Multifunctional reduction-responsive SPIO&DOX-loaded PEGylated polymeric lipid vesicles for magnetic resonance imaging-guided drug delivery.

Multifunctional superparamagnetic iron-oxide (SPIO)-based nanoparticles have been emerging as candidate nanosystems for cancer diagnosis and therapy. Here, we report the use of reduction- responsive SPIO/doxorubicin (DOX)-loaded poly(ethylene glycol) monomethyl ether (PEG)ylated polymeric lipid vesicles (SPIO&DOX-PPLVs) as a novel theranostic system for tumor magnetic resonance imaging (MRI) diagnosis and controlled drug delivery. These SPIO&DOX-PPLVs are composed of SPIOs that function as MR contrast agents for tumor enhancement and PPLVs as polymer matrices for encapsulating SPIO and antitumor drugs. The in vitro characterizations show that the SPIO&DOX-PPLVs have nanosized structures (∼80 nm), excellent colloidal stability, good biocompatibility, as well as T2-weighted MRI capability with a relatively high T2 relaxivity (r2 = 213.82 mM(-1) s(-1)). In vitro drug release studies reveal that the release rate of DOX from the SPIO&DOX-PPLVs is accelerated in the reduction environment. An in vitro cellular uptake study and an antitumor study show that the SPIO&DOX-PPLVs have magnetic targeting properties and effective antitumor activity. In vivo studies show the SPIO&DOX-PPLVs have excellent T2-weighted tumor targeted MRI capability, image-guided drug delivery capability, and high antitumor effects. These results suggest that the SPIO&DOX-PPLVs are promising nanocarriers for MRI diagnosis and cancer therapy applications.

Upconverting rare-earth nanoparticles with a paramagnetic lanthanide complex shell for upconversion fluorescent and magnetic resonance dual-modality imaging.

Multi-modal imaging based on multifunctional nanoparticles is a promising alternative approach to improve the sensitivity of early cancer diagnosis. In this study, highly upconverting fluorescence and strong relaxivity rare-earth nanoparticles coated with paramagnetic lanthanide complex shells and polyethylene glycol (PEGylated UCNPs@DTPA-Gd(3+)) are synthesized as dual-modality imaging contrast agents (CAs) for upconverting fluorescent and magnetic resonance dual-modality imaging. PEGylated UCNPs@DTPA-Gd(3+) with sizes in the range of 32-86 nm are colloidally stable. They exhibit higher longitudinal relaxivity and transverse relaxivity in water (r1 and r2 values are 7.4 and 27.8 s(-1) per mM Gd(3+), respectively) than does commercial Gd-DTPA (r1 and r2 values of 3.7 and 4.6 s(-1) per mM Gd(3+), respectively). They are found to be biocompatible. In vitro cancer cell imaging shows good imaging contrast of PEGylated UCNPs@DTPA-Gd(3+). In vivo upconversion fluorescent imaging and T1-weighted MRI show excellent enhancement of both fluorescent and MR signals in the livers of mice administered PEGylated UCNPs@DTPA-Gd(3+). All the experimental results indicate that the synthesized PEGylated UCNPs@DTPA-Gd(3+) present great potential for biomedical upconversion of fluorescent and magnetic resonance dual-modality imaging applications.

Salt-leached silk scaffolds with tunable mechanical properties.

Substrate mechanical properties have remarkable influences on cell behavior and tissue regeneration. Although salt-leached silk scaffolds have been used in tissue engineering, applications in softer tissue regeneration can be encumbered with excessive stiffness. In the present study, silk-bound water interactions were regulated by controlling processing to allow the preparation of salt-leached porous scaffolds with tunable mechanical properties. Increasing silk-bound water interactions resulted in reduced silk II (ß-sheet crystal) formation during salt-leaching, which resulted in a modulus decrease in the scaffolds. The microstructures as well as degradation behavior were also changed, implying that this water control and salt-leaching approach can be used to achieve tunable mechanical properties. Considering the utility of silk in various fields of biomedicine, the results point to a new approach to generate silk scaffolds with controllable properties to better mimic soft tissues by combining scaffold preparation methods and silk self-assembly in aqueous solutions.

Green Synthesis of Sub-10 nm Gadolinium-Based Nanoparticles for Sparkling Kidneys, Tumor, and Angiogenesis of Tumor-Bearing Mice in Magnetic Resonance Imaging.

Gadolinium (Gd)-based nanoparticles are known for their high potential in magnetic resonance imaging (MRI). However, further MRI applications of these nanoparticles are hampered by their relatively large sizes resulting in poor organ/tumor targeting. In this study, ultrafine sub-10 nm and biocompatible Gd-based nanoparticles are synthesized in a bioinspired, environmentally benign, and straightforward fashion. This novel green synthetic strategy is developed for growing dextran-coated Gd-based nanoparticles (GdNPs@Dex). The as-prepared GdNPs@Dex is not only biocompatible but also stable with a sub-10 nm size. It exhibits higher longitudinal and transverse relaxivities in water (r1 and r2 values of 5.43 and 7.502 s-1 × 10-3 m-1 of Gd3+ , respectively) than those measured for Gd-DTPA solution (r1 and r2 values of 3.42 and 3.86 s-1 × 10-3 m-1 of Gd3+ , respectively). In vivo dynamic T1 -weighted MRI in tumor-bearing mice shows GdNPs@Dex can selectively target kidneys and tumor, in addition to liver and spleen. GdNPs@Dex is found particularly capable for determining the tumor boundary with clearly enhanced tumor angiogenesis. GdNPs@Dex is also found cleared from body gradually mainly via hepatobiliary and renal processing with no obvious systemic toxicity. With this green synthesis strategy, the sub-10 nm GdNPs@Dex presents promising potentials for translational biomedical imaging applications.

pH- and NIR light responsive nanocarriers for combination treatment of chemotherapy and photodynamic therapy.

The side effects of antitumor drugs and low treatment efficacy are two major challenges of current chemotherapy. To address these issues, we developed a new kind of smart nanocarriers that combine pH-responsive chemotherapy and near-infrared (NIR) light triggered photodynamic therapy. These nanocarriers were based on upconversion nanoparticle (UCN)-loaded folate-conjugated polymeric lipid vesicles (UFPLVs). Merocyanine 540 (MC540), as a photosensitizer, was loaded in the UFPLVs; doxorubicin hydrochloride (DOX), as an antitumor drug, was conjugated to the surfaces of UFPLVs by pH-sensitive hydrazone bonds. The newly developed MC540&DOX-UFPLVs had a nanosized structure with targeting ligand modification, so they had the potential to accumulate into tumor sites via a combination of passive and active targeting effects. An in vitro singlet oxygen test showed that the nanocarriers can generate cytotoxic singlet oxygen successfully under the irradiation of NIR light. In vitro DOX release profiles demonstrated that the nanocarriers can achieve a pH-triggered drug release. It has been demonstrated by a cellular uptake study that the nanocarriers can efficiently deliver drugs and photosensitizers into tumor cells. In vitro and in vivo combination treatments evidenced the high antitumor effects of MC540&DOX-UFPLVs under NIR light irradiation. These results suggest that the MC540&DOX-UFPLVs may be promising nanocarriers for tumor combination therapy applications.

Facile Synthesis of Gd-Cu-In-S/ZnS Bimodal Quantum Dots with Optimized Properties for Tumor Targeted Fluorescence/MR In Vivo Imaging.

Dual-modal imaging techniques have gained intense attention for their potential role in the dawning era of tumor early accurate diagnosis. Chelate-free robust dual-modal imaging nanoprobes with high efficiency and low toxicity are of essential importance for tumor targeted dual-modal in vivo imaging. It is still a crucial issue to endow Cd-free dual-modal nanoprobes with bright fluorescence as well as high relaxivity. Herein, a facile synthetic strategy was developed to prepare Gd-doped CuInS/ZnS bimodal quantum dots (GCIS/ZnS, BQDs) with optimized properties. The fluorescent properties of the GCIS/ZnS BQDs can be thoroughly optimized by varying reaction temperature, aging time, and ZnS coating. The amount of Gd precursor can be well-controlled to realize the optimized balance between the MR relaxivity and optical properties. The obtained hydrophobic GCIS/ZnS BQDs were surface engineered into aqueous phase with PEGylated dextran-stearyl acid polymeric lipid vesicles (PEG-DS PLVs). Upon the phase transfer, the hydrophilic GCIS/ZnS@PLVs exhibited pronounced near-infrared fluorescence as well as high longitudinal relaxivity (r1 = 9.45 mM(-1) S(-1)) in water with good colloidal stability. In vivo tumor-bearing animal experiments further verified GCIS/ZnS@PLVs could achieve tumor-targeted MR/fluorescence dual-modal imaging. No toxicity was observed in the in vivo and ex vivo experiments. The GCIS/ZnS@PLVs present great potential as bimodal imaging contrast agents for tumor diagnosis.

One-pot facile synthesis of PEGylated superparamagnetic iron oxide nanoparticles for MRI contrast enhancement.

Polyethylene glycol (PEG)-coated superparamagnetic iron oxide nanoparticles (PEG·SPIONs) were prepared by a facile one-pot approach. The synthesized PEG·SPIONs were found to be uniform in size with an average hydrodynamic diameter of 11.7 nm. PEG·SPIONs exhibited excellent dispersibility in water, colloidal stability, and biocompatibility. The magnetic resonance imaging (MRI) properties of PEG·SPIONs were characterized both in vitro and in vivo. The dual contrast both in T1 and T2-weighted imaging was well enhanced with longitudinal and transverse relaxivity (r1, r2) of 35.92 s(-1) per mM of Fe(3+) and 206.91 s(-1) per mM of Fe(3+) respectively. In vivo T2-weighted MRI shows pronounced enhancement in the liver and spleen but not in T1-weighted MRI. Accumulations of nanoparticles were found primarily in the liver, spleen, and intestine, while much lower uptake in the kidney, heart, and lungs. A gradual excretion of PEG·SPIONs was observed via hepatobiliary (HB) processing over a period of 14 days. The toxicity of PEG·SPIONs was also evaluated in vitro and in vivo. PEG·SPIONs were found to be biocompatible by investigating organ tissues after hematoxylin-eosin staining. The conclusion of the study indicates a high potential of PEG·SPIONs in medical MRI.

Synthesis of Zn-Cu-In-S/ZnS core/shell quantum dots with inhibited blue-shift photoluminescence and applications for tumor targeted bioimaging.

A facile strategy is reported here for synthesis of Zn-Cu-In-S/ZnS (ZCIS/ZnS) core/shell QDs to address the synthetic issues that the unexpected blue-shift of CuInS(2)-based nanocrystals. In this strategy, Zn(2+) ions are intentionally employed for the synthesis of alloyed ZCIS core QDs before ZnS shell coating, which contributes to the reduced blue-shift in photoluminescence (PL) emission. The experimental results demonstrate this elaborate facile strategy is effective for the reduction of blue-shift during shell growth. Particularly, a hypothesis is proposed and proved for explanation of this effective strategy. Namely, both cation exchange inhibition and ions accumulation are involved during the synthesis of ZCIS/ZnS QDs. Furthermore, the obtained near infrared (NIR) ZCIS/ZnS QDs are transferred into aqueous phase by a polymer coating technique and coupled with cyclic Arg-Gly-Asp peptide (cRGD) peptides. After confirmation of biocompability by cytotoxicity test on normal 3T3 cells, these QDs are injected via tail vein into nude mice bearing U87 MG tumor. The result indicates that the signals detected in the tumor region are much more distinguishing injected with ZCIS/ZnS-cRGD QDs than that injected with ZCIS/ZnS QDs.

[On-chip magnetic separation of microcantilever immunosensor based on the CdSe QDs-tagged magnetic microbead].

We designed a novel microcantilever immuosensor based on magnetic microbead, applying different-sized CdSe QDs as fluorescent probes and polystyrene magnetic microbead. The novel microcantilever immuosensor used fluorescent probes embedded polystyrene microbeads and specific antibodies on the surface of the polystyrene microbead. In addition, we studied the mechanism of the on-chip magnetic separation, the structure of micro-electromagnet and the microbead magnetization by the micro-magnetic field, the snake-shaped planar micro-electromagnet for the novel microcantilever immuosensor.