Shun Shen

Targeting mesoporous silica-encapsulated gold nanorods for chemo-photothermal therapy with near-infrared radiation

Mesoporous silica-encapsulated gold nanorods (GNRs@mSiO(2)) have great potential both in photothermal therapy and drug delivery. In this paper, we firstly developed GNRs@mSiO(2) as a synergistic therapy tool for delivery heat and drug to the tumorigenic region. We studied the ablation of tumor both in vitro and in vivo by the combination of photothermal therapy and chemotherapy using doxorubicin (DOX)-loaded GNRs@mSiO(2). Significantly greater cell killing was observed when A549 cells incubated with DOX-loaded GNRs@mSiO(2) were irradiated with near-infrared (NIR) illumination, attributable to both GNRs@mSiO(2)-mediated photothermal ablation and cytotoxicity of light-triggered DOX release. We then performed in vivo therapy studies and observed a promising tumor treatment. Compared with chemotherapy or photothermal treatment alone, the combined treatment showed a synergistic effect, resulting in higher therapeutic efficacy. Furthermore, the lower systematic toxicity of GNRs@mSiO(2) has been validated.

The targeted delivery of anticancer drugs to brain glioma by PEGylated oxidized multi-walled carbon nanotubes modified with angiopep-2

In this study, a dual-targeting drug delivery system based on PEGylated oxidized multi-walled carbon nanotubes (O-MWNTs) modified with angiopep-2 (O-MWNTs-PEG-ANG) was successfully developed for treatment of brain glioma. O-MWNTs can not only distribute in brains but also accumulate in tumors, and have ultrahigh surface area with remarkably high loading anticancer drug of doxorubicin (DOX), which was selected as drug carrier. Angiopep-2 can specifically combine to the low-density lipoprotein receptor-related protein (LRP) receptor overexpressed on the blood-brain barrier (BBB) and glioma cells, which was selected as targeting ligand. The cooperative dual-targeting to brain glioma by O-MWNTs-PEG-ANG was evaluated by intracellular tracking in vitro and fluorescence imaging in vivo, which demonstrated that the combination of O-MWNTs-PEG and angiopep-2 constituted an ideal dual-targeting drug delivery system. The anti-glioma effect of DOX-loaded O-MWNTs-PEG-ANG (DOX-O-MWNTs-PEG-ANG) was assessed by C6 cytotoxicity and median survival time of glioma bearing mice, which showed a better anti-glioma effect than DOX. The biological safety of O-MWNTs-PEG-ANG was evaluated by BCEC and C6 cytotoxicity, hematology analysis and CD68 immunohistochemical analysis, which proved O-MWNTs-PEG-ANG was good biocompatibility and low toxicity. The biological safety of DOX-O-MWNTs-PEG-ANG was evaluated by histopathological analysis, which suggested a lower cardiac toxicity than DOX. In conclusion, O-MWNTs-PEG-ANG is a promising dual-targeting carrier to deliver DOX for the treatment of brain tumor.

Synthesis of discrete and dispersible hollow mesoporous silica nanoparticles with tailored shell thickness for controlled drug release

By employing poly (tert-butylacrylate) (PTBA) nanospheres as the dissolvable core templates, we develop a new method to synthesize hollow mesoporous silica nanoparticles (HMSN). Both the PTBA core and the structure-directing surfactant, cetyltrimethylammonium bromide (CTAB), can be easily and synchronously removed through solvent extraction in ethanol, which ensures the complete structure and ideal dispersibility of the products compared with the previous template synthesis that often needs calcination to remove the templates. Given that hollow core diameter and shell thickness are the key properties of HMSN, the hollow core diameter and shell thickness can be tailored precisely. In addition, as novel inorganic nanomaterials with a tuned structure, HMSN show notable biocompatibility and efficient doxorubicin (DOX) loading. In in vitro tests, the release rate of DOX-loaded HMSN exhibit a surprising shell-thickness-dependent and a pH responsive drug release character, suggesting that HMSN are a very promising drug delivery system for shell-thickness-controlled drug release. The results of intracellular tracking and cytotoxicity assays further demonstrate the potential and efficiency of HMSN as a drug delivery system.

Magnetic graphene-based nanotheranostic agent for dual-modality mapping guided photothermal therapy in regional lymph nodal metastasis of pancreatic cancer

Although regional lymph nodes (RLN) dissection remains the only way to cure pancreatic cancer metastasis, it is unavoidably associated with sizable trauma, multiple complications, and low surgical resection rates. Thus, exploring a treatment approach for the ablation of drug-resistant pancreatic cancer is always of great concern. Moreover, reoperative and intraoperative mapping of RLN is also important during treatment, because only a few lymph nodes can be detected by the naked eye. In our study, graphene oxides modified with iron oxide nanoparticles (GO-IONP) as a nanotheranostic agent is firstly developed to diagnose and treat RLN metastasis of pancreatic cancer. The approach was designed based on clinical practice, the GO-IONP agent directly injected into the tumor was transported to RLN via lymphatic vessels. Compared to commercial carbon nanoparticles currently used in the clinic operation, the GO-IONP showed powerful ability of dual-modality mapping of regional lymphatic system by magnetic resonance imaging (MRI), as well as dark color of the agent providing valuable information that was instrumental for surgeon in making the preoperative plan before operation and intraoperatively distinguish RLN from surrounding tissue. Under the guidance of dual-modality mapping, we further demonstrated that metastatic lymph nodes including abdominal nodes could be effectively ablated by near-infrared (NIR) irradiation with an incision operation. The lower systematic toxicity of GO-IONP and satisfying safety of photothermal therapy (PTT) to neighbor tissues have also been clearly illustrated in our animal experiments. Using GO-IONP as a nanotheranostic agent presents an approach for mapping and photothermal ablation of RLN, the later may serve as an alternative to lymph node dissection by invasive surgery.

Gold nanorods@mSiO2 with a smart polymer shell responsive to heat/near-infrared light for chemo-photothermal therapy

Novel composite nanoparticles based on poly(N-isopropylacrylamide-co-N-hydroxymethyl acrylamide) (P(NIPAM-co-NHMA)) layer coated gold nanorod@mesoporous silica (GNR@mSiO2) has been successfully synthesized by precipitation polymerization. The composite nanoparticles exhibited a thermo/near-infrared (NIR) light sensitivity. The volume phase transition temperature (VPTT) could be precisely regulated by the content of NHMA in monomers and an excellent photothermal conversion effect was expressed due to the surface plasmon resonance of gold nanorods in the composite nanoparticles. Doxorubicin hydrochloride (DOX) was applied as a model drug and the drug storage/release behavior was investigated. The results demonstrated that DOX could be effectively loaded into the composite nanoparticles with 21% loading capacity. The cumulative release of DOX-loaded composite nanoparticles was temperature dependent and the release rate was significantly enhanced above the VPTT. Therefore, the composite nanoparticles applied as a drug delivery system could reduce the side effect of DOX to normal tissues as only a small fraction of DOX was released from the composite nanoparticles at 37 °C. In addition, the DOX-loaded composite nanoparticles demonstrated a synergistic effect, the therapeutic efficacy was improved significantly by the combination of photothermal therapy and traditional chemotherapy with low composite nanoparticle concentration and short laser irradiation time in an in vitro study.

Targeting fibronectins of glioma extracellular matrix by CLT1 peptide-conjugated nanoparticles.

The abundant extracellular matrix (ECM) in the glioma microenvironment play a critical role in the maintenance of glioma morphology, glioma cells differentiation and proliferation, but little has been done to understand the feasibility of ECM as the therapeutic target for glioma therapy. In this study, a drug delivery system targeting fibronectins (FNs), a prevailing component in the ECM of many solid tumors, was constructed for glioma therapy based on the interaction between the abundant FNs in glioma tissues and the FNs-targeting moiety CLT1 peptide. CLT1 peptide was successfully conjugated to PEG-PLA nanoparticles (CNP). FNs were demonstrated to be highly expressed in the ECM of glioma spheroids in vitro and glioma tissues in vivo. CLT1 modification favored targeting nanoparticles penetration into the core of glioma spheroids and consequently induced more severe inhibitive effects on glioma spheroids growth than traditional NP. In vivo imaging, ex vivo imaging and glioma tissue slides showed that CNP enhanced nanoparticles retention in glioma site, distributed more extensively and more deeply into glioma tissues than that of conventional NP, and mainly located in glioma cells rather than in extracellular matrix as conventional NP. Pharmacodynamics outcomes revealed that the median survival time of glioma-bearing mice models treated with paclitaxel-loaded CNP (CNP-PTX) was significantly prolonged when compared with that of any other group. TUNEL assay demonstrated that more extensive cell apoptosis was induced by CNP-PTX treatment compared with other treatments. Altogether, these promising results indicated that this ECM-targeting drug delivery system enhanced retention and glioma cell uptake of nanoparticles and might have a great potential for glioma therapy in clinical applications.

Polydopamine-Coated Magnetic Composite Particles with an Enhanced Photothermal Effect

Recently, photothermal therapy (PTT) that utilizes photothermal conversion (PTC) agents to ablate cancer under near-infrared (NIR) irradiation has attracted a growing amount of attention because of its excellent therapeutic efficacy and improved target selectivity. Therefore, exploring novel PTC agents with an outstanding photothermal effect is a current research focus. Herein, we reported a polydopamine-coated magnetic composite particle with an enhanced PTC effect, which was synthesized simply through coating polydopamine (PDA) on the surface of magnetic Fe3O4 particles. Compared with magnetic Fe3O4 particles and PDA nanospheres, the core-shell nanomaterials exhibited an increased NIR absorption, and thus, an enhanced photothermal effect was obtained. We demonstrated the in vitro and in vivo effects of the photothermal therapy using our composite particles and their ability as a contrast agent in the T2-weighted magnetic resonance imaging. These results indicated that the multifunctional composite particles with enhanced photothermal effect are superior to magnetic Fe3O4 particles and PDA nanospheres alone.

Development of superparamagnetic high-magnetization C18-functionalized magnetic silica nanoparticles as sorbents for enrichment and determination of methylprednisolone in rat plasma by high performance liquid chromatography

In this study, a novel extraction and enrichment technique based on superparamagnetic high-magnetization C(18)-functionalized magnetic silica nanoparticles (C(18)-MNPs) as sorbents was successfully developed for the determination of methylprednisolone (MP) in rat plasma by high performance liquid chromatography (HPLC). The synthesized silica-coated magnetite modified with chlorodimethyl-n-octadecylsilane was about 320 nm in diameter with strong magnetism and high surface area. It provided an efficient way for extraction and concentration of MP in the samples through hydrophobic interaction by the interior C(18) groups. Moreover, MP adsorbed with C(18)-MNPs could be simply and rapidly isolated through placing a strong magnet on the bottom of container, and then easily eluted from C(18)-MNPs by n-hexane solution. Extraction conditions such as amounts of C(18)-MNPs added, adsorption time and desorption solvent, were investigated. Method validations including linear range, detection limit, precision, and recovery were also studied. The results showed that the proposed method based on C(18)-MNPs was a simple, accurate and high efficient approach for the analysis of MP in the complex plasma samples.

EGFP-EGF1-conjugated nanoparticles for targeting both neovascular and glioma cells in therapy of brain glioma.

As neovascular and glioma cells were closely associated and might be mutually promoted in glioma growth, a dual-targeting strategy targeting to both neovascular and glioma cells would be more promising as compared with those targeting one of them. In this study, we reported a drug delivery system where nanoparticles were decorated with EGFP-EGF1 (ENP), a fusion protein derived from factor VII with special affinity for tissue factor (TF) over-expressed in glioma tissues, to facilitate anti-glioma delivery of paclitaxel (PTX) by targeting both neovascular and glioma cells. In vitro protein binding assay demonstrated that EGFP-EGF1 bound well to C6 cells and perturbed human umbilical vein endothelial cells (HUVEC) with a concentration-dependent manner but not to unperturbed HUVEC. EGFP-EGF1-TF interaction significantly enhanced nanoparticles uptake by perturbed HUVEC and glioma C6 cells as well as nanoparticles penetration in C6 glioma spheroids, and thus improved the cytotoxicity of their payload in both monolayer cells and glioma spheroids models. In vivo imaging of glioma-bearing mice demonstrated the specific accumulation of ENP in glioma tissues. In vivo distribution of nanoparticles intuitively showed ENP mainly sited in both extravascular glioma cells and neovascular cells. Pharmacodynamic results revealed that PTX-loaded ENP (ENP-PTX) significantly prolonged the median survival time of glioma-bearing mice compared with that of any other group. TUNEL assay and H&E staining showed that ENP-PTX treatment induced significantly more cell apoptosis and tumor necrosis compared with other treatments. In conclusion, the results of this contribution demonstrated the great potential of EGFP-EGF1-functionalized nanoparticles for dual-targeting therapy of brain glioma.

Magnetic solid-phase extraction and determination of puerarin in rat plasma using C18-functionalized magnetic silica nanoparticles by high performance liquid chromatography

In the paper, we presented a magnetic solid-phase extraction (MSPE) method based on C(18)-functionalized magnetic silica nanoparticles for the analysis of puerarin in rat plasma. The approach involves two steps including synthesis of magnetic solid-phase sorbents and bioanalysis. The synthesized magnetic silica microspheres modified with chloro(dimethyl)octylsilane (namely Fe(3)O(4)@SiO(2)-C(18)) can provide an efficient way for the extraction of puerarin through C(18) hydrophobic interaction. The puerarin could be easily enriched using milligram-level Fe(3)O(4)@SiO(2)-C(18) sorbents with vibration for 10min. By means of a magnet, puerarin adsorbed with Fe(3)O(4)@SiO(2)-C(18) sorbents was easily isolated from the matrix, and desorbed with CAN. No carryover was observed, and the sorbents could be recycled in our study. The method recoveries were obtained from 85.2% to 92.3%. Limits of quantification and limits of detection of 0.1μgmL(-1) and 0.05μgmL(-1), respectively were achieved. The precision was from 8.1 to 13.7% for intra-day measurement, and from 9.4 to 15.2% for inter-day variation. The accuracy ranged from 94.7 to 106.3% for intra-day measurement, and from 93.3 to 107.8% for inter-day measurement. The MSPE method was applied for analysis of puerarin in rat plasma samples. The results indicated that it was convenient and efficient for the determination of puerarin in biosamples.