Multifunctional Nanoprobes Research Articles

Synthesis of Ultrathin MnS Shell on ZnS: Mn Nanorods by One‐Step Coating and Doping for MRI and Fluorescent Imaging

Multifunctional nanoprobes for bioimaging have attracted considerable interest in terms of their potential applications in clinical medicine and diagnosis. This article reports the fabrication of a new bifunctional nanoprobe, consisting of an ultrathin MnS shell coating on ZnS:Mn nanorods (NRs), for bioimaging in combination with fluorescence and magnetic resonance imaging (MRI) techniques. The prepared ZnS:Mn/MnS core–shell NRs show an orange emission at 587 nm in wavelength, suggesting they are well suited for fluorescent bio‐imaging due to their large Stokes shift. After surface modification, the obtained core–shell NRs show a very high relaxivity, 9.30 mM−1s−1 at 0.47 T, in aqueous solution. This value is much higher than most Mn‐based nanocrystal contrast agents reported before. The high relaxivity is strongly related to the ultrathin thickness of the MnS shell, as well as its one‐dimensional nanostructure. The prepared bifunctional nanoprobe also shows effective fluorescent imaging in vitro and MRI enhancement in vivo, which verifies its feasibility and effectiveness.

Realizing efficient upconversion and down-shifting dual-mode luminescence in lanthanide-doped NaGdF4 core–shell–shell nanoparticles through gadolinium sublattice-mediated energy migration

Monodisperse rod-like colloidal core–shell–shell NaGdF4:Yb/Tm@NaGdF4:Ce/Ln@NaYF4 (Ln = Tb, Eu, Dy and Sm) nanoparticles (25 nm in diameter and 37 nm in length) have been successfully synthesized through a facile wet chemical method. X-ray diffraction, transmission electron microscopy, upconversion and down-shifting photoluminescence were used to characterize the samples. The prepared nanoparticles exhibited both tunable upconversion and down-shifting emissions from Tb, Eu, Dy and Sm activators under 980 nm near-infrared and 254 nm ultraviolet excitation, respectively. The dual-model luminescence was achieved through gadolinium (Gd3+) sublattice-mediated energy migration: Yb3+ → Tm3+→n(Gd3+) → Ln3+ and Ce3+ → n(Gd3+)→Ln3+ energy-transfer process, respectively. The advances on these dual-mode luminescent nanoparticles offer exciting opportunities for developing multifunctional optical nanoprobes for biological applications.

In vivo Near-infrared Fluorescence Tumor Imaging Using DiR-loaded Nanocarriers.

The hydrophobic long-chain dialkylcarbocyanine 1,1'-dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine iodide (DiR) is an important near infrared (NIR) fluorescent dye, which has a satisfactory photo stability for continuous excitation. During the past decade, it has been widely used for in vivo monitoring of cells. With the fast emergence of novel tumor-targeted nanocarriers, the applications of DiR in the development of fluorescent or multifunctional nano-probes for in vivo tumor imaging are also reported. In these studies, DiR-loaded nanocarriers have resulted in good fluorescence images, indicating the great potential of this dye. However, some important issues about DiR-loaded nanocarriers were often overlooked. These issues include the in vivo fluorescent properties, stability, toxicity, retention and metabolization of DiR-loaded nanocarriers. This review introduced the current use and the properties of DiR-loaded nanocarriers for in vivo tumor imaging. The perspective outlook at the last section highlights the future application of DiR-loaded nanocarriers.

A multifunctional mesoporous Fe3O4/SiO2/CdTe magnetic-fluorescent composite nanoprobe

A multifunctional mesoporous, magnetic and fluorescent Fe3O4/SiO2/CdTe nanoprobe with well-defined core–shell nanostructures was prepared. This multifunctional nanoprobe was synthesized through a novel method mainly including two steps. The first step involved the controlled growth of mesoporous silica layer onto the surface of Fe3O4 nanoparticle using tetraethyl orthosilicate as silica source, cationic surfactant cetyltrimethylammonium bromide as template, and 1,3,5-triisopropylbenzene as pore swelling agents. The second step involved the layer-by-layer assembly of 3-aminopropyltrimethoxysilane and fluorescent CdTe quantum dots with the mesoporous Fe3O4/SiO2 nanoparticles. The well-designed nanoprobe exhibits strong excitonic photoluminescence and superparamagnetism at room temperature. In attention, the mesoporous silica layer of the nanoprobe with great loading capacity makes it a promising candidate as targeted drug delivery platform.

Ultrahigh (19)F Loaded Cu1.75S Nanoprobes for Simultaneous (19)F Magnetic Resonance Imaging and Photothermal Therapy.

(19)F magnetic resonance imaging (MRI) is a powerful noninvasive, sensitive, and accurate molecular imaging technique for early diagnosis of diseases. The major challenge of (19)F MRI is signal attenuation caused by the reduced solubility of probes with increased number of fluorine atoms and the restriction of molecular mobility. Herein, we present a versatile one-pot strategy for the fabrication of a multifunctional nanoprobe with high (19)F loading (∼2.0 × 10(819)F atoms per Cu1.75S nanoparticle). Due to the high (19)F loading and good molecular mobility that results from the small particle size (20.8 ± 2.0 nm) and ultrathin polymer coating, this nanoprobe demonstrates ultrahigh (19)F MRI signal. In vivo tests show that this multifunctional nanoprobe is suitable for (19)F MRI and photothermal therapy. This versatile fabrication strategy has also been readily extended to other single-particle nanoprobes for ablation and sensitive multimodal imaging.

Biomolecular environment, quantification, and intracellular interaction of multifunctional magnetic SERS nanoprobes.

Multifunctional composite nanoprobes consisting of iron oxide nanoparticles linked to silver and gold nanoparticles, Ag-Magnetite and Au-Magnetite, respectively, were introduced by endocytic uptake into cultured fibroblast cells. The cells containing the non-toxic nanoprobes were shown to be displaceable in an external magnetic field and can be manipulated in microfluidic channels. The distribution of the composite nanostructures that are contained in the endosomal system is discussed on the basis of surface-enhanced Raman scattering (SERS) mapping, quantitative laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) micromapping, and cryo soft X-ray tomography (cryo soft-XRT). Cryo soft-XRT of intact, vitrified cells reveals that the composite nanoprobes form intra-endosomal aggregates. The nanoprobes provide SERS signals from the biomolecular composition of their surface in the endosomal environment. The SERS data indicate the high stability of the nanoprobes and of their plasmonic properties in the harsh environment of endosomes and lysosomes. The spectra point at the molecular composition at the surface of the Ag-Magnetite and Au-Magnetite nanostructures that is very similar to that of other composite structures, but different from the composition of pure silver and gold SERS nanoprobes used for intracellular investigations. As shown by the LA-ICP-MS data, the uptake efficiency of the magnetite composites is approximately two to three times higher than that of the pure gold and silver nanoparticles.

Targeting Negative Surface Charges of Cancer Cells by Multifunctional Nanoprobes.

A set of electrostatically charged, fluorescent, and superparamagnetic nanoprobes was developed for targeting cancer cells without using any molecular biomarkers. The surface electrostatic properties of the established cancer cell lines and primary normal cells were characterized by using these nanoprobes with various electrostatic signs and amplitudes. All twenty two randomly selected cancer cell lines of different organs, but not normal control cells, bound specifically to the positively charged nanoprobes. The relative surface charges of cancer cells could be quantified by the percentage of cells captured magnetically. The activities of glucose metabolism had a profound impact on the surface charge level of cancer cells. The data indicate that an elevated glycolysis in the cancer cells led to a higher level secretion of lactate. The secreted lactate anions are known to remove the positive ions, leaving behind the negative changes on the cell surfaces. This unique metabolic behavior is responsible for generating negative cancer surface charges in a perpetuating fashion. The metabolically active cancer cells are shown to a unique surface electrostatic pattern that can be used for recovering cancer cells from the circulating blood and other solutions.

A novel photoacoustic nanoprobe of ICG@PEG-Ag2S for atherosclerosis targeting and imaging in vivo.

Atherosclerosis is a major cause of cardiovascular and cerebrovascular diseases that have high mortality and disability rates. Because of its unclear pathogenic mechanism and heterogeneous distribution feature, it is still a big challenge to achieve precise diagnosis and therapy of atherosclerosis at its early stage in vivo. Herein, we fabricated a new ICG@PEG-Ag2S nanoprobe by a simple self-assembly of DT-Ag2S QDs, amphipathic C18/PEG polymer molecules and ICG. The ICG@PEG-Ag2S nanoprobe showed relatively long blood retention and was selectively accumulated in the region of atherosclerotic plaque due to the lipophilicity of the C18 chain to the atherosclerosis microenvironment, and thus the atherosclerosis was real-time monitored by high contrast-enhanced photoacoustic (PA) imaging of ICG. Combining the high signal-to-noise ratio (SNR) and high spatial resolution fluorescence imaging of Ag2S QDs in the second near-infrared window (NIR-II) and related histological assessment in vitro, the feasibility of this new nanoprobe for atherosclerosis targeting in an Apoe(-/-) mouse model was verified. Additionally, hemolysis and coagulation assays of the ICG@PEG-Ag2S revealed its decent hemocompatibility and no histological changes were observed in the main organs of the mouse. Such a simple, multifunctional nanoprobe for targeting and PA imaging of atherosclerosis will have a great potential for future clinical applications.

Iron oxide nanoparticles protected by NIR-active multidentate-polymers as multifunctional nanoprobes for NIRF/PA/MR trimodal imaging.

We designed and synthesized new kinds of near-infrared catechol-based multidentate polymers which were intended to yield compact NIR-active iron oxide nanoparticles with excellent stability and biocompatibility. The resulted multifunctional nanoprobes showed great potential as multimodal contrast agents for NIRF/PA/MR trimodal imaging in vivo.

Tumor Detection: Remarkable NIR Enhancement of Multifunctional Nanoprobes for In Vivo Trimodal Bioimaging and Upconversion Optical/T2‐Weighted MRI‐Guided Small Tumor Diagnosis (Adv. Funct. Mater. 46/2015)

Tumor Detection: Remarkable NIR Enhancement of Multifunctional Nanoprobes for In Vivo Trimodal Bioimaging and Upconversion Optical/T₂‐Weighted MRI‐Guided Small Tumor Diagnosis (Adv. Funct. Mater. 46/2015)

Self-assembled mPEG-PCL-g-PEI micelles for multifunctional nanoprobes of doxorubicin delivery and magnetic resonance imaging and optical imaging

In this paper, a novel bifunctional nanoprobe based on polyethylene glycol(MPEG)-poly(ϵ-caprolactone)(ϵ-CL)-polyethylenimine(PEI) labeled with FITC (MPEG-PCL-PEI-FITC, PCIF) were prepared to provide tumor therapy and simultaneous diagnostic information via magnetic resonance imaging (MRI) and optical imaging. Superparamagnetic iron oxide (SPIO) and doxorubicin (DOX) loaded PCIF (PCIF/SPIO/DOX) nanoprobes were prepared by self-assembling into micelles, which had uniformly distributed particle size of 130±5nm and a zeta potential of +35±2mV. Transmission electronic microscopy(TEM) showed that SPIO NPs were loaded into PCIF micelles. The PCIF/SPIO/DOX nanoprobes were superparamagnetic at 300K with saturated magnetization of 20.5emu/g Fe by vibrating-sample-magnetomete (VSM). Studies on cellular uptake of PCIF/SPIO/DOX nanoprobes demonstrated that SPIO NPs, DOX and FITC labeled MPEG-PCL-PEI were simultaneously taken up by the breast cancer (4T1) cells. After intravenous injection of PCIF/SPIO/DOX nanoprobes in 4T1 tumor-bearing mice, SPIO NPs, DOX and FITC labeled MPEG-PCL-PEI micelles were simultaneously delivered into tumor tissue by histochemisty. This work is important for the applications to multimodal diagnostic and theragnosis as nanomedicine.

MicroRNA-Responsive Cancer Cell Imaging and Therapy with Functionalized Gold Nanoprobe.

Integration of cancer cell imaging and therapy is critical to enhance the theranostic efficacy and prevent under- or overtreatment. Here, a multifunctional gold nanoprobe is designed for simultaneous miRNA-responsive fluorescence imaging and therapeutic monitoring of cancer. By assembling with folic acid as the targeted moiety and a dye-labeled molecular beacon (MB) as the recognition element and signal switch, the gold nanoprobe is folate receptor-targeted delivered into the cancer cells, and the fluorescence is lighted with the unfolding of MB by intracellular microRNA (miRNA), resulting in an efficient method for imaging and detecting nucleic acid. The average quantity of miRNA-21 is measured to be 1.68 pg in a single HeLa cell. Upon the near-infrared irradiation at 808 nm, the real-time monitoring and assessing of photothermal therapeutic efficacy is achieved from the further enhanced fluorescence of the dye-labeled MB, caused by the high photothermal transformation efficiency of the gold nanocarrier to unwind the remaining folded MB and depart the dye from the nanocarrier. The fluorescence monitoring is also feasible for applications in vivo. This work provides a simple but powerful protocol with great potential in cancer imaging, therapy, and therapeutic monitoring.

Raman Reporter-Coupled Ag(core)@Au(shell) Nanostars for in Vivo Improved Surface Enhanced Raman Scattering Imaging and Near-infrared-Triggered Photothermal Therapy in Breast Cancers.

Noble-metal nanomaterials were widely investigated as theranostic systems for surface enhanced Raman scattering (SERS) imaging, and also for photothermal therapy (PTT) of cancers. However, it was still a major challenge to explore multifunctional nanoprobes with high performance, high stability, and low toxicity. In this work, Raman reporter (DTTC)-coupled Agcore@Aushell nanostars (Ag@Au-DTTC) were synthesized and investigated for in vivo improved SERS imaging and near-infrared (NIR)-triggered PTT of breast cancers. By the two-step coupling of DTTC, the SERS signal was improved obviously, and the cytotoxicity of nanoparticles was also decreased by coating Au nanostars onto Ag nanoparticles. The as-prepared Ag@Au-DTTC nanostars showed high photostability and excellent photothermal performance, in which the photothermal conversion efficiency was up to 79.01% under the irradiation of an 808 nm laser. The in vitro and in vivo SERS measurements of Ag@Au-DTTC nanostars showed that the many sharp and narrow Raman peaks located at 508, 782, 844, 1135, 1242, 1331, 1464, 1510, and 1580 cm(-1) could be obviously observed in MCF-7 cells and in MCF-7 tumor-bearing nude mice, compared with that in pure DTTC. In 14-day treatments, the tumor volume of MCF-7 tumor-bearing nude mice injected with Ag@Au-DTTC nanostars and irradiated by an 808 nm laser almost disappeared. This study demonstrated that the as-prepared Ag@Au-DTTC nanostars could be excellent multifunctional agents for improved SERS imaging and NIR-triggered PTT of breast cancers with low risk.

Preparation of Multifunctional Nanoprobes for Tumor-Targeted Fluorescent Imaging and Therapy.

Nanoparticles are emerging as versatile nanoplatforms for the construction of multifunctional nanoprobes, which not only can deliver drugs into desired tumor regions but also are able to monitor the delivery, release and biodistribution of drugs in real time. In order to assist drug delivery, fluorescent imaging that can make the transportation viewable is often used. Then, various fluorescent nanoprobes that are composed of fluorescent or non-fluorescent nanocarrier, small-molecular fluorophore, drug, targeting ligand are developed and applied in biomedical applications. In this review paper, we will summarize chemical strategies for the construction of multifunctional nanoprobes and for controlled release of drugs. Then, recent examples on fluorescent nanoprobes, which are based on quantum dots, carbon nanodots, upconversion nanoparticles and other nanomaterials, and their applications in optical-guided drug delivery will be reviewed.

Design, Properties, and In Vivo Behavior of Super­paramagnetic Persistent Luminescence Nanohybrids

With the fast development of noninvasive diagnosis, the design of multimodal imaging probes has become a promising challenge. If many monofunctional nanocarriers have already proven their efficiency, only few multifunctional nanoprobes have been able to combine the advantages of diverse imaging modalities. An innovative nanoprobe called mesoporous persistent luminescence magnetic nanohybrids (MPNHs) is described that shows both optical and magnetic resonance imaging (MRI) properties intended for in vivo multimodal imaging in small animals. MPNHs are based on the assembly of chromium-doped zinc gallate oxide and ultrasmall superparamagnetic iron oxide nanoparticles embedded in a mesoporous silica shell. MPNHs combine the optical advantages of persistent luminescence, such as real time imaging with highly sensitive and photostable detection, and MRI negative contrast properties that ensure in vivo imaging with rather high spatial resolution. In addition to their imaging capabilities, these MPNHs can be motioned in vitro with a magnet, which opens multiple perspectives in magnetic vectorization and cell therapy research.

Multifunctional Nanoprobes for Cancer Cell Targeting, Imaging and Anticancer Drug Delivery

The diagnosis and treatment of cancer have been greatly improved with recent developments in bio-nanotechnology, including engineering of multifunctional probes. One of the promising nanoscale tools for cancer imaging is fluorescent quantum dots (QDs), whose small size and unique optical properties allow them to penetrate into cells and ensure highly sensitive optical diagnosis of cancer at the cellular level. Furthermore, novel multi-functional probes have been developed in which QDs are conjugated with one or several functional molecules, including targeting moieties and therapeutic agents. Here, the strategy for engineering novel nanocarriers for controlled nucleus-targeted antitumor drug delivery and real-time imaging by single- or two-photon microscopy is described. A triple multifunctional nanoprobe is being developed that consists of a nitrogen-based heterocyclic derivative, an anticancer agent interacting with a DNA in living cells; a recognized molecule serving as a vector responsible for targeted delivery of the probe into cancer cells; and photoluminescent QDs providing the imaging capability of the probe. Subsequent optimization of the multifunctional nanoprobe will offer new possibilities for cancer diagnosis and treatment.

Core-shell hybrid upconversion nanoparticles carrying stable nitroxide radicals as potential multifunctional nanoprobes for upconversion luminescence and magnetic resonance dual-modality imaging.

Nitroxide radicals, such as 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) and its derivatives, have recently been used as contrast agents for magnetic resonance imaging (MRI) and electron paramagnetic resonance imaging (EPRI). However, their rapid one-electron bioreduction to diamagnetic N-hydroxy species when administered intravenously has limited their use in in vivo applications. In this article, a new approach of silica coating for carrying stable radicals was proposed. A 4-carboxyl-TEMPO nitroxide radical was covalently linked with 3-aminopropyl-trimethoxysilane to produce a silanizing TEMPO radical. Utilizing a facile reaction based on the copolymerization of silanizing TEMPO radicals with tetraethyl orthosilicate in reverse microemulsion, a TEMPO radicals doped SiO2 nanostructure was synthesized and coated on the surface of NaYF4:Yb,Er/NaYF4 upconversion nanoparticles (UCNPs) to generate a novel multifunctional nanoprobe, PEGylated UCNP@TEMPO@SiO2 for upconversion luminescence (UCL) and magnetic resonance dual-modality imaging. The electron spin resonance (ESR) signals generated by the TEMPO@SiO2 show an enhanced reduction resistance property for a period of time of up to 1 h, even in the presence of 5 mM ascorbic acid. The longitudinal relaxivity of PEGylated UCNPs@TEMPO@SiO2 nanocomposites is about 10 times stronger than that for free TEMPO radicals. The core-shell NaYF4:Yb,Er/NaYF4 UCNPs synthesized by this modified user-friendly one-pot solvothermal strategy show a significant enhancement of UCL emission of up to 60 times more than the core NaYF4:Yb,Er. Furthermore, the PEGylated UCNP@TEMPO@SiO2 nanocomposites were further used as multifunctional nanoprobes to explore their performance in the UCL imaging of living cells and T1-weighted MRI in vitro and in vivo.

In vivo targeted magnetic resonance imaging and visualized photodynamic therapy in deep-tissue cancers using folic acid-functionalized superparamagnetic-upconversion nanocomposites.

Multifunctional nanoprobes used in magnetic resonance imaging (MRI) and photodynamic therapy (PDT) also have potential applications in diagnosis and visualized therapy of cancers, and hence it is important to investigate the active-targeting ability and in vivo reliability of these nanoprobes. In this work, folic acid (FA)-targeted, photosensitizer (PS)-loaded Fe3O4@NaYF4:Yb/Er (FA-NPs-PS) nanocomposites were synthesized for in vivo T2-weighted MRI and visualized PDT of cancers by modeling MCF-7 tumor-bearing nude mice. By measuring the upconversion luminescence (UCL) and fluorescence emission spectra, the as-prepared FA-NPs-PS nanocomposites showed near-infrared (NIR)-triggered PDT performance due to the production of a singlet oxygen species. Moreover, by tracing PS fluorescence in MCF-7, HeLa cells and in MCF-7 tumors, the FA-targeted nanocomposites demonstrated good targeting ability both in vitro and in vivo. Under the irradiation of a 980 nm laser, the viabilities of MCF-7 and HeLa cells incubated with FA-NPs-PS nanocomposites could decrease to about 18.4% and 30.7%, respectively, and the inhibition of MCF-7 tumors could reach about 94.9%. The transverse MR relaxivity of 63.79 mM(-1) s(-1) (r2 value) and in vivo MR imaging of MCF-7 tumors indicated an excellent T2-weighted MR performance. This work demonstrated that FA-targeted MRI/PDT nanoprobes are effective for in vivo diagnosis and visualized therapy of breast cancers.

A self-assembling lanthanide molecular nanoparticle for optical imaging.

Chromophores that incorporate f-block elements have considerable potential for use in bioimaging applications because of their advantageous photophysical properties compared to organic dye, which are currently widely used. We are developing new classes of lanthanide-based self-assembling molecular nanoparticles as reporters for imaging and as multi-functional nanoprobes or nanosensors for use with biological samples. One class of these materials, which we call lanthanide "nano-drums", are homogeneous 4d-4f clusters approximately 25 to 30 Å in diameter. These are capable of emitting from the visible to near-infrared wavelengths. Here, we present the synthesis, crystal structure, photophysical properties and comparative cytotoxicity data for a 32 metal Eu-Cd nano-drum [Eu(8)Cd(24)L(12)(OAc)(48)] (1). We also explored the imaging capabilities of this nano-drum using epifluorescence, TIRF, and two-photon microscopy platforms.

Nanostructured magnetic nanocomposites as MRI contrast agents.

Magnetic resonance imaging (MRI) has become an integral part of modern clinical imaging due to its non-invasiveness and versatility in providing tissue and organ images with high spatial resolution. With the current MRI advancement, MRI imaging probes with suitable biocompatibility, good colloidal stability, enhanced relaxometric properties and advanced functionalities are highly demanded. As such, MRI contrast agents (CAs) have been an extensive research and development area. In the recent years, different inorganic-based nanoprobes comprising inorganic magnetic nanoparticles (MNPs) with an organic functional coating have been engineered to obtain a suitable contrast enhancement effect. For biomedical applications, the organic functional coating is critical to improve colloidal stability and biocompatibility. Simultaneously, it also provides a building block for generating a higher dimensional secondary structure. In this review, the combinatorial design approach by a self-assembling pre-formed hydrophobic inorganic MNPs core (from non-polar thermolysis synthesis) into various functional organic coatings (e.g. ligands, amphiphilic polymers and graphene oxide) to form water soluble nanocomposites will be discussed. The resultant magnetic ensembles were classified based on their dimensionality, namely, 0-D, 1-D, 2-D and 3-D structures. This classification provides further insight into their subsequent potential use as MRI CAs. Special attention will be dedicated towards the correlation between the spatial distribution and the associated MRI applications, which include (i) coating optimization-induced MR relaxivity enhancement, (ii) aggregation-induced MR relaxivity enhancement, (iii) off-resonance saturation imaging (ORS), (iv) magnetically-induced off-resonance imaging (ORI), (v) dual-modalities MR imaging and (vi) multifunctional nanoprobes.