLLOW NANOMATERIALS
  8. FABRICATION STRATEGIES FOR LANTHANIDE-DOPED HOLLOW NANOCOMPOSITES
  9. BIOAPPLICATIONS OF LDHNs
  10. BIODETECTION
  11. IMAGING
  12. DRUG/GENE DELIVERY
  13. OTHER THERAPEUTIC APPLICATIONS
  14. CONCLUSION AND OUTLOOK
  15. ACKNOWLEDGMENTS
  16. REFERENCES

Hard Template Method

Employing carbon spheres as templates is an attractive way to fabricate hollow spheres.[18][23] This fabrication process involves three steps, as indicated in Figure 1(I). First, uniform carbon colloidal spheres templates were prepared by an environmentally friendly hydrothermal method using D-glucose as raw materials. The surface of templates are hydrophilic and functionalized with abundant –OH and C=O groups, so no prior surface modification or activation steps are required. Second, carbon spheres are immersed in the solution containing rare earth ions and precipitation agent, resulting in the formation of core-shell structured precursor Ln(OH)CO3@carbon. Last step is calcination process, which has a dual function: the removal of carbon spheres cores and formation of hollow crystalline structures from Ln(OH)CO3 precursor layer. Besides carbon spheres, other hard templates (polystyrene, silica spheres, and melamine formaldehyde) are also applied for the fabrication of hollow spheres.[24][26],[28], [29], [30]

image

Figure 1. (a) Schematic illustration of the carbon-sphere templating process for fabricating rare earth oxide hollow spheres. TEM images of carbon spheres (b), uncalcined precursor (c), and Lu2O3:Eu3+ hollow spheres. (Reprinted with permission from Ref [18]. Copyright 2011 American Chemical Society) II: Typical TEM images of hollow-structured La2O3 (a), Y2O3 (b), Gd2O3 (c) and NaYF4:Yb3+,Er3+ (d) using PS, silica, MF and AAO as templates, respectively. (Reprinted with permission from Ref [24]. Copyright 2013 Royal Society of Chemistry; Reprinted with permission from Ref [25]. Copyright 2011 John Wiley and Sons; Reprinted with permission from Ref [26]. Copyright 2010 American Chemical Society; Reprinted with permission from Ref [27]. Copyright 2009 Springer)

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Tube is also a form of hollow architecture. Zhao et al. synthesized NaYF4 nanotube arrays by using the anodic aluminum oxide (AAO) as the template (Figure 1(II)(d)). The self-assembly of as-prepared α-NaYF4 nanocrystals impregnated into the channels of the porous AAO and dissolution of the template yielded the tubular nanostructures.[27] Similarly, the Eu2O3 nanotubes with the outer diameter of 70 nm and wall thickness of 5 nm were obtained.[31] However, the hard template strategy has its intrinsic limitations. For example, most products are oxides (Y2O3:Eu3+, Gd2O3:Yb3+, Er3+, etc.). The monodispersity is usually poor due to the calcination treatment for elimination of template.

Soft Template Method

Frequently used soft templates include micelles, biomolecules, gas bubbles, and surfactants. Wang et al. applied soluble sodium poly(4-styrenesulfonate) (SPSS) micelles as soft template to fabricate lanthanide-doped SrMO4 hollow microspheres (Figure 2(I)).[32] SPSS can be easily eliminated by washing with water. Tunable multicolor and bright white up-conversion emission can be realized by precisely adjusting the concentration of dopants (Yb3+, Ho3+, Tm3+). Leidinger and co-workers prepared La(OH)3 hollow nanospheres through hydrolysis of tris(cyclopentadienyl)Lanthanum(III) via a water-in-oil (W/O) microemulsion templating route.[35] Cetyl trimethylammonium bromide (CTAB) and 1-hexanol are responsible for stabilization of the emulsion droplets. While pure water as the polar phase, massive La(OH)3 NPs were obtained. They deduced that a slow hydrolysis of lanthanocene and a fast precipitation of La(OH)3 may lead to a cavity. The latter process can be realized by increasing the ionic strength inside the micelle. Hence, the introduction of KF or KCl into water plays a critical role in the formation of such hollow spheres. Sasidharan'group reported a facile protocol for preparation of 30-nm La2O3 hollow nanospheres using triblock copolymer micelles (polystyrene-b-polyacrylic acid-b-polyethylene oxide) with core–shell–corona architecture.[36] Gas bubbles have also been utilized as soft templates to synthesize single-phase lanthanide-doped hollow nanomaterials. Wang et al. prepared fluffy CePO4:Tb3+, Gd3+ hollow spheres via the self-assembly of crystallites around O2 bubbles produced from the reaction between Ce4+ and H2O2.[37]

image

Figure 2. Representative single-phase lanthanide-doped hollow nanomaterials prepared by soft template method. I: (a) Schematic illustration for the formation process of SrMO4 hollow spheres. (b) UC emission spectra and CIE chromaticity diagram of SrMO4:16%Yb3+/x%Ho3+/ (1 – x)%Tm3+ (x = 0, 0.3, 0.5, 0.7, and 1) (Reprinted with permission from Ref [32]. Copyright 2013 Royal Society of Chemistry) II: SEM (a) and TEM (b) images of BaF2 hollow cubes. (c) Emission spectra for Ln-doped BaF2 (Ln = Nd, Er, Yb) hollow cubes. (Reprinted with permission from Ref [33]. Copyright 2010 Royal Society of Chemistry) III: The formation mechanism (a), TEM image (b), small-angle XRD pattern (c), HRTEM image (d), EDS (e), and N2 sorption isotherms (f) of the Gd2O3 nanotubes. (Reprinted with permission from Ref [34]. Copyright 2013 Elsevier)

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Most hollow particles are of spherical shape, the fabrication of nonspherical hollow structures remains a significant challenge. Barium fluoride hollow microcubes have been synthesized by Hou and co-workers via a combination of soft-templating and oriented attachment process (Figure 2(II)).[33] Introduction lanthanide ions into host matrix did not alter the shape and structure of the samples. Lanthanide ions (Er3+, Nd3+, and Yb3+) doped BaF2 hollow cubes exhibit near-infrared luminescent properties.

The morphology of products is conformed to the geometry of the soft template. Amphiphilic block copolymer P123 (P123 is EO20PO70EO20) formed the micellar structure of hexagonal arrays, which provides active sites for the nucleation and growth of Gd monomers. Hence, the mesoporous Gd2O3 nanotubes were yielded after pyrolytic removal of the template (Figure 2(III)).[34] The hexagonal walls are constructed by self-assembly of highly crystalline Gd2O3 NPs. Yada et al. successfully prepared a series of Ln2O3 (Ln = Er, Tm, Yb, Lu) nanotubes templated by rodlike dodecylsulfate assemblies.[38]

Template-Free Method

Although template strategy is straightforward and effective for producing hollow architecture, this method has inherent drawbacks. For instance, removal of templates is an inevitable step, which is both time- and energy-consuming. Template-free method has been paid more and more attention because of its simplicity of processing. For example, the polyethyleneimine (PEI)-induced localized Ostwald ripening mechanism has been used to synthesize β-NaYF4:Yb3+,Er3+ hollow spheres with diameter of 500 nm.[39] At the initial stage of hydrothermal process, α-NaYF4 solid spheres were obtained. The surface layer gradually transformed to a thermodynamically more stable form (e.g., β-NaYF4). Further increasing the reaction time resulted in the dissolution of the inner core and formation of hollow structure. The concentration of PEI obviously influenced the phase and morphology of products.

Zhang et al. described a facile, template-free, and one-step hydrothermal approach based on Ostwald ripening mechanism to preparation of CaF2 hollow spheres, as illustrated in Figure 3.[40] The size of the hollow spheres can be controlled from 300 to 930 nm. These monodisperse Ce3+/Tb3+-codoped CaF2 hollow spheres show strong green emission with high quantum efficiency due to the efficient energy transfer from Ce3+ to Tb3+. Tb(OH)3 single-crystalline nanotubes were synthesized by hydrothermal treatment of bulk Tb4O7 crystals.[41] The tubular morphology of hydroxide is determined by its highly anisotropic crystal structure. Fullerene-like LaF3 particles and lanthanium carboxylate capsules were also obtained under hydrothermal condition.[42], [43] Microwave irradiation can obviously shorten reaction time. It takes just 20 min to synthesize PrF3 hollow spheres with average diameter of 31 nm by the microwave-assisted heating hydrothermal treatment.[44]

image

Figure 3. (a) Schematic illustration of the formation process of the CaF2 hollow spheres. TEM images of the CaF2 hollow spheres with the diameter of 300 nm (b), 480 nm (c), 750 nm (d), and 930 nm (e), respectively. (f) PL excitation and emission spectra for CaF2:Ce3+,Tb3+ hollow spheres. (g) Integrated PL emission intensity and PL quantum efficiency of CaF2:Ce3+,Tb3+ hollow spheres as a function of particle size. (Reprinted with permission from Ref [40]. Copyright 2010 John Wiley and Sons)

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Self-Sacrificing Template Method

The self-sacrificing templating method possesses intrinsic advantages compared with other methods. The intentional removal of template is evitable because template is consumed as reactant during experimental process. Additionally the shape and size of hollow structure can be easily determined by self-sacrificing template. Xu et al., for example, utilized this approach to synthesize GdPO4:Eu3+ hollow spheres with nanorods assembled shells.[45] The Gd(OH)CO3 solid spheres generated a large number of free Gd3+ ions under an acidic condition. Then, they reacted with PO43- in the solution to form GdPO4 nanorods which deposited on the surface of precursor. With the reaction proceeding, the layer of GdPO4 nanorods grows. Because the diffusion velocity of Gd3+ is faster than that of PO43-, the consumption rate of precursor core is larger than the production rate of GdPO4 on the inside of the shell, resulting in the core-shell morphology. When the reaction time is prolonged to 24 h, the urchin-like GdPO4:Eu3+ hollow spheres were yielded. When Gd element is replaced with Yb element, the inner core could not be entirely consumed.[46] Similar evolution of structure was also observed in study by Zhang et al., where amorphous Y(OH)CO3:Eu3+ were transformed to core-shell structure composites, afterwards completely converted to tetragonal phase YPO4:Eu3+ after being treated with nitric acid.[47] As for GdVO4:Dy3+ prepared by above method, the shell of hollow structure constructed by numerous rice-like NPs.[48] Moreover, YVO4:Eu3+ hollow spheres with double shells could be obtained by introducing excess amount of NH4VO3.[49] Lanthanide hydroxylcarbonate spheres are proven to be versatile templates, which can also convert to EuF3 hollow spheres.[50] This method can be extended to synthesize hollow spheres of other fluorides, such as NdF3, SmF3, and GdF3.

Recently, Li et al. successfully prepared YF3 hollow nanofibers by fluorination of electrospun Y2O3 hollow fibers.[51] Zhang et al. report the production of single-crystal β-NaYF4 nanotubes, which replicate the shape and size of Y(OH)3 nanotubes.[52] In addition, they have also prepared α-NaYF4 hollow spheres by using cubic phase Y2O3 solid spheres as a self-sacrificing template.[53] As shown in Figure 4, Y2O3 template was gradually consumed and transformed into α-NaYF4 hollow spheres due to the nanoscale Kirkendall effect. The key of this transformation is crystal structural similarities. In addition, the emission of α-NaYF4:Yb3+,Er3+ hollow nanospheres changes significantly with reaction time, which can be ascribed to the oxygen effect. However, HF used in this experiment is hazardous. While NaBF4, amorphous Y(OH)CO3 spheres and PEI ligands served as fluoride source, sacrificial templates and surface-protecting agent, respectively, α-NaYF4 hollow spheres with similar diameter could also be fabricated.[54] The formation of hollow structure based on Kirkendall effect is generally accompanied by an increase in size. Feng et al. synthesized 20-nm β-NaYF4 hollow spheres under electron-beam irradiation from solid NPs without variation in particle size.[55] As depicted in Figure 5, the in situ solid-to-hollow transition takes relatively short time (120 seconds). Under irradiation organic species decomposed and dissolved the surrounding β-NaYF4 nanocrystals, resulting in hollow structures. Interestingly, it is able to manipulate even one NP of the hollow structure from the ensemble. Diverse patterns can be produced by this facile method. Recently, α-NaREF4 (RE = Y, Yb, Lu) hollow spheres were fabricated by electron-beam lithography.[56]

image

Figure 4. α-NaYF4 hollow nanospheres prepared by self-sacrificing template method. TEM images of samples obtained with different reaction times: 1 (a), 1.5 (b), 2 (c), and 3 h (d). (e) Illustration of the α-NaYF4 hollow nanospheres formation process. UC luminescence spectra of α-NaYF4:Yb3+,Er3+ (g), α-NaYF4:Yb3+,Tm3+, and samples as a function of the reaction time (h). (i) Photographs of the UC luminescence. (Reprinted with permission from Ref [53]. Copyright 2009 American Chemical Society)

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image

Figure 5. Fabrication of hollow nanostructures by electron-beam lithography. (a) HRTEM images of a single 20-nm β-NaYF4:Yb3+,Er3+ nanocrystal with electron-beam irradiation intervals of 0, 15, 30, 60, 90, and 120 seconds. (b) Illustration of solid-to-hollow transition of β-NaYF4:Yb3+,Er3+ nanocrystals under electron-beam irradiation. (c) Different patterns produced by electron-beam lithography. TEM images of α-NaLuF4 NPs before (d) and after (e) electron-beam irradiation. (Reprinted with permission from Ref [55]. Copyright 2009 John Wiley and Sons; Reprinted with permission from Ref [56]. Copyright 2013 John Wiley and Sons)

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Lanthanide-based complexes can be served as another useful source for hollow nanomaterials. CeO2:Sm3+ hollow spheres and Eu2O3 nanotubes were fabricated via the calcinations of corresponding complexes with spherical and nanowire structure.[57], [58] Recently, Gd2O3:Eu3+ hollow spheres were obtained from Gd2O3:Eu3+ solid spheres via the simple etching process induced by the acidic moieties in the sodium salt solution of poly(acrylic acid).[59] Table 2 summaries the synthetic strategies and textural parameters of single-phase lanthanide-doped hollow nanomaterials.

Table 2. Fabrication Route and Textural Properties of Single-Phase Lanthanide-Doped Hollow Nanomaterials
Fabrication RouteMaterialsaSize/Shell ThicknessReference
  1. a

    Unmarked materials are spherical shape.

Hard template methodCarbon spheres as template

La2O3:Ln3+

(Ln = Yb/Er, Yb/Ho)

400 nm/40 nm[21]
Gd2O3: Yb3+, Er3+250 nm/20 nm[23]
Y2O3:Eu3+250 nm/20 nm[22]
Y2O3: Yb3+, Er3+190 nm/20 nm[19]
Gd2O3:Ln3+ (Ln = Eu, Sm)300 nm/30 nm[20]
Lu2O3:Ln (Ln = Eu, Tb)250 nm/20 nm[18]
PS spheres as templateTiO2:Eu3+200 nm/5 nm[28]
SiO2:Yb3+, Er3+550 nm/50 nm[29]

La2O3:Ln3+

(Ln = Yb, Er, Tm)

2.2 µm/250 nm[24]
Silica spheres as templateGd2O31 µm/40 nm[25]
Eu2O31 µm/48 nm 
Y2O31 µm/31 nm 

Melamine formaldehyde (MF)

as template

Gd2O3:Ln3+

(Ln = Eu, Er, Yb/Er, Yb/Tm)

2 µm/200 nm[26]

Lu2O3:Ln3+

(Ln = Eu, Er, Yb)

1.8 µm/100 nm[30]
Porous anodic alumina as templateEu2O3 nanotubes70 nm/5 nm[31]
α-NaYF4:Yb3+,Er3+ nanotubes228 nm/35 nm[27]
Soft template methodO2 bubbles as templateCePO4:Tb3+, Gd3+400 nm/50 nm[37]

Poly (4-styrenesulfonate) (PSS)

as template

SrMO4:Yb3+,Ln3+

(Ln = Tm, Ho, Tm/Ho)

600 nm/70 nm[32]

Triblock copolymer micells

as template

La2O330 nm/7 nm[36]

Both soft-templating mechanism and oriented attachment

(P123 and citrate as template)

BaF2:Nd 3+ microcubes1.3 µm/80 nm[33]
Water-in-oil micelles as templateLa(OH)3

Tunable

11–30 nm/4-6 nm

[35]

Dececylsulfate assemblies

as template

RE2O3

(RE = Er, Tm, Yb, Lu) nanotubes

6 nm/1 nm[38]
P123 as templateGd2O3 nanotubes60 nm/20 nm[37]
Template-free methodOstwald ripeningCaF2:Ce3+, Tb3+

Tunable

300–930 nm/40 nm

[40]
PEI-induced Ostwald ripeningβ-NaYF4:Yb3+, Er3+500 nm/50 nm[39]
Microwave-assisted hydrothermal synthesisPrF331 nm/8 nm[44]
Hydrothermal methodLaF3

Tunable

10–90 nm/

4–20 nm

[42]
Hydrothermal methodTb(OH)3 nanotubes70 nm/15 nm[41]
Kirkendall effectCerium carboxylate200 nm/40 nm[43]
Self-sacrificing template method

Ln(OH)CO3 solid spheres

as template

GdPO4:Eu3+

250 nm/40 nm

220 nm/50 nm

[45],[60]
Yb(OH)CO3@YbPO4:Er3+420 nm/40 nm[46]
YPO4:Eu3+500 nm/25 nm[47]
REPO4 (RE = Yb, Gd, Y)400 nm/30 nm[61]
GdVO4:Dy3+290 nm/50 nm[48]
YVO4:Eu3+600 nm/70 nm[49]
EuF395 nm/20 nm[50]
α- NaYF4:Yb3+, Er3+130 nm/15 nm[53]
Y2O3 solid spheres as templateα- NaYF4:Yb3+, Er3+125 nm/30 nm[54]
M(OH)3 tubes as template

β-NaMF4 nanotubes

(M = Pr, Sm, Gd, Tb, Dy, Er)

Tunable

80–500 nm/25–80 nm

[52]
Y2O3:Eu3+ hollow fibers as templateYF3:Eu3+ hollow fibers200 nm/50 nm[51]

Gd2O3:Eu3+ solid spheres

as template

Gd2O3:Eu3+90 nm/25 nm[59]
Eu(MA)3 nanowires as templateEu2O3 nanotubes116 nm/16 nm[58]
Ce-organic precursor solid spheres as templateCeO2:Sm3+600 nm/100 nm[57]
Electron-beam lithographyβ-NaYF4:Yb3+, Er3+20 nm/4 nm[55]
α-NaLuF418 nm/2.3 nm[56]

FABRICATION STRATEGIES FOR LANTHANIDE-DOPED HOLLOW NANOCOMPOSITES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. BRIEF INTRODUCTION OF LANTHANIDE ELEMENTS
  5. LUMINESCENCE CHARACTERISTICS OF LANTHANIDE IONS
  6. FABRICATION STRATEGIES FOR LDHNs
  7. FABRICATION STRATEGIES FOR SINGLE-PHASE LANTHANIDE-DOPED HOLLOW NANOMATERIALS
  8. FABRICATION STRATEGIES FOR LANTHANIDE-DOPED HOLLOW NANOCOMPOSITES
  9. BIOAPPLICATIONS OF LDHNs
  10. BIODETECTION
  11. IMAGING
  12. DRUG/GENE DELIVERY
  13. OTHER THERAPEUTIC APPLICATIONS
  14. CONCLUSION AND OUTLOOK
  15. ACKNOWLEDGMENTS
  16. REFERENCES

The aforementioned section discussed is single-phase lanthanide-doped hollow nanomaterials. Herein, we introduce the other class of LDHNs, lanthanide-doped hollow nanocomposites. This kind of nanomaterials has attracted great research interests because they provide opportunity for their widespread use in biomedicine by combining the merits of each building block. Herein, the fabrication strategies for lanthanide-doped hollow nanocomposites can be divided into three categories: one-step method, two-step method, and multistep method. The fabrication routes and bioapplications of lanthanide-doped hollow nanocomposites are listed in Table 3.

Table 3. Fabrication Route and Bioapplications of Lanthanide-Doped Hollow Composites
Fabrication RouteMaterialsBioapplications

Experimental

Level

Reference

One-step

method

NaYF4:Yb3+,Er3+,Gd3+@SiO2 tubes

Anticancer drug carrier/

MRI/UCL imaging

In vitro[62]
Gd2O3/C nanoshellsMRI/Photothermal therapyIn vivo[63], [64]

Two-step

method

CaWO4:Tb3+@void@SiO2 spherespH-responsive drug carrierIn vitro[65]
Eu2O3@H-SiO2 spheres[66]
CaWO4:Tb3+@ SiO2 tubesLysozyme immobilizationIn vitro[67]

GdF3:Tb3+ NPs-loaded

PSS/PAH capsules

Fluorescent imagingIn vitro[68]

PAA@CaF2:Ce3+,Tb3+

hollow spheres

pH-responsive drug carrierIn vitro[69]

PAA@GdVO4:Ln3+

(Ln = Yb/Er, Yb/Ho, Yb/Tm)

hollow spheres

pH-responsive drug carrier/MRI/UCL imagingIn vitro[67]
H-SiO2@Gd2O2S:Ln3+ (Ln = Eu, Tb)pH-responsive drug carrier/MRI/In vivo[70]
LaF3:Eu3+@PS hollow spheres[71]
H-SiO2@YVO4:Eu3+ spheres

Drug carrier/

fluorescent imaging

In vitro[72]

Multistep

method

β-NaYF4:Yb3+,Er3+,Gd3+

@void@SiO2 tubes

[73]

β-NaYF4:Yb3+,Er3+/

NaGdF4@void@SiO2 spheres

Anticancer drug carrier/

radiotherapy/MRI/UCL imaging

In vivo[74]
Fe3O4@void@Y2O3:Eu3+ spheres[75]

Fe3O4@void@

α-NaLuF4:Yb3+,Er3+/Tm3+ spheres

MRI/CT/UCL imagingIn vivo[76]
Fe3O4@void@α-NaYF4:Yb3+,Er3+ spheresMagnetic targeted drug delivery/UCL imagingIn vivo[77]
Au@void@Y2O3:Eu3+ spheres[78]
Gd2O3:Eu3+@Hydrogel@H-SiO2 spheres

Temperature-responsive

drug carrier/MRI

In vitro[79]

One-Step Method

Shell-like carbon coated Gd2O3 nanomaterials (Gd2O3/C) were reported by Huang et al. via one-step method. Gd2O3 hollow nanospheres were produced with biological gelatin particles as a template, and simultaneously carbon coating resulted from incomplete decomposition of organometallics.[63] Further thermal treatment of the composites under inert atmosphere generated crystalline cubic Gd2O3 with a graphitic carbon structure.[64] SiO2 tubes can be obtained via single-nozzle electrospinning based on a phase separation effect. Li et al. dispersed α-NaYF4:Yb3+,Er3+,Gd3+ NPs into the electrospinning precursor, directly yielding UCL SiO2 tubes after annealing.[62]

Two-Step Method

The most extensively used method is that the shells are pre-casted first, followed by decorated with the other component to fabricate lanthanide-doped hollow nanocompsites. Zhai et al. applied this method to fabricate CaWO4:Tb3+@SiO2 nanorattles.[65] CaWO4:Tb3+ precursor solution was filled into hollow SiO2 capsules via the vacuum nanocasting route and converted to luminescent NPs after annealing. Lanthanide-doped nanophophors can be also combined with polymer capsules. Firstly, polystyrene sulfonate (PSS)/polyallylamine hydrochloride (PAH) polymer capsules were synthesized via hard template strategy and layer-by-layer (LBL) assembly technique.[68] Secondly, LaF3:Tb3+ NPs were loaded into the cavity of capsules. In addition, lanthanide-doped NPs, such as YVO4:Eu3+ and Gd2O2S:Tb3+ can be attached on the outer surface of hollow particles.[70],[72] Another example is mesoporous silica tubes loaded with CaWO4:Tb3+, used for the immobilization of lysozyme.[80]

As effective drug vehicles, they are expected to control the release of drug molecules. However, single-phase lanthanide-doped hollow nanomaterials without any modification do not show the stimuli-responsive controlled release behavior. The network change of ‘smart’ hydrogels can regulate the rate of drug release in response to external stimulation, such as temperature, pH, magnetic. Hence, the nanoplatforms based on lanthanide-doped hollow spheres and hydrogels are promising from the standpoint of biomedical applications. Lin's group employed CaF2:Ce3+,Tb3+ and GdVO4:Yb3+,Er3+ hollow spheres as microreactors and impregnated pH-sensitive hydrogel into voids.[67], [69]

Another strategy for fabricating this kind of nanocomposites is post-treatment of core-shell structure. Wang et al. coated silica shell on organic/inorganic hybrid core containing Eu3+ ions.[66] Calcination is used to remove the organic components of the cores, so that ultrasmall Eu2O3 NPs were well dispersed in the entire inner shell of SiO2 hollow nanospheres. PS spheres are usually used as hard template and removed by annealing. Wu's group reported a facile method for synthesis of hollow spheres with PS/lanthanide-doped NPs hybrid shell.[71] PS solid spheres were deposited by lanthanide-doped NPs. Under capillary force, polymer chains diffused from core into the interspace between inorganic NPs and yielded hollow spheres.

Multistep Method

Morphology of lanthanide-doped hollow nanocomposites prepared by multistep method are commonly rattle-type. Rattle-type or yolk/shell is one class of complex hollow structure, which is composed of hollow shells encapsulating movable cores with an interstitial space between them. The nanomaterials with this special structure have gained increasing attention since they not only have large cavity but also possess diverse functions. In particular, rattle-type nanocomposites consist of iron oxide and lanthanide-doped phosphors have been considered as ideal candidates for biological application due to their unique features. For example, Zhu and co-workers synthesized multifunctional Fe3O4@void@NaLuF4:Yb3+,Er3+ nanorattles.[76] The procedure involves four steps: pre-preparation of Fe3O4 spheres, coating the Fe3O4 core with silica layer and NaLuF4 shell, and subsequently elimination of the SiO2 middle layer [Figure 6(I)]. The outer shell can be substituted by other lanthanide-doped UC or DC nanophosphors.[75],[77] Liu et al. designed superparamagnetic iron oxide (SPIO)@Y2O3:Eu3+ nanorattles with controllable shell thickness and inner voids.[75] Yu's group adopted the same method to prepare Au@Y2O3:Eu3+ nanorattles, that is, luminescent hollow spheres with movable Au core.[78]

image

Figure 6. Multistep method for synthesizing lanthanide-doped hollow nanocomposites. (a) Schematic illustration for the formation process of Fe3O4@void@α-NaLuF4:Yb3+,Er3+ spheres. TEM (b, d) and EDS maps (c, e) of the distribution of Fe, Si, and Lu elements in Fe3O4@SiO2@Lu2O3 (b, c) and Fe3O4@void@α-NaLuF4:Yb3+,Er3+ spheres (d, e). (f) TEM images of Fe3O4@void@α-NaLuF4:Yb3+,Er3+. (g) The visual and total luminescence photograph of Fe3O4@void@α-NaLuF4:Yb3+,Er3+ aqueous solution without and with applied magnetic field. (Reprinted with permission from Ref [65]. Copyright 2012 Elsevier) (h) Schematic illustration for the formation process β-NaYF4:Yb3+,Er3+,Gd3+@void@SiO2 tubes. TEM images of β-NaYF4:Yb3+,Er3+,Gd3+ (i), β-NaYF4:Yb3+,Er3+,Gd3+@SiO2 (j), and β-NaYF4:Yb3+,Er3+,Gd3+@void@SiO2 tubes (k). (Reprinted with permission from Ref [77]. Copyright 2012 John Wiley and Sons)

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The above-introduced approach required two steps to build up core/shell/shell structure with different components and selectively removed middle layer. A facile ‘surface-protected etching’ strategy was applied to fabricate β-NaYF4:Yb3+,Er3+,Gd3+@SiO2 rod-like rattle-structures, as shown in Figure 6(II).[73] Monodisperse β-NaYF4:Yb3+,Er3+,Gd3+ nanorods were synthesized and subsequently coated with mesoporous silica shell. With the surface protection of PEI, core–shell architecture was transformed into rattle-type nanorods upon water etching under mild conditions. Fan et al. employed this method to synthesize similar products, but with the morphology of spheres.[74] Temperature-responsive hydrogel can be filled in the interstitial space of Gd2O3:Eu3+@SiO2 microrattles as drug carriers to regulate the rate of drug release.[79] Despite such tedious procedures, the fabricated multifunctional lanthanide-doped hollow nanocomposites have superiority in diverse applications.

BIOAPPLICATIONS OF LDHNs

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. BRIEF INTRODUCTION OF LANTHANIDE ELEMENTS
  5. LUMINESCENCE CHARACTERISTICS OF LANTHANIDE IONS
  6. FABRICATION STRATEGIES FOR LDHNs
  7. FABRICATION STRATEGIES FOR SINGLE-PHASE LANTHANIDE-DOPED HOLLOW NANOMATERIALS
  8. FABRICATION STRATEGIES FOR LANTHANIDE-DOPED HOLLOW NANOCOMPOSITES
  9. BIOAPPLICATIONS OF LDHNs
  10. BIODETECTION
  11. IMAGING
  12. DRUG/GENE DELIVERY
  13. OTHER THERAPEUTIC APPLICATIONS
  14. CONCLUSION AND OUTLOOK
  15. ACKNOWLEDGMENTS
  16. REFERENCES

Ingenious combination of lanthanide elements and hollow structures destine the multifunctionalities of LDHNs. Almost each LDHN has the potential to be as the theranostic. To clearly comprehend every function of LDHNs, here we introduce the biomedical applications of LDHNs as follows.

BIODETECTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. BRIEF INTRODUCTION OF LANTHANIDE ELEMENTS
  5. LUMINESCENCE CHARACTERISTICS OF LANTHANIDE IONS
  6. FABRICATION STRATEGIES FOR LDHNs
  7. FABRICATION STRATEGIES FOR SINGLE-PHASE LANTHANIDE-DOPED HOLLOW NANOMATERIALS
  8. FABRICATION STRATEGIES FOR LANTHANIDE-DOPED HOLLOW NANOCOMPOSITES
  9. BIOAPPLICATIONS OF LDHNs
  10. BIODETECTION
  11. IMAGING
  12. DRUG/GENE DELIVERY
  13. OTHER THERAPEUTIC APPLICATIONS
  14. CONCLUSION AND OUTLOOK
  15. ACKNOWLEDGMENTS
  16. REFERENCES

The separation and detection of biomolecules is one function of LDHNs. REPO4 (RE = Yb, Gd, Y) hollow microspheres covered with nanothorns were developed as affinity probes for the selective capture and tagging of phosphopeptides.[60] These probes have high sensitivity and specificity for directly detecting the target phosphopeptides owing to their peculiar structure of prickly hollow spheres and coordination affinities of lanthanide ions with phosphate moieties.

IMAGING

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. BRIEF INTRODUCTION OF LANTHANIDE ELEMENTS
  5. LUMINESCENCE CHARACTERISTICS OF LANTHANIDE IONS
  6. FABRICATION STRATEGIES FOR LDHNs
  7. FABRICATION STRATEGIES FOR SINGLE-PHASE LANTHANIDE-DOPED HOLLOW NANOMATERIALS
  8. FABRICATION STRATEGIES FOR LANTHANIDE-DOPED HOLLOW NANOCOMPOSITES
  9. BIOAPPLICATIONS OF LDHNs
  10. BIODETECTION
  11. IMAGING
  12. DRUG/GENE DELIVERY
  13. OTHER THERAPEUTIC APPLICATIONS
  14. CONCLUSION AND OUTLOOK
  15. ACKNOWLEDGMENTS
  16. REFERENCES

Medical imaging including fluorescent imaging, MRI, CT, and positron emission tomography (PET) is the technique and process used to rapidly diagnose with visualization and quantitative assessment or guide a medical procedure.

Fluorescent Imaging

In view of the unique spectroscopic properties of Ln3+ ions, such as sharp emission bandwidth, large Stoke's shift and long excited-state lifetimes, scientists have used LDHNs to get images of cells. For instance, CePO4: Tb3+, Gd3+ hollow nanospheres stain the cytoplasm of HeLa cervical cancer cells. They are internalized and the bright green luminescence from Tb3+ was observed (Figure 7(I)).[37] LaF3:Tb3+ NPs-loaded PSS/PAH capsules were also be effectively uptaken by HeLa cells. Sivakumar'group investigated the uptake kinetics of these capsules as a function of incubation time with HeLa cells.[68] The internalization process has initiated around 2–5 h and is verging to a completion around of 8 h, which was validated by fluorescence microscopy images. Some intrinsic disadvantages of this imaging modality such as photoleaching, toxicity and autofluorescence have impeded their biomedical application. Radioluminescence can overcome this obstacle because of greater tissue penetration, elimination of autofluorescence and the ability to perform high-resolution imaging through thick tissue. Chen et al. applied X-ray excited optical luminescence (XEOL) approaches to perform in vitro and in vivo optical imaging for H-SiO2@Gd2O2S:Eu3+ nanocapsules.[70] Figure 7(II)(a) shows the intense fluorescence signal of H-SiO2@Gd2O2S:Eu3+ nanocapsules incubated with MCF-7 cancer cells. XEOL images of the excised organs indicated that the nanocapsules accumulated in liver and spleen. However, UV light, as the excitation source of traditional fluorescence imaging, is harmful to cells. At the same time, X-rays contain many risks to the human body and cells. By contrast, lanthanide-doped UC NPs are an appealing choice, which is excited by noninvasive NIR laser (e.g., 980 nm). It is difficult for cells to absorb the long wavelength photons. Thereby, UCL imaging technique has the advantages of high signal–noise ratio and high sensitivity. A certain amount of 250-nm Gd2O3:Yb3+,Er3+ hollow spheres were subcutaneously injected into the foot, back and thigh of a mouse.[23] The red emission signals could be easily penetrate these tissues and provide high-quality UCL imaging. Poly(acrylic acid) modified GdVO4:Yb3+,Er3+ nanocomposites were used as bio-probes for cell imaging.[67] UCL images of α-NaYF4:Yb3+,Er3+ and α-NaLuF4:Yb3+,Er3+ hollow nanospheres showed bright green emission without background noise.[53], [56]

image

Figure 7. Fluorescence imaging of LDHNs with different excitation sources: UV light (I), X-ray (II), and NIR laser (III). I: (a) Emission spectra of CePO4:Gd3+, CePO4:Tb3+ and CePO4:Tb3+,Gd3+. (b) Fluorescent microscopy image of HeLa cells after incubation with CePO4:Tb3+,Gd3+ hollow nanospheres. (Reprinted with permission from Ref [37]. Copyright 2012 Royal Society of Chemistry) II: (a) Photograph of MCF-7 cells with and without H-SiO2@Gd2O2S:Eu3+ nanocapsules viewed under room light and X-ray irradiation. (b) Fluorescence microscopy image of MCF-7 cells with internalized nanocapsules. (c) Radioluminescent images of accumulation of nanocapsules in organs after 24 h. (Reprinted with permission from Ref [70]. Copyright 2013 American Chemical Society) III: In vivo upconversion luminescence imaging of Kunming mouse: Gd2O3:Yb3+,Er3+ hollow spheres injected into translucent skin of foot (a), below skin of back (b), and thigh muscles (c) show red luminescence. (Reprinted with permission from Ref [23]. Copyright 2011 American Chemical Society)

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MRI

LDHNs containing Gd3+ ions can be served as T1 CAs because Gd3+ ions possess seven unpaired electrons. Figure 8 provides the r1 value of seven representative LDHNs as T1-weighted CAs. The longitudinal relaxivity (r1) not only closed related with applied magnetic field strength of MR equipment but also depends on the composition, morphology, and particle size.[48] The relaxivity increases as the applied magnetic field increased. The CAs with large specific surface area generally have higher r1, because they can provide more effective Gd3+ ions and give greater accessibility and interaction between the water molecules and the contrast agents. On the basis of this principle, the smaller the size, the larger the r1 value (the other parameters keep consistent). In addition, r1 of the Gd-based NPs with hollow structure should be larger than that of solid NPs with same diameter under same magnetic field. As T1 CAs, hollow NPs might be more predominate compared with solid NPs.

image

Figure 8. (a) The r1 value of seven representative LDHNs as T1-weighted CAs. (b) T1-weighted images of male BALB/c mice administrated with Gd2O3/C nanoshells at the indicated temporal points. (c) The signal intensities of liver and kidney in T1-weighted imaging at the indicated temporal points. (Reprinted with permission from Ref [80]. Copyright 2012 John Wiley and Sons)

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Here we take a simple example to elaborate the MR imaging capability of LDHNs containing Gd3+ ions. The r1 value and r2/r1 ratio of 138-nm Gd2O3/C nanoshells at 3.0 T was calculated to be 10.3 second–1 mM–1 and 1.1, which indicated they act as T1 CAs.[64] Hence, Huang et al. monitored T1-weighted images of BALB/C mice administrated with Gd2O3/C. The samples increased signal intensity in both liver and kidney.

Nowadays multimodal bioimaging becomes a frontier and hotspot in research of biology and medicine, because the ingenious integration of several imaging agents into one single entity can diagnose various diseases more precisely. The rattle-structured Fe3O4@NaLuF4:Yb3+,Er3+/Tm3+ nanocomposites provide the ternary modality of MR, CT and UCL imaging.[65] MRI-optical probes can also be Gd-based hollow nanomaterials doped other lanthanide ions, such as Eu3+ and Er3+.[62], [70]

DRUG/GENE DELIVERY

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. BRIEF INTRODUCTION OF LANTHANIDE ELEMENTS
  5. LUMINESCENCE CHARACTERISTICS OF LANTHANIDE IONS
  6. FABRICATION STRATEGIES FOR LDHNs
  7. FABRICATION STRATEGIES FOR SINGLE-PHASE LANTHANIDE-DOPED HOLLOW NANOMATERIALS
  8. FABRICATION STRATEGIES FOR LANTHANIDE-DOPED HOLLOW NANOCOMPOSITES
  9. BIOAPPLICATIONS OF LDHNs
  10. BIODETECTION
  11. IMAGING
  12. DRUG/GENE DELIVERY
  13. OTHER THERAPEUTIC APPLICATIONS
  14. CONCLUSION AND OUTLOOK
  15. ACKNOWLEDGMENTS
  16. REFERENCES

The most conspicuous feature of LDHNs is their hollow structure. Drug molecules could be loaded into huge cavity with a high loading efficacy and diffuse through the mesoporous shell without burst effect.[37], [49], [72] The released drug retained its pharmacological activity to kill cancer cells. At the same time, lanthanide-doped nanophosphor plays an important role as the luminescent tag for tracking the drug loading and release.[45], [69]

Additional functionalities could be added to the hollow structures to better control drug release. Chen et al. coated H–SiO2@Gd2O2S:Tb3+ nanocapsules with polyelectrolyte multilayer (PSS/PAH) to realize pH-responsive doxorubicin (DOX) release (Figure 9(I)).[49] The release rate time constant was 36 days at pH 7.4 and 21 h at pH 5.0. It is well known that the extracellular pH of many solid tumors is lower than normal tissues. This pH-responsive drug release behavior is beneficial to the targeting cancerous tissues. Another significant feature is that the release process of DOX can be monitored by detecting the radioluminescence of Gd2O2S:Tb3+. Similar phenomenon was observed in other LDHNs, such as GdVO4:Dy3+ hollow spheres, CaWO4:Tb3+@void@SiO2 spheres and Yb(OH)CO3@YbPO4:Er3+ nanorattles. [46], [48], [65] For instance, the emission intensity of GdVO4:Dy3+ hollow spheres was weaken after DOX loading and underwent a recovery process with a continued release of drug.[48] It can be explained by the spectral overlap between PL emission of sample and absorbance of DOX. On the other hand, the emission of lanthanide ions can be quenched to some extent in the environments where high phonon frequencies (such as organic group in DOX) are present. Hence, this property makes the drug delivery system be easily identifiable and monitorable by the change of luminescence.

image

Figure 9. LDHNs as anticancer drug carriers. I: (a) Schematic illustration of the synthesis of DOX@Gd2O2S:Tb3+@PSS/PAH and pH-responsive release of DOX. (b) HRTEM image of a single DOX@Gd2O2S:Tb3+@PSS/PAH nanocapsule. (c) Cumulative release of doxorubicin from DOX@Gd2O2S:Tb3+@PSS/PAH at pH 5.0 and 7.4. (d) Absorption spectra of DOX (0.05 mg/mL at pH 5.0 and 7.4) and radioluminescence spectrum of Gd2O2S:Tb3+@PSS/PAH. (e) Radioluminescent spectra of DOX@Gd2O2S:Tb3+@PSS/PAH at pH 5.0 taken at three different times during drug release. (Reprinted with permission from Ref [70]. Copyright 2013 American Chemical Society) II: TEM image (a) and biocompatibility (b) of α-NaYF4:Yb3+,Er3+ hollow nanospheres. (c) In vitro cytotoxicity of HeLa cells after incubation with α-NaYF4:Yb3+,Er3+, α-NaYF4:Yb3+,Er3+-DOX, FA-α-NaYF4:Yb 3+,Er3+-DOX, and free DOX. CLSM images of HeLa cells incubated with α-NaYF4:Yb3+,Er3+-DOX (d) and FA-α-NaYF4:Yb3+,Er3+-DOX (e). (Reprinted with permission from Ref [54]. Copyright 2013 Elsevier)

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Another example of LDHNs with stimulate-responsive property is Gd2O3:Eu3+@Hydrogel@H-SiO2 spheres.[79] In this system, the loading amount of drug reached as high as 28.6 wt%. The temperature-sensitive hydrogel was impregnated into the middle layer of the microrattles. The indomethacin (IMC) drug molecules were entrapped and liberated due to the swelling and shrinking of hydrogel by changing temperature.

Most anticancer drugs have severe side effects due to nonspecific action to normal tissue. It is a useful tool to prepare nanomaterials conjugated with antibodies and peptides to achieve target delivery. Yang et al. fabricated folic acid (FA)-conjugated NaYF4:Yb3+,Er3+ hollow mesoporous nanospheres for cell imaging and targeted anticancer drug delivery (Figure 9(II)).[53] FA-modified hollow spheres enhance the efficiency of cell uptake by HeLa cells due to receptor-mediated endocytosis. The DOX-loaded samples after FA modification exhibit higher therapeutic efficacy.

LDHNs have also been applied as gene delivery vehicle. Li's report showed the plasmid DNA was protected from cell enzymatic cleavage when transported by GdPO4:Eu3+ hollow mesoporous nanospheres.[61] Hence, the transfection efficiency of these hollow particles increased.

OTHER THERAPEUTIC APPLICATIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. BRIEF INTRODUCTION OF LANTHANIDE ELEMENTS
  5. LUMINESCENCE CHARACTERISTICS OF LANTHANIDE IONS
  6. FABRICATION STRATEGIES FOR LDHNs
  7. FABRICATION STRATEGIES FOR SINGLE-PHASE LANTHANIDE-DOPED HOLLOW NANOMATERIALS
  8. FABRICATION STRATEGIES FOR LANTHANIDE-DOPED HOLLOW NANOCOMPOSITES
  9. BIOAPPLICATIONS OF LDHNs
  10. BIODETECTION
  11. IMAGING
  12. DRUG/GENE DELIVERY
  13. OTHER THERAPEUTIC APPLICATIONS
  14. CONCLUSION AND OUTLOOK
  15. ACKNOWLEDGMENTS
  16. REFERENCES

Chemotherapy is not only pathway to cure cancer. Photothermal therapy (PTT) is an alternative cancer treatment modality that does not require invasive surgery or induce side effect of anticancer drugs. Huang and colleages showed that Gd2O3/C nanoshells could be used for PTT.[64] Poly(styrene-alt-maleic acid) (PSMA) polymer was coated on their surface to improve water dispersion for further antibody conjugation. A549 cancer cells suffer photothermal destruction due to graphite carbon serving as a NIR photoabsorber. As PTT agents, Gd2O3/C@PSMA has a higher cancer cell killing capacity compared with Au nanorods and silica@Au nanoshells. A crucial concern for NPs-based treatments is whether the injected NPs accumulated or excreted. The biodistribution studies indicated that the Gd2O3/C@PSMA nanoshells injected into mice can be cleared out gradually from organs after 24 h.

Recently, Shi's group synthesized rattle-structured multifunctional up-conversion core/porous silica shell nanotheranostics (UCSNs) (Figure 10).[74] Besides as UCL/MR imaging probe for tumor diagnosis, the nanocomposites can realize synergetic chemo-/radiotherapy by use of cisplatin (CDDP) as an anticancer drug and a radiosensitizer. The mice treated with UCSNs-CDDP + radiation showed the most significant tumor growth delay.

image

Figure 10. (a) Schematic illustration of radiosensitization by UCSNs-CDDP. (b) In vitro CDDP release profile from UCSNs in deionized water. (c) In vitro evaluation of HeLa cells with chemo-/radiotherapy. (d) Digital photos of mice bearing xenograft tumors before and after chemo-/radiotherapy and images of hematoxylin and eosin stained tumor sections from mice treated with CDDP + radiation and FA-UCSNs-CDDP + radiation, respectively. (Reprinted with permission from Ref [73]. Copyright 2013 American Chemical Society)

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CONCLUSION AND OUTLOOK

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. BRIEF INTRODUCTION OF LANTHANIDE ELEMENTS
  5. LUMINESCENCE CHARACTERISTICS OF LANTHANIDE IONS
  6. FABRICATION STRATEGIES FOR LDHNs
  7. FABRICATION STRATEGIES FOR SINGLE-PHASE LANTHANIDE-DOPED HOLLOW NANOMATERIALS
  8. FABRICATION STRATEGIES FOR LANTHANIDE-DOPED HOLLOW NANOCOMPOSITES
  9. BIOAPPLICATIONS OF LDHNs
  10. BIODETECTION
  11. IMAGING
  12. DRUG/GENE DELIVERY
  13. OTHER THERAPEUTIC APPLICATIONS
  14. CONCLUSION AND OUTLOOK
  15. ACKNOWLEDGMENTS
  16. REFERENCES

Rational design of LDHNs as theranostics is an appealing option to realize simultaneous diagnositics and therapeutics. These nanotheranostics are firstly engineered and synthesized by materials scientists and chemists before utilization for biomedical applications by biologist. Hence, it needs the close collaboration between these different scientific disciplines. In this review, we have introduced the synthetic strategies of LDHNs. Each approach has its own pros and cons. For single-phase lanthanide-doped hollow nanomaterials, hard template method and self-sacrificing template method are two kinds of popular routes, which are more convenient for controlling the size and structure. The soft template method is convenient to remove template but difficult to obtain monodisperse and uniform products with hollow structures. And the template-free strategy is only suitable for the fabrication of certain special products. Furthermore, it needs two steps or even multi steps to obtain most of lanthanide-doped hollow nanocomposites. Such complicated process endows the nanocomposites with multiple functions.

The successes in design and fabrication of LDHNs have provided opportunities to use them in the biomedical field. Despite not less relative work has been done, there remains some aspects should be gained more attention in the future investigations of LDHNs. Recent studies indicated that dysprosium (Dy)-based NPs such as NaDyF4, Dy(OH)3 and Dy2O3 are promising candidates for T2 MRI at ultrahigh field. However, Dy-based hollow nanomaterials have not been reported yet. The outstanding properties or unprecedented synergistic effect may be emerged for diagnosis and therapy.

Most researchers focused on production of miscellaneous LDHNs through different techniques, the development of LDHNs as theranostics is still in their fancy. While medical potential offered by nanotechnologies increases, the safety assessment of nanomaterials is requisite.[81] A tremendous effort is required to evaluate the safety of LDHNs, because lanthanide elements are not essential components of biological systems. We believe that there are broad prospects for development of LDHNs for clinical application.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. BRIEF INTRODUCTION OF LANTHANIDE ELEMENTS
  5. LUMINESCENCE CHARACTERISTICS OF LANTHANIDE IONS
  6. FABRICATION STRATEGIES FOR LDHNs
  7. FABRICATION STRATEGIES FOR SINGLE-PHASE LANTHANIDE-DOPED HOLLOW NANOMATERIALS
  8. FABRICATION STRATEGIES FOR LANTHANIDE-DOPED HOLLOW NANOCOMPOSITES
  9. BIOAPPLICATIONS OF LDHNs
  10. BIODETECTION
  11. IMAGING
  12. DRUG/GENE DELIVERY
  13. OTHER THERAPEUTIC APPLICATIONS
  14. CONCLUSION AND OUTLOOK
  15. ACKNOWLEDGMENTS
  16. REFERENCES
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