Lingchao Xiang

Multifunctional photosensitizer-conjugated core–shell Fe3O4@NaYF4:Yb/Er nanocomplexes and their applications in T2-weighted magnetic resonance/upconversion luminescence imaging and photodynamic therapy of cancer cells

Due to non-invasive deep imaging and therapy, multifunctional agents of magnetic resonance (MR)/upconversion luminescence (UCL) imaging and photodynamic therapy (PDT) play an important role in clinical diagnosis and treatment of cancers, and also in the assessment of therapy effect. In this paper, tetra-sulfonic phthalocyanine aluminium (AlPcS4) photosensitizers-conjugated Fe3O4@NaYF4:Yb/Er (NPs-AlPcS4) nanocomplexes were synthesized for the T2-weighted MR/UCL imaging and PDT of cancer cells. The PEG-coated Fe3O4@NaYF4:Yb/Er nanoparticles (NPs) with a core–shell structure showed strong T2-weighted MR relaxivity (r2 = 42.131 mM−1 s−1) and UCL emission in the visible region (the bands at about 654–674 nm, 545 nm and 524 nm), and were conjugated successfully with AlPcS4 photosensitizer by electrostatic interaction. By direct observation of XFM and staining with Prussian blue, the element distribution and location of NPs in MCF-7 cells were characterized, respectively. Under irradiation from a 980 nm laser, the death ratio of MCF-7 cells incubated with NPs-AlPcS4 nanocomplexes could be up to about 70%. The results indicated that the as-prepared NPs-AlPcS4 nanocomplexes would be a potential candidate as multifunctional nanoprobes for the dual-modal T2-weighted MR/UCL imaging and PDT of cancers in the future.

Silica-coated super-paramagnetic iron oxide nanoparticles (SPIONPs): a new type contrast agent of T1 magnetic resonance imaging (MRI)

Magnetic resonance imaging (MRI), a sophisticated promising three-dimensional tomographic noninvasive diagnostic technique, has an intrinsic advantage in safety compared with radiotracer and optical imaging modalities; however, MRI contrast agents are less sensitive than complexes used in other imaging techniques. Usually the clinically used Gd-based complexes MRI-T1 contrast agents are toxic; therefore, the demand for nontoxic novel T1-weighted MRI candidates with ultrasensitive imaging and advanced functionality is very high. In this research, silica-coated ultra-small monodispersed super-paramagnetic iron oxide nanoparticles were synthesized via a thermal decomposition method, which demonstrated themselves as a high performance T1-weighted MRI contrast agent for heart, liver, kidney and bladder based on in vivo imaging analyses. Transmission electron microscopy (TEM) results illustrated that the diameter of the SPIONPs was in the range of 4 nm and the average size of Fe3O4@SiO2 was about 30-40 nm. X-ray diffraction (XRD) and Raman spectroscopy analyses revealed the phase purity of the prepared SPIONPs. These magnetite nanoparticles exhibited a weak magnetic moment at room temperature because of the spin-canting effect, which promoted a high positive signal enhancement ability. MTT assays and histological analysis demonstrated good biocompatibility of the SPIONPs in vitro and in vivo. In addition, the silica-coated ultra-small (4 nm sized) magnetite nanoparticles exhibited a good r1 relaxivity of 1.2 mM-1 s-1 and a low r2/r1 ratio of 6.5 mM-1 s-1. In vivo T1-weighted MR imaging of heart, liver, kidney and bladder in mice after intravenous injection of nanoparticles further verified the high sensitivity and biocompatibility of the as-synthesized magnetite nanoparticles. These results reveal silica-coated SPIONPs as a promising candidate for a T1 contrast agent with extraordinary capability to enhance MR images.

Biocompatible composite nanoparticles with large longitudinal relaxivity for targeted imaging and early diagnosis of cancer

Early diagnosis of cancer greatly increases the chances of successful treatment by radical resection. The sensitivity of magnetic resonance imaging (MRI) techniques for detecting early stage tumors can be increased with the assistance of a positive MRI contrast agent. However, the traditional positive MRI contrast agents, such as Gd-chelates and Gd-based inorganic nanoparticles, are often limited by their cytotoxicity and low specificity. Here, we propose a new design of MRI contrast agent based on gadolinium oxide nanocrystals (GON) for targeted imaging and cancer early diagnosis with good biocompatibility. The GON were prepared using a polyol method and then encapsulated into albumin nanoparticles (AN), which were cross-linked with glutaraldehyde and found to exhibit bright and stable autofluorescence without conjugation to any fluorescent agent. After that, a target molecule, folic acid (FA), was conjugated onto the surface of the GON-loaded AN (GON-AN) to construct a GON-AN-FA composite. The as-prepared nanoparticles are biocompatible and stable in serum. The results of MRI relaxation studies show that the longitudinal relaxivities (r1) of GON-AN (11.6 mM-1 s-1) and GON-AN-FA (10.8 mM-1 s-1) are much larger than those of traditional positive MRI contrast agents, such as Magnevist (3.8 mM-1 s-1). The results of cell viability assays indicate that GON-AN and GON-AN-FA are almost non-cytotoxic. Furthermore, the specificities of GON-AN and GON-AN-FA were evaluated with two kinds of cancer cells which overexpress folate receptor alpha (FRα). The results reinforce that the autofluorescent GON-AN-FA is able to target cancer cells via recognition of the ligand FA and the receptor FRα. Therefore, our autofluorescent GON-AN-FA possessing a large longitudinal relaxivity and good biocompatibility represents a significant advance for the targeted imaging and early diagnosis of cancer.

Enhanced doxorubicin transport to multidrug resistant breast cancer cells via TiO2 nanocarriers

In order to overcome the multidrug resistance of breast cancer cells, doxorubicin was loaded onto TiO2 nanoparticles in which the electrostatic interactions hold the drug and the nanoparticles together. The anticancer activity of this nanocomposite was evaluated in multidrug resistant breast cancer cells. In nanocomposite treated MCF-7/ADM cells, drug accumulation increased with enhanced anticancer activity about 2.4 times compared to that of doxorubicin alone. The potential mechanism of enhanced drug accumulation is ascribed to the fact that the nanocomposite directly transports the drugs into cells via internalization, bypassing the P-glycoprotein mediated doxorubicin pumping system. Our results reinforce that the nanocomposite, as a pH controlled drug release system, could be used to overcome multidrug resistance of human breast cancer cells.

Neuropeptide Y Y1 receptors meditate targeted delivery of anticancer drug with encapsulated nanoparticles to breast cancer cells with high selectivity and its potential for breast cancer therapy.

By enabling nanoparticle-based drug delivery system to actively target cancer cells with high selectivity, active targeted molecules have attracted great attention in the application of nanoparticles for anticancer drug delivery. However, the clinical application of most active targeted molecules in breast cancer therapy is limited, due to the low expression of their receptors in breast tumors or coexpression in the normal and tumor breast tissues. Here, a neuropeptide Y Y1 receptors ligand PNBL-NPY, as a novel targeted molecule, is conjugated with anticancer drug doxorubicin encapsulating albumin nanoparticles to investigate the effect of Y1 receptors on the delivery of drug-loaded nanoparticles to breast cancer cells and its potential for breast cancer therapy. The PNBL-NPY can actively recognize and bind to the Y1 receptors that are significantly overexpressed on the surface of the breast cancer cells, and the drug-loaded nanoparticles are delivered directly into the cancer cells through internalization. This system is highly selective and able to distinguish the breast cancer cells from the normal cells, due to normal breast cells that express Y2 receptors only. It is anticipated that this study may provide a guidance in the development of Y1 receptor-based nanoparticulate drug delivery system for a safer and more efficient breast cancer therapy.

Improved double emulsion technology for fabricating autofluorescent microcapsules as novel ultrasonic/fluorescent dual-modality contrast agents

The aim of this study is to explore an improved double emulsion technology with in situ reaction of lysine (Lys) and glutaraldehyde (GA) for fabricating autofluorescent Lys-poly(lactic-co-glycolic acid)-GA (Lys-PLGA-GA) microcapsules as novel ultrasonic/fluorescent dual-modality contrast agents. Scanning electron microscope (SEM) and static light scattering (SLS) results show that 80% of the Lys-PLGA-GA microcapsules are larger than 1.0 μm and 90% of them are smaller than 8.9 μm. SEM and laser confocal scanning microscope (LCSM) data demonstrate that the structure of our Lys-PLGA-GA microcapsules is hollow. Compared with the FT-IR spectrum of PLGA microcapsules, a new peak at 1,644 cm(-1) in that of Lys-PLGA-GA microcapsules confirms the formed Schiff base in Lys-PLGA-GA microcapsules. LCSM images and fluorescence spectra show that our Lys-PLGA-GA microcapsules exhibit bright and stable autofluorescence without conjugation to any fluorescent agent, which can be ascribed to the n-π transitions of the CN bonds in the formed Schiff base. Our autofluorescent Lys-PLGA-GA microcapsules might have more wide applications than traditional fluorescent dyes because their excitation and emission spectra are both broad. The fluorescence intensity can also be tuned by the feeding amount of Lys and GA. The MTT assays reveal that the autofluorescent microcapsules are biocompatible. The results of fluorescent imaging in cells and in vitro ultrasonic imaging demonstrate the feasibility of our autofluorescent Lys-PLGA-GA microcapsules as ultrasonic/fluorescent dual-modality contrast agents. This novel ultrasonic/fluorescent dual-modality contrast agent might have potential for a variety of biological and medical applications.

A Ultrasensitive Near‐Infrared Fluorescent Probe Reveals Pyroglutamate Aminopeptidase 1 Can Be a New Inflammatory Cytokine

Abstract Previous study showed that pyroglutamate aminopeptidase 1 (PGP‐1) has a relationship with the immune response in cells. However, whether PGP‐1 is involved in inflammatory response in vivo and can serve as a new inflammatory cytokine are still unclear. To address these issues, a new near‐infrared fluorescent probe, which exhibits high selectivity and super sensitivity, is developed. With this probe, the up‐regulation of PGP‐1 (evidenced by western blot) in BALB/c mice legs and livers under the stimulation of two main immunopotentiators is revealed for the first time. The occurrence of inflammatory process (including tissue necrosis) in mice is determined by up‐regulation of tumor necrosis factor‐α and hematoxylin‐eosin staining. Interestingly, it is revealed for the first time that knocking down PGP‐1 leads to the weakness of inflammatory process in RAW264.7 cells. These new findings suggest that PGP‐1 is indeed involved in inflammatory response in vivo and can be a new inflammatory cytokine.

A novel fibroblast activation protein-targeted near-infrared fluorescent off–on probe for cancer cell detection, in vitro and in vivo imaging

A new hemicyanine-based fibroblast activation protein-targeted near-infrared fluorescent probe is designed and it shows high selectivity and sensitivity to cancer cell detection, and in vitro and in vivo imaging. This probe is successfully applied in fluorescence detection of living cells (with a detection limit of 1500 cells per mL). It is believed that many new functions or distributions of FAP could be discovered by this new probe later.

A Flexible Caterpillar-Like Gold Nanoparticle Assemblies with Ultrasmall Nanogaps for Enhanced Dual-Modal Imaging and Photothermal Therapy

Gold nanoparticle (AuNP) assemblies (GNAs) have attracted attention since enhanced coupling plasmonic resonance (CPR) emerged in the nanogap between coupling AuNPs. For one dimensional GNAs (1D-GNAs), most CPR from the nanogaps could be easily activated by electromagnetic waves and generate drastically enhanced CPR because the nanogaps between coupling AuNPs are linearly distributed in the 1D-GNAs. The reported studies focus on the synthesis of 1D-GNAs and fundamental exploration of CPR. There are still problems which impede further applications in nanomedicine, such as big size (>500 nm), poor water solubility, and/or poor stability. In this study, a kind of 1D flexible caterpillar-like GNAs (CL-GNAs) with ultrasmall nanogaps, good water solubility, and good stability is developed. The CL-GNAs have a flexible structure that can randomly move to change their morphology, which is rarely reported. Numerous ultrasmall nanogaps (<1 nm) are linearly distributed along the structure of CL-GNAs and generate enhanced CPR. The toxicity assessments in vitro and vivo respectively demonstrate that CL-GNAs have a low cytotoxicity and good biocompatibility. The CL-GNAs can be used as an efficient photothermal agent for photothermal therapy, a probe for Raman imaging and photothermal imaging.