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ABSTRACT: Herein, we develop FePt@Fe2O3 core-shell magnetic nanoparticles as a T2 magnetic resonance (MR) imaging contrast agent as well as a drug carrier for potential cancer theranostic applications. The FePt@Fe2O3 core-shell nanoparticles are synthesized and then functionalized with polyethylene glycol (PEG). Folic acid (FA) is conjugated on the surface of FePt@Fe2O3-PEG nanoparticles for effective targeting of folate receptor (FR)-positive tumor cells. A chemotherapy drug, doxorubicin (DOX), is then loaded onto those nanoparticles via hydrophobic physical adsorption, for targeted intracellular drug delivery and selective cancer cell killing. We then use those FePt@Fe2O3-PEG nanoparticles for in vivo MR imaging, observing obvious tumor MR contrasts, which are resulted from both passive tumor accumulation and active tumor targeting of nanoparticles. Moreover, both in vitro and in vivo studies uncover no obvious toxicity for FePt@Fe2O3-PEG nanoparticles. Therefore, our PEGylated FePt@Fe2O3 core-shell nanoparticles could serve as a multifunctional theranostic nano-platform promising in imaging guided cancer therapy.
Nanomedicine: nanotechnology, biology, and medicine 03/2013; · 5.44 Impact Factor
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ABSTRACT: Potential toxicity and risk of inducing allergy and inflammation have always been a great concern of using nanomaterials in biomedicine. In this work, we investigate the serum behaviors of graphene oxide (GO) and how such behaviors are affected by its surface modification such as PEGylation. The results show that, when incubated with human sera, unfunctionalized GO adsorbs a significant amount of serum proteins and strongly induces complement C3 cleavage (part of the complement activation cascade), generating C3a/C3a(des-Arg), an anaphylatoxin involved in local inflammatory responses, whereas PEGylated nano-GO (nGO-PEG) exhibits dramatic reductions in both protein binding in general and complement C3 activation. Moreover, we uncover that PEGylation on GO nanosheets apparently generates an interesting nano-interface, evidenced by the acquired certain selectivity and increased binding capacities of nGO-PEG towards a few serum proteins. Further mass spectrometry analysis identifies six nGO-PEG binding proteins, four of which are immune-related factors, including C3a/C3a(des-Arg). A series of western blot analysis demonstrate that nGO-PEG binds up to 2-fold amount of C3a/C3a(des-Arg) than unfunctionalized GO, and can efficiently decrease the level of C3a/C3a(des-Arg) in treated sera, preventing the normal interaction of C3a with its receptor. In a proof-of-concept experiment, we demonstrate that nGO-PEG may serve to help eliminate the C3a/C3a(des-Arg) induced by other nanomaterials such as as-made GO, indicating a new strategy to modulate the immune responses evoked by one nanomaterial through the addition of another type of nanomaterial. Our results highlight the great importance of nano-bio interface in regulating the biological effects of nanomaterials.
ACS Applied Materials & Interfaces 01/2013; · 4.53 Impact Factor
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ABSTRACT: Graphene oxide (GO) and its functionalized derivatives have attracted great attention in biomedicine in recent years. A number of groups including ours have studied the in vivo behaviors of functionalized nano-graphene after intravenous injection or inhalation, and uncovered the surface coating & size dependent biodistribution and toxicology profiles for this type of nanomaterials. However, the fate of GO derivatives in animals after oral feeding and intraperitoneal (i.p.) injection, which are two other major drug administration routes, remain unclear. Therefore, in this work, we sought to systematically investigate in vivo biodistribution and potential toxicity of as-made GO and a number of polyethylene glycol (PEG) functionalized GO derivatives with different sizes and surface coatings, after oral and intraperitoneal administration at high doses. It is found that (125)I labeled PEGylated GO derivatives show no obvious tissue uptake via oral administration, indicating the rather limited intestinal adsorption of those nanomaterials. In contrast, high accumulation of PEGyalted GO derivatives, but not as-made GO, in the reticuloendothelial (RES) system including liver and spleen is observed after i.p. injection. Further investigations based on histological examination of organ slices and hematological analysis discover that although GO and PEGylated GO derivatives would retain in the mouse body over a long period of time after i.p. injection, their toxicity to the treated animals is insignificant. Our work is an important fundamental study that offers a deeper understanding of in vivo behaviors and toxicology of functionalized nano-graphene in animals, depending on their different administration routes.
Biomaterials 01/2013; · 7.40 Impact Factor
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ABSTRACT: Owing to their unique physical and chemical properties, graphene and its derivatives such as graphene oxide (GO), reduced graphene oxide (RGO) and GO-nanocomposites have attracted tremendous interest in many different fields including biomedicine in recent years. With every atom exposed on its surface, single-layered graphene shows ultra-high surface area available for efficient molecular loading and bioconjugation, and has been widely explored as novel nano-carriers for drug and gene delivery. Utilizing the intrinsic near-infrared (NIR) optical absorbance, in vivo graphene-based photothermal therapy has been realized, achieving excellent anti-tumor therapeutic efficacy in animal experiments. A variety of inorganic nanoparticles can be grown on the surface of nano-graphene, obtaining functional graphene-based nanocomposites with interesting optical and magnetic properties useful for multi-modal imaging and imaging-guided cancer therapy. Moreover, significant efforts have also been devoted to study the behaviors and toxicology of functionalized nano-graphene in animals. It has been uncovered that both surface chemistry and sizes play key roles in controlling the biodistribution, excretion, and toxicity of nano-graphene. Biocompatibly coated nano-graphene with ultra-small sizes can be cleared out from body after systemic administration, without rendering noticeable toxicity to the treated mice. In this review article, we will summarize the latest progress in this rapidly growing field, and discuss future prospects and challenges of using graphene-based materials for theranostic applications.
Chemical Society Reviews 10/2012; · 28.76 Impact Factor
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ABSTRACT: Graphene, as a class of 2D carbon nanomaterial, has attracted tremendous interest in different areas in recent years including biomedicine. The toxicity and behavior of graphene in biological systems are thus important fundamental issues that require significant attention. In this article, the toxicity of graphene is reviewed by describing the behavior of graphene and its derivatives in microorganisms, cells, and animals. Despite certain inconsistencies in several detailed experimental results and hypotheses of toxicity mechanisms, results from numerous reports all agree that the physicochemical properties such as surface functional groups, charges, coatings, sizes, and structural defects of graphene may affect its in vitro/in vivo behavior as well as its toxicity in biological systems. It is hoped that this review article will provide an overview understanding of the impacts, behavior, and toxicology of graphene and its derivatives in various biological systems.
Small 09/2012; · 8.35 Impact Factor
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ABSTRACT: Poly(vinyl alcohol)-coated polypyrole, a conductive polymer that forms nanoparticles in the aqueous phase, is used as a near-infrared light-absorbing agent for photothermal therapy of cancer, obtaining excellent cancer ablation therapeutic effects in both cellular and animal experiments.
Advanced Materials 08/2012; · 13.88 Impact Factor
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ABSTRACT: In recent years, a wide range of near-infrared (NIR) light absorbing nanomaterials, mostly inorganic ones, have been developed for photothermal therapy (PTT) of cancer. In this work, we develop a novel organic PTT agent based on poly-(3,4-ethylenedioxythiophene):poly(4-styrenesulfonate) (PEDOT:PSS), a conductive polymer mixture with strong NIR absorbance, for in vivo photothermal treatment of cancer. After being layer-by-layer coated with charged polymers and then conjugated with branched polyethylene glycol (PEG), the obtained PEDOT:PSS-PEG nanoparticles are highly stable in the physiological environment and exhibit a stealth-like behavior after intravenous injection with a long blood circulation half-life. As a result, an extremely high in vivo tumor uptake of PEDOT:PSS-PEG attributed to the tumor-enhanced permeability and retention effect is observed. We further use PEDOT:PSS-PEG as a PTT agent for in vivo cancer treatment and realize excellent therapeutic efficacy in a mouse tumor model under NIR light irradiation at a low laser power density. Comprehensive blood tests and careful histological examination reveal no apparent toxicity of PEDOT:PSS-PEG to mice at our treated dose within 40 days. To our best knowledge, this work is the first to use systemically administrated conductive polymer nanoparticles for highly effective in vivo PTT treatment in animals and encourages further explorations of those organic nanomaterials for cancer theranostic applications.
ACS Nano 05/2012; 6(6):5605-13. · 10.77 Impact Factor
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ABSTRACT: The understanding of interactions between nanomaterials and biomolecules is of fundamental importance to the area of nanobiotechnology. Graphene and its derivative, graphene oxide (GO), are two-dimensional (2-D) nanomaterials with interesting physical and chemical properties and have been widely explored in various directions of biomedicine in recent years. However, how functionalized GO interacts with bioactive proteins such as enzymes and its potential in enzyme engineering have been rarely explored. In this study, we carefully investigated the interactions between serine proteases and GO functionalized with different amine-terminated polyethylene glycol (PEG). Three well-characterized serine proteases (trypsin, chymotrypsin, and proteinase K) with important biomedical and industrial applications were analyzed. It is found that these PEGylated GOs could selectively improve trypsin activity and thermostability (60-70% retained activity at 80 °C), while exhibiting barely any effect on chymotrypsin or proteinase K. Detailed investigation illustrates that the PEGylated GO-induced acceleration is substrate-dependent, affecting only phosphorylated protein substrates, and that at least up to 43-fold increase could be achieved depending on the substrate concentration. This unique phenomenon, interestingly, is found to be attributed to both the terminal amino groups on polymer coatings and the 2-D structure of GO. Moreover, an enzyme-based bioassay system is further demonstrated utilizing our GO-based enzyme modulator in a proof-of-concept experiment. To our best knowledge, this work is the first success of using functionalized GO as an efficient enzyme positive modulator with great selectivity, exhibiting a novel potential of GO, when appropriately functionalized, in enzyme engineering as well as enzyme-based biosensing and detection.
ACS Nano 05/2012; 6(6):4864-75. · 10.77 Impact Factor
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ABSTRACT: The latest progress of using carbon nanotubes (CNTs) for in vivo cancer nanotechnology is reviewed. CNTs can be functionalized by either covalent or non-covalent chemistry to produce functional
bioconjugates for many in vivo applications. In vivo behaviors and toxicology studies of CNTs are summarized, suggesting no significant toxicity of well functionalized CNTs to
the treated mice. Owing to their unique chemical and physical properties, CNTs, especially single-walled carbon nanotubes
(SWNTs), have been widely used for various modalities of in vivo cancer treatment and imaging. Future development of CNT-based nanomedicine may bring novel opportunities to cancer diagnosis
and therapy.
Keywordscarbon nanotubes-
in vivo behaviors-cancer therapy-cancer imaging
Science China-Chemistry 04/2012; 53(11):2217-2225. · 1.02 Impact Factor
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ABSTRACT: Lanthanide-based upconversion nanoparticles (UCNPs) have been widely explored in various fields, including optical imaging,
in recent years. Although earlier work has shown that UCNPs with different lanthanide (Ln3+) dopants exhibit various colors, multicolor-especially in vivo multiplexed biomedical imaging-using UCNPs has rarely been reported. In this work, we synthesize a series of UCNPs with different
emission colors and functionalize them with an amphiphilic polymer to confer water solubility. Multicolor in vivo upconversion luminescence (UCL) imaging is demonstrated by imaging subcutaneously injected UCNPs and applied in multiplexed
in vivo lymph node mapping. We also use UCNPs for multicolor cancer cell labeling and realize in vivo cell tracking by UCL imaging. Moreover, for the first time we compare the in vivo imaging sensitivity of quantum dot (QD)-based fluorescence imaging and UCNP-based UCL imaging side by side, and find the
in vivo detection limit of UCNPs to be at least one order of magnitude lower than that of QDs in our current non-optimized imaging
system. Our data suggest that, by virtue of their unique optical properties, UCNPs have great potential for use in highly-sensitive
multiplexed biomedical imaging.
KeywordsUpconversion nanoparticles-multicolor imaging-lymphatic mapping-cell tracking-sensitive imaging
Nano Research 04/2012; 3(10):722-732. · 6.97 Impact Factor
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ABSTRACT: A nanoscale reduced graphene oxide-iron oxide nanoparticle (RGO-IONP) complex is nonco-valently functionalized with polyethylene glycol (PEG) by Z. Liu and co-workers on page 1868, obtaining a RGO-IONP-PEG nanocomposite which displays excellent physiological stability, strong NIR optical absorbance, and superpara-magnetic properties. This theranostic nanoprobe allows multimodal tumor imaging - in vivo triple modal fluorescence, photoacoustic, and magnetic resonance imaging are carried out, uncovering high passive tumor targeting, which is further used for the effective photothermal ablation of tumors in mice.
Advanced Materials 04/2012; 24(14):1867. · 13.88 Impact Factor
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ABSTRACT: In this work, a nanoscale reduced graphene oxide-iron oxide nanoparticle (RGO-IONP) complex is noncovalently functionalized with polyethylene glycol (PEG), obtaining a RGO-IONP-PEG nanocomposite with excellent physiological stability, strong NIR optical absorbance, and superparamagnetic properties. Using this theranostic nanoprobe, in-vivo triple modal fluorescence, photoacoustic, and magnetic resonance imaging are carried out, uncovering high passive tumor targeting, which is further used for effective photothermal ablation of tumors in mice.
Advanced Materials 02/2012; 24(14):1868-72. · 13.88 Impact Factor
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ABSTRACT: Owing to their interesting physical and chemical properties, carbon nanotubes (CNTs) have attracted wide attentions in nanomedicine for applications in biological sensing, drug delivery, as well as biomedical imaging. The in vivo behaviors and toxicology of CNTs in biological systems, which are important fundamental questions, although have been intensively studied in recent years, remain to be clarified as distinctive results have been reported by various teams, confusing the scientific community as well as the public. In this article, we review the research on the in vivo behaviors of CNTs, and summarize the toxicity studies of CNTs in animals by different groups. Similar to other nanomaterials, the in vivo pharmacokinetics and biodistribution of CNTs are closely associated with their surface coatings. The excretion of CNTs from animals may happen via renal and fecal pathways, depending on the CNT surface chemistry, shape, and sizes. Regarding the toxicology of CNTs, which has been a debating topic for years, the administration routes, doses, and again the surface functionalization are critical to the in vivo toxicity of nanotubes. Much more efforts are still required to develop functional CNT bioconjugates with improved biocompatible coatings and controllable optimal sizes to achieve fast excretion and minimal toxicity, for various applications in biomedicine.
Current Drug Metabolism 02/2012; · 5.11 Impact Factor
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ABSTRACT: Photothermal therapy as a physical treatment approach to destruct cancer has emerged as an alternative of currently used cancer therapies. Previously we have shown that polyethylene glycol (PEG) functionalized nano-graphene oxide (nGO-PEG) with strong optical absorption in the near-infrared (NIR) region was a powerful photothermal agent for in vivo cancer treatment. In this work, by using ultra-small reduced graphene oxide (nRGO) with non-covalent PEG coating, we study how sizes and surface chemistry affect the in vivo behaviors of graphene, and remarkably improve the performance of graphene-based in vivo photothermal cancer treatment. Owing to the enhanced NIR absorbance and highly efficient tumor passive targeting of nRGO-PEG, excellent in vivo treatment efficacy with 100% of tumor elimination is observed after intravenous injection of nRGO-PEG and the followed 808 nm laser irradiation, the power density (0.15 W/cm(2), 5 min) of which is an order of magnitude lower than that usually applied for in vivo tumor ablation using many other nanomaterials. All mice after treatment survive over a period of 100 days without a single death or any obvious sign of side effect. Our results highlight that both surface chemistry and sizes are critical to the in vivo performance of graphene, and show the promise of using optimized nano-graphene for ultra-effective photothermal treatment, which may potentially be combined with other therapeutic approaches to assist our fight against cancer.
Biomaterials 12/2011; 33(7):2206-14. · 7.40 Impact Factor
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ABSTRACT: Theranostics, the combination of diagnostics and therapies, has become a new concept in the battles with various major diseases such as cancer. Herein, we develop multifunctional nanoparticles (MFNPs) with highly integrated functionalities including upconversion luminescence, superparamagnetism, and strong optical absorption in the near-infrared (NIR) region with high photostability. In vivo dual modal optical/magnetic resonance imaging of mice uncovers that by placing a magnet nearby the tumor, MFNPs tend to migrate toward the tumor after intravenous injection and show high tumor accumulation, which is ~8 folds higher than that without magnetic targeting. NIR laser irradiation is then applied to the tumors grown on MFNP-injected mice under magnetic tumor-targeting, obtaining an outstanding photothermal therapeutic efficacy with 100% of tumor elimination in a murine breast cancer model. We present here a strategy for multimodal imaging-guided, magnetically targeted physical cancer therapy and highlight the promise of using multifunctional nanostructures for cancer theranostics.
Biomaterials 12/2011; 33(7):2215-22. · 7.40 Impact Factor
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ABSTRACT: Oxidization of carbon nanotubes by a mixed acid has been utilized as a standard method to functionalize carbon nanomaterials for years. Here, the products obtained from carbon nanotubes and graphite after a mixed-acid treatment are carefully studied. Nearly identical carbon dot (Cdot) products with diameters of 3-4 nm are produced using this approach from a variety of carbon starting materials, including single-walled carbon nanotubes, multiwalled carbon nanotubes, and graphite. These Cdots exhibit strong yellow fluorescence under UV irradiation and shifted emission peaks as the excitation wavelength is changed. In vivo fluorescence imaging with Cdots is then demonstrated in mouse experiments, by using varied excitation wavelengths including some in the near-infrared (NIR) region. Furthermore, in vivo biodistribution and toxicology of those Cdots in mice over different periods of time are studied; no noticeable signs of toxicity for Cdots to the treated animals are discovered. This work provides a facile method to synthesize Cdots as safe non-heavy-metal-containing fluorescent nanoprobes, promising for applications in biomedical imaging.
Small 11/2011; · 8.35 Impact Factor
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ABSTRACT: We investigated the in vivo pharmacokinetics, long-term biodistribution and toxicology of polymer-coated upconversion nanoparticles (UCNPs) in mice.
Near infrared emitting Yb(3+)/Tm(3+)-doped NaYF(4) UCNPs coated with either polyethylene glycol (PEG) or polyacrylic acid (PAA) were intravenously injected into mice. Blood levels of UCNPs were measured. Yttrium levels in various organs were measured to determine the biodistribution of UCNPs over 3 months. Serum biochemistry, hematology and histology assays were conducted for in vivo toxicology assays.
UCNP-PEG exhibited improved stability in physiological solutions and prolonged blood circulation half-lives more than UCNP-PAA. No noticeable toxic side effect was noticed for either UCNP-PAA or UCNP-PEG in our toxicology study, despite the long-term retention of those nanoparticles in the reticuloendothelial systems including the liver and spleen of mice.
Although more systematic investigations are still required, the absence of appreciable toxicity shown in our study encourages future explorations of UCNPs for in vivo biomedical applications.
Nanomedicine 08/2011; 6(8):1327-40. · 5.05 Impact Factor
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Angewandte Chemie International Edition 06/2011; 50(32):7385-90. · 13.45 Impact Factor
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ABSTRACT: Graphene has emerged as interesting nanomaterials with promising applications in a range of fields including biomedicine. In this work, for the first time we study the long-term in vivo biodistribution of (125)I-labeled nanographene sheets (NGS) functionalized with polyethylene glycol (PEG) and systematically examine the potential toxicity of graphene over time. Our results show that PEGylated NGS mainly accumulate in the reticuloendothelial system (RES) including liver and spleen after intravenous administration and can be gradually cleared, likely by both renal and fecal excretion. PEGylated NGS do not cause appreciable toxicity at our tested dose (20 mg/kg) to the treated mice in a period of 3 months as evidenced by blood biochemistry, hematological analysis, and histological examinations. Our work greatly encourages further studies of graphene for biomedical applications.
ACS Nano 01/2011; 5(1):516-22. · 10.77 Impact Factor
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ABSTRACT: Upconversion nanoparticles (UCNPs) based on sodium yttrium fluoride (NaYF4) nanocrystals are synthesized, functionalized with an amphiphilic polymer, and loaded with fluorescent and quenching molecules by physical adsorption. The formed supramolecular UCNP−dye complexes show tuned visible emission spectra owing to the luminescence resonance energy transfer (LRET) from nanoparticles to the organic dyes under near-infrared (NIR) excitation, and can be well separated in multicolor imaging after spectral decovolution. Our work provides a facile and flexible method to modulate the upconversion luminescence (UCL) spectra of UCNPs for in vivo multicolor UCL imaging in animals.
01/2011;
