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Silicon particles have garnered attention as promising biomedical probes for hyperpolarized 29Si magnetic resonance imaging and spectroscopy. However, due to the limited levels of hyperpolarization for nanosized silicon particles, microscale silicon particles have primarily been the focus of dynamic nuclear polarization (DNP) applications, including in vivo magnetic resonance imaging (MRI). To address these current challenges, we developed a facile synthetic method for partially 29Si-enriched porous silicon nanoparticles (NPs) (160 nm) and examined their usability in hyperpolarized 29Si MRI agents with enhanced signals in spectroscopy and imaging. Hyperpolarization characteristics, such as the build-up constant, the depolarization time (T1), and the overall enhancement of the 29Si-enriched silicon NPs (10 and 15%), were thoroughly investigated and compared with those of a naturally abundant NP (4.7%). During optimal DNP conditions, the 15% enriched silicon NPs showed more than 16-fold higher enhancements─far beyond the enrichment ratio─than the naturally abundant sample, further improving the signal-to-noise ratio in in vivo29Si MRI. The 29Si-enriched porous silicon NPs used in this work are potentially capable to serve as drug-delivery vehicles in addition to hyperpolarized 29Si in vivo, further enabling their potential future applicability as a theragnostic platform.

Herein, lipid-coated polyaniline (LiPAni) nanoparticles were fabricated to monitor the redox state of cancer cells. To confirm the characteristics of LiPAni, we firstly analyzed the size and chemical structures of the LiPAni nanoparticles. The absorbance properties of the LiPAni nanoparticles were observed to vary with the pH conditions. Furthermore, cell viability tests conducted with breast cancer cell lines showed that the cell viability of the cells with LiPAni nanoparticles was dramatically increased compared to those with the Tween80-coated polyaniline nanoparticles (TPAni) as a control. Subsequently, the colors of the LiPAni nanoparticles were observed and analyzed using spectroscopic methods. Finally, in order to investigate the more accurate sensing of the redox state using the color changes of the LiPAni nanoparticles with cancer cell lines, dark field microscopic images and scattering spectra were recorded at the single nanoparticle scale. For the TPAni nanoparticles, there was only a change in brightness and no change in color, but for the LiPAni nanoparticles, there was a change of color from yellow to pink in the dark field images.

We have successfully fabricated a nanocomposite, which is composed of polyaniline (PAni) and pyrene butyric acid (Pyba) via a solvent shift method, which was self-doped at a neutral pH value. This PAni nanocomposite can act as a fine nanoagent expressing absorbance, fluorescence, and Raman properties according to the surrounding pH values.

We propose that nanogels (HLGs) prepared by simply blending an epidermal growth factor (EGF)-loaded hyaluronan (HA)-based nanoformulation and poloxamers can be efficient transdermal drug carriers. In particular, due to the thermogelling behavior of poloxamer, when the HLGs, which are liquid at room temperature, are applied to the skin's surface, they form a gel at skin temperature. First, lipid-based nanoformulations (EGF-LNs) were fabricated by the lipid thin film method and then chemically conjugated with HA on the surface of the films to prepare EGF-loaded HA-based nanoformulations (EGF-HLNs). Both EGF-LNs and EGF-HLNs exhibited a uniform size and spherical lamellar structure. The EGF-HLN was added to a poloxamer solution to form EGF-HLG, which is a liquid at room temperature and a gel at skin temperature. HLGs have been shown to be able to deliver and permeate EGF well into the skin using both in vitro and in vivo systems, thus serving as an effective transdermal delivery system. In addition, it has been confirmed that this system could be a possible implantable drug carrier. Therefore, HLGs, which are uncomplicated and easily prepared, are expected to be easily used not only in the pharmaceutical field but also in the cosmetic field.

We report minimal amount of hyaluronic acid (HA) conjugated magnetic nanocrystals (mHMs) for targeted imaging of CD44 abundant breast cancer cells via MRI. These mHMs lead to less induced cancer migration and drug resistance, which is distinct from conventional approaches using nanoplatforms (imaging or therapeutic systems) that are completely covered with HA. To synthesize mHMs, magnetic nanocrystals (MNCs), as MRI contrast agents, were encapsulated mostly with polysorbate 80 (P80, non-reactive to HA) and partially with aminated P80 (reactive to HA). This system enabled conjugation of an immensely diminished amount of HA onto MNCs. While these nanoparticles maintained good CD44 targeted imaging efficacy, they also showed no cytotoxicity and colloidal stability. We varied the HA ratios on an equal amount of MNCs and identified that when more HA was attached on nanoparticles, there was more facilitated cancer migration and drug resistant potentials. We chose the lowest amount of HA conjugated mHMs (mHM1) and demonstrated that mHM1 selectively diagnosed tumor regions in vivo. We believe that the technique described herein can be applied to various applications using HA to detect CD44 abundant cancer cell lines and offer a basis to understand the interaction between the cellular response and surface modification of nanoparticles.

Real-time quantitative and qualitative analyses of metastasis-associated proteases are critical for precise diagnosis and novel therapeutic treatment of advanced cancers. However, conventional methods based on DNA, peptides, and proteins require sophisticated chemistry and additional processes to expose detection moieties, and they lack elements of temporal control, which limit their applicability. We designed unique protease-activatable polymersomes (PeptiSomes) for high sensitivity, in situ quantitative analysis of activating membrane-type 1 matrix metalloproteinases (MT1-MMP, MMP14). To do this, we first synthesized an amphiphilic block polymer–peptide and a copolypeptide based on mPEG-b-pLeu and MT1-peptide-b-pLeu, respectively. Amphiphilic self-assembled PeptiSomes in water were capable of disassembling and releasing the encapsulated self-quenched fluorescence dye (calcein) via enzymatic activation by MT1-MMP. Our PeptiSome system may potentially prevent the initiation and progression of cancer metastasis. Furthermore, the PeptiSome approach described here is likely to facilitate the development of rapid protease assay techniques and further extend the role of proteases as metastasis indicators and therapeutic targets.

Manganese oxide (MnO) nanocubes were fabricated and their surface were modified by ligand encapsulation or ligand exchange, to render them water-soluble. And then, MnO formed the hollow structure by etching using acidic solution (phthalate buffer, pH 4.0). Depending on the ligand of the MnO surface, it increases the interaction between MnO and water molecules. Also, the hollow structure of MnO, as well as the ligand, can greatly enhance the accessibility of water molecules to metal ions by surface area-to-volume ratio. These factors provide high R1 relaxation, leading to strong T1 MRI signal. We have confirmed T1-weighted MR contrast effect using 4-kinds of MnO nanocubes (MnOEn, MnOEnHo, MnOEx and MnOExHo). They showed enough a MR contrast effect and biocompatibility. Especially, among them, MnOExHo exhibited high T1 relaxivity (r1) (6.02 mM−1 s−1), even about 1.5 times higher sensitivity than commercial T1 MR contrast agents. In vitro/in vivo studies have shown that MnOExHo provides highly sensitive T1-weighted MR imaging, thereby improving diagnostic visibility at the disease site.

We investigated molecular structure change of d - and l -glucose by proton beam irradiation of 7.8 MeV, using terahertz time-domain spectroscopy. Both glucose pellets exposed to the irradiation of 1013, 4 × 1013, 6 × 1013, and 8 × 1013 particles/cm2 of the particle’s fluence, were characterized using complex refractive indices in terahertz frequency region. We found that fingerprints of two types of glucose in terahertz frequency were disappeared above 8 × 1013 particles/cm2. Crystallinity breaking and molecular structure change by proton irradiation was reaffirmed using X-ray diffraction (XRD) and Fourier transform infrared (FTIR) spectroscopy.

Multifunctional nano-systems are an enticing approach toward the design of nanoparticles with desired characteristics because of interactions between various components of the system. The combination of various imaging modalities often augments the advantages and simultaneously overcomes restrictions encountered by the individual techniques. This report describes the development of multifunctional gold core/iron oxide porous-shell nanoparticles (AuFe NPs) functionalized with matrix metalloproteinase peptide for targeted multi-mode magnetic resonance and computed tomography imaging. This study demonstrates that AuFe NPs simultaneously possess both T2-based contrast effect and X-ray attenuation properties in vitro. The drug loading capacity of porous iron oxide shell is also proposed.

The use of drug-eluting stents (DESs) is a promising strategy for non-vascular diseases, especially human biliary cancer. However, the implementation of DESs suffers from two major obstacles: the side effects of drugs and the difficulty of controlling the drug release. These problems can be overcome if the stent elutes targeting nanoparticles that release drugs at time intervals that are dictated by the mechanisms of those drugs. We designed temporally controlled polymeric multi-prodrug nanoparticles (TCMPNs) that can be eluted from stents comprising polyurethane (PU) nanofiber as a polymeric matrix and paclitaxel (PTX)-loaded, CD44-targeting, hyaluronic acid-conjugated poly(lactic-co-glycolic acid) and gemcitabine (GEM) (P-H-G). TCMPNs enable two different types of drugs to be released temporally; PTX is released first owing to the collapse of the structure in the endosomes, and GEM, which induces synergistic anticancer activities, is hydrolyzed from P-H-G later in response to low pH. Embedded in the PU nanofiber, the TCMPNs demonstrate low initial burst behavior and sustainable release of the prodrug in vitro. Furthermore, TCMPN-eluting stents (TESs) exhibit continuous synergistic efficacy as available targeted cellular uptake prodrug delivery systems in tumor-bearing mice. These results demonstrate that this technology will open up cancer therapy by combining localized delivery and functional multi-drug-loaded nanoparticles.

We detected keratinizing squamous cell carcinoma (SCC) of the tongue using terahertz reflection imaging and reported unexpected characteristics that THz reflection intensity of tumor was low in normal regions.

A portable and nonlabeled plasmonic biosensor was advanced to enable the sensitive and selective detection of microRNA (miRNA) in a biological sample. miRNAs can act on several key cellular processes, including cell differentiation, cell cycle progression, and function as oncogenes. Detection of circulating miRNAs, especially in blood or urine samples, allows noninvasive and simple diagnosis of diseases. Herein, we report a localized surface plasmon resonance sensor (LSPR) based on an enzyme-assisted target recycling system and a developed LSPR probe for the detection of gastric cancer relevant miRNAs, miR-10b. The sensitivity of the sensor was improved by increasing the concentration of the signal-amplifying agent using the duplex-specific nuclease and by strongly binding the developed LSPR probe, tannic acid capping gold nanoparticles, to the DNA. Under optimal conditions, miR-10b detection could be realized in the range of 5 pM-10 nM with a detection limit of 2.45 pM. This integrated detection system represents an approach to sensitive detection of miRNAs and offers great applications in personalized medicine and monitoring of cancer.

We designed a high-sensitivity magnetic resonance imaging contrast agent that could be used to diagnose diseases. First, magnetic nanocrystals were synthesized by a thermal decomposition method on an organic solvent to obtain a high magnetism and methoxy poly(ethylene glycol)-poly(lactic acid) as an amphiphilic polymer using the ring-opening polymerization method to stably disperse the magnetic nanocrystals in an aqueous phase. Subsequently, the magnetic nanoclusters simultaneously self-assembled with methoxy poly(ethylene glycol)-poly(lactic acid) using the nano-emulsion method to form magnetic nanoclusters. Because their shape was similar to a raspberry, they were named PEGylated magnetic nano-assemblies. The PEGylated magnetic nano-assemblies were dispersed stably in the aqueous phase with a uniform size of approximately 65&ndash, 70 nm for an extended period (0 days: 68.8 &plusmn, 5.1 nm, 33 days: 69.2 &plusmn, 2.0 nm, and 44 days: 63.2 &plusmn, 5.6). They exhibited both enough of a magnetic resonance (MR) contrast effect and biocompatibility. In an in vivo study, the PEGylated magnetic nano-assemblies provided a high contrast effect for magnetic resonance images for a long time after one treatment, thereby improving the diagnostic visibility of the disease site.

Small animal positron emission tomography (PET) is a noninvasive imaging modality that enables in vivo imaging and quantification of the biological processes of small experimental animals. We have developed a small animal PET that utilizes a high-resolution multiplexed readout and charge signal transmission (CST) method. The small animal PET was composed of six detector blocks consisting of SiPMs and LYSO arrays. Six detector blocks were mounted on a PET gantry having an inner diameter of 76 mm, outer diameter of 112 mm, and axial length of 40.8 mm. The charge signals of SiPM output were transmitted to the input of multiplexed readout using 4 m flexible flat cables. The multiplexed readout was composed of six main boards, each of which included 36 detector boards, to reduce the number of readout channels by a factor of 36, with a multiplexing ratio of 144:4. The performance of the small animal PET was evaluated using NEMA NU 4-2008 standards, and its imaging capability was demonstrated by in vivo mouse imaging studies. The average energy and time resolutions were 13.2% ± 0.3% and 3.8 ns, respectively. The spatial resolution at the center of the transaxial FOV was 1.1 mm, and the peak sensitivity at the center of the axial FOV was 1.5%. The peak noise equivalent count (NEC) rate and scatter fraction were 21.1 kcps at 18.2 MBq and 21%, respectively. The acquired images demonstrated high quality tracer uptake patterns of small experimental animals. The results of performance evaluation and animal imaging indicate that the small animal PET developed in this study can provide high-quality small animal imaging with cost-effectiveness and compactness.

T1/T2 dual-mode magnetic resonance (MR) contrast agents (DMCAs) have gained much attention because of their ability to improve accuracy by providing two pieces of complementary information with one instrument. However, most of these agents are "always ON" systems that emit MR contrast regardless of their interaction with target cells or biomarkers, which may result in poor target-to-background ratios. Herein, we introduce a rationally designed magnetic relaxation switch (MGRS) for an activatable T1/T2 dual MR imaging system. Redox-responsive heteronanocrystals, consisting of a superparamagnetic Fe3O4 core and a paramagnetic Mn3O4 shell, are synthesized through seed-mediated growth and subsequently surface-modified with polysorbate 80. The Mn3O4 shell acts as both a protector of Fe3O4 in aqueous environments to attenuate T2 relaxation and as a redoxable switch that can be activated in intracellular reducing environments by glutathione. This simultaneously generates large amounts of magnetically decoupled Mn(2+) ions and allows Fe3O4 to interact with the water protons. This smart nanoplatform shows an appropriate hydrodynamic size for the EPR effect (10-100 nm) and demonstrates biocompatibility. Efficient transitions of OFF/ON dual contrast effects are observed by in vitro imaging and MR relaxivity measurements. The ability to use these materials as DMCAs is demonstrated via effective passive tumor targeting for T1- and T2-weighted MR imaging in tumor-bearing mice.

Porous noble metal nanoparticles exhibit many attractive nanoplasmonic features, and these structures have potential applications in many fields. However, such applications have been hindered by a lack of synthetic methods with the ability to mass-produce mono-disperse nanoparticles. Current synthetic approaches to porous gold nanostructure fabrication involve galvanic replacement approaches or electrochemical deposition methods that are generally limited by stringent multi-step protocols and relatively low yields. Here, we introduce the facile synthesis of scalable, mono-disperse, mesoporous gold nanoparticles (MPGNs) using an acidic emulsification method. This method facilitates high synthetic yields (>93%) and tunable particle sizes (130–400 nm). MPGNs exhibit enhanced payloads of gadolinium (Gd), a contrast agent for magnetic resonance imaging. Additionally, they permit photo-thermal conversion under near-infrared light (NIR) irradiation due to the increased surface area to volume ratio and the unique, structure-mediated LSPR effect. Specifically, MPGNs fabricated using our method provided Gd payloads 2–4 orders of magnitude greater than previously reported theranostic nano-probes. We believe that our novel synthetic technique will not only contribute to large-scale production of homogeneous porous gold nanoparticles, but will also promote further research in porous noble metal nanostructures.

Superparamagnetic iron oxide nanoparticles (SPIONs) are actively used as highly sensitive imaging probes to provide contrast in MRI. In this study, we propose the use of SPIONs encapsulated with antibody-conjugated poly(lactic-co-glycolic acid) (PLGA) as a potent theragnostic agent. The SPIONs were synthesized by a chemical co-precipitation method of ferric and ferrous ions, and subsequently encapsulated with PLGA by using an emulsification-diffusion method. Herceptin was chemically conjugated to the SPION-encapsulating PLGA nanoparticles to target the human epidermal growth factor receptor 2 (Her2/neu) overexpressing breast cancers. FACS and MR molecular imaging revealed that the Her2/neu overexpressing cell line showed a stronger contrast enhancement than the Her2/neu non-expressing cell lines, and the signal intensity of in vivo MR imaging decreased as the concentration of Herceptin increased. This strategy of encapsulating SPIONs with PLGA will be highly useful in functionalizing magnetic nanoparticles and improving the diagnostic and therapeutic efficacy of a wide array of cancer treatments.

Localized surface plasmon resonance (LSPR) biosensors have attracted much interest due to their capacity for multiplexing, miniaturization, and high performance, which offers the potential for their integration into lab-on-a-chip platforms for point-of-care (POC) diagnostics. The need for microRNA (miRNA)-sensing platforms is particularly urgent because miRNAs are key regulators and biomarkers in numerous pathological processes and diseases. Unfortunately, however, development of such miRNA-sensing platforms has not yet been achieved. In order to realize the detection of these important biomarkers, there has been an increasing demand for POC-sensing platforms that enable label-free quantification with low sample consumption, good sensitivity, real-time responsiveness, and high throughput. Here, we developed a highly specific, sensitive LSPR miRNA-sensing platform on a flexible, scalable plasmonic nanostructure to enable single-base mismatch discrimination and attomole detection of miRNAs in clinically relevant samples. The hairpin probe contained a locked nucleic acid (LNA) that enabled the discrimination of single base mismatches based on differences in melting temperatures of perfectly matched or single base mismatched miRNAs when they formed base pairs with probes. In addition, through hybridization induced signal amplification based on precipitate formation on the gold surface through the enzyme reaction, we observed a dramatic LSPR peak shift, which enabled attomole detection. Additionally, our LSPR miRNA sensor enabled the detection of miR-200a-3p in total RNA extracts from primary cancer cell lines without purification or labeling of the miRNA. This label-free and highly specific miRNA sensing platform may have applications in POC cancer diagnostics without the need for gene amplification.

Study of the absorption spectrum in film dosimetry is important because the spectral absorbance of the film is related to the film’s total absorption dose. We investigated the absorption spectra of Gafchromic EBT2 film at various rotational angles in a visible wavelength band. The film was irradiated with 6- MV photon beams for a total dose of 300 cGy. The absorption spectra for different angles of rotation were obtained 24 h after the irradiation and we fitted the spectra by using Lorentzian functions. Two dominant absorption peaks, one at approximately 586 nm (green) and the other at 634 nm (red) were observed. The measured spectrum was decomposed into peaks at 542 nm, 558 nm, 578 nm, 586 nm, 626 nm, 634 nm, and 641 nm. The maximum total area of the red absorption band occurred at 45° (225°) and the minimum at 90° (270°). As the angle of rotation changed, the intensities and integrated areas of the blue and the green peaks also changed with a 180° period, with minima at 90° and 270°, and maxima at 0° and 180°, although the overall absorbance was very low. The spectral peak wavelengths remained constant within ±1.2 nm for all angles. The absorption spectrum of the film should no hysteresis of; spectra taken at 0° and 360° were substantially the same and showed similar behaviors for all rotational angles. The change in the absorbance with the rotational angle of the film affected the dosimetric properties, resulting in rotational variations of the film’s dosimetry in each red-green-blue channel.

To access smart optical theragnosis for cancer, an easily processable heterocyclic conjugated polymer (poly(sodium3-((3-methyl-3,4-dihydro-2H-thieno[3,4-b][1,4]dioxepin-3-yl)methoxy)propane-1-sulfonate), PPDS) nanoassembly is fabricated by a surfactant-free one-step process, without the laborious ordinary multicoating process. The conjugated nanoassembly, with a self-doped structure, provides strong absorbance in the near-infrared (NIR) range even in a neutral pH medium and exhibits excellent stability (>six months). In addition, the prepared PPDS nanoassembly shows a high photothermal conversion efficiency of 31.4% in organic photothermal nanoparticles. In particular, the PPDS nanoassembly is stably suspended in the biological medium without any additives. Through a simple immobilization with the anti-CD44 antibody, the prepared biomarker-targetable PPDS nanoassembly demonstrates specific targeting toward CD44 (expressed in stem-like cancer cells), allowing NIR absorbance imaging and the efficient targeted photothermal damaging of CD44-expressing cancer cells, from in vitro 3D mammospheres (similar to the practical structure of tumor in the body) to in vivo xenograft mice tumor models (breast cancer and fibrosarcoma). In this study, the most simplified preparation method is for this organic conjugated polymer-based nanoassembly by a molecular approach is reported, and demonstrated as a highly promising optical nanoagent for optical cancer theragnosis.

The integration of contrast-enhanced diagnostic imaging and therapy could utilize image guided therapy to plan treatment strategy. Toward this goal, a unique construction and operation of a pseudo metal based photothermal therapeutic agent (PPAM) is introduced by polyaniline (PANI) generation templated on iron oxide metal nanoclusters (MNCs). Notably, MNC core interferes as a catalytic agent and enables aniline polymerization under ambient acidic conditions. The intrusion of transition metal enhanced the proton sensitivity of PANI, which led to pH responsive conversion even at dilute proton concentrations (pH 5, 6) compared to the PANI particles prepared by conventional methods. Under physiological pH, PPAM reveals no special features; however, under low pH conditions, which is a notable characteristic of the cancer microenvironment, PPAM automatically converts into its emeraldine salt (ES) state and thus activates as a photothermal therapeutic agent. Utilizing this specific redox responsive switched off-on behavior of PPAM, precise and systemized photothermal therapy is demonstrated, proving itself as a smart and efficient photothermal therapeutic agent.

Various types of nanoprobes have recently been utilized to monitor living organisms by detecting and imaging intracellular biomarkers, such as microRNAs (miRs). We here present a simple one-pot method to prepare stellate gold nanoparticles functionalized with miR-detecting molecular beacons (SGNP-MBs); low pH conditions permitted the rapid-high loading of MBs on the surface of SGNPs. Compared to the conventional gold nanoparticle-based MBs, SGNPs carried a 4.5-fold higher load of MBs and exhibited a 6.4-fold higher cellular uptake. We demonstrated that SGNP-MBs were successfully internalized in human gastric cancer cell lines and could be used to accurately detect and image intracellular miRs in an miR-specific manner. Furthermore, the relative levels of intracellular miRs in three different cell lines expressing miR-10b (high, moderate, and low levels) could be monitored using SGNP-MBs. Consequently, these results indicated that SGNP-MBs could have applications as highly potent, efficient nanoprobes to assess intracellular miR levels in living cells.

The development of a synchronized delivery and imaging system for small interfering RNA (siRNA) is required for the clinical application of RNA interference (RNAi) in cancer treatment. Herein, we report a pH-responsive, magnetic nanoparticle-based siRNA delivery system that can facilitate the safe and efficient delivery and visualization of therapeutic siRNA by high-resolution magnetic resonance (MR) imaging. Cationic poly-l-lysine-graft-imidazole (PLI) with a reactive silane moiety was stably immobilized onto the surface of the assembled manganese ferrite nanoparticles (MFs) through an emulsion process, ensuring high water solubility, enhanced MR contrast effect, and endosome-disrupting functionality. The synthesized nanovectors were then complexed with siRNA targeting the CD44 gene via electrostatic interactions to verify the specific gene-silencing effect. The imidazolized magnetic nanovector (ImMNV) architectures developed here facilitated improved cellular internalization and exhibited a high level in vitro downregulation compared to non-imidazolized MNVs in metastatic breast cancer cells.

Here, wire-framed Au nanobundles (WNBs), which consist of randomly oriented and mutually connected Au wires to form a bundle shape, are synthesized. In contrast to conventional nanoparticles (spheres, rods, cubes, and stars), which exhibit nanostructure only on the surface, cross-sectional view image shows that WNBs have nanostructures in a whole volume. By using this specific property of WNBs, an externally controllable multistep photothermic-driven drug release (PDR) system is demonstrated for in vivo cancer treatment. In contrast to conventional nanoparticles that encapsulate a drug on their surface, WNBs preserve the drug payload in the overall inner volume, providing a drug loading capacity sufficient for cancer therapy. An improved in vivo therapeutic efficacy of PDR therapy is also demonstrated by delivering sufficient amount of drugs to the target tumor region.

Oleyl dextran-coated magnetic nanoclusters (ODMCs) are fabricated for the accurate detection of macrophage-rich atherosclerotic plaques using magnetic resonance (MR) imaging. Dextran is introduced to the cluster surface of magnetic nanocrystals (MNCs) through self-assembly using amphiphilic oleic acid-conjugated dextran (ODex) to provide not only hydrophilicity but also a high affinity to macrophages. Enhanced magnetism of the ODMCs is engineered by optimizing the degree of substitution (DS) of the oleyl group in ODex and the concentration of ODex used for the synthesis of ODMC. Consequently, ODMCs exhibit significantly increased T2 relaxivity and excellent macrophage-targeting ability without cytotoxicity, in vitro. Moreover, in vivo T2-weighted MR imaging after intravenous injection of ODMCs into a rat artery balloon injury model demonstrates considerable MR contrast strength efficacy in the plaques of the injured carotid artery. These novel ODMCs may offer a highly efficient MR imaging nanoprobes for the selective diagnosis of atherosclerosis.

By loading Gd(III) inside NIR-absorbing polyaniline nanostructures, a novel diagnostic and photothermal agent with enhanced MR sensitivity, targeting ability, and photothermal ability to treat epithelial cancer is developed.

We have synthesized water-stable polyaniline nanoparticles coated with triarmed polyethylene glycol chains using a solvent-shift method and confirmed their colloidal size and aqueous solubility. Furthermore, we have demonstrated that the polyaniline nanoparticles can be doped with biological dopants to produce distinct color changes allowing the detection of live cancer cells.

An electrohydrodynamic atomization (EHDA) system that generates an electrospray can achieve particle formation and encapsulation by accumulating an electric charge on liquid flowing out from the nozzle. A novel coaxial EHDA system for continuous fabrication of water-stable magnetic nanoparticles (MNPs) is established, based on a cone-jet mode of electrospraying. Systemic variables, such as flow rates from dual nozzles and inducing voltages, are controlled to enable the preparation of water-soluble MNPs coated by polysorbate 80. The PEGylated MNPs exhibit water stability. The magnetic resonance imaging potential of these MNPs is confirmed by in vivo imaging using a gastric cancer xenograft mouse model. Thus, this advanced coaxial EHDA system demonstrates remarkable capabilities for the continuous encapsulation of MNPs to render them water-stable while preserving their properties as imaging agents.

Magnetic nanoparticles offer potential advances in cancer treatment. One example is cancer theranostics, which refers to the combination of a diagnostic tool, i.e., magnetic resonance (MR) imaging, and therapeutic entities such as drugs, oligonucleotides, antibodies, and peptides. They can be conjugated with bioactive molecules and have the ability to form a magnetic field gradient under an external magnetic field. They can offer a variety of active drug delivery and imaging strategies along with modalities such as magnetic hyperthermia. Imaging with magnetic nanoparticles can facilitate more effective cancer therapy through more well informed decision-making. In this article, we review notable progress in magnetic particle design, including surface modifications and multi-functionalization, and we discuss the recent bioapplications of magnetic nanoparticles in simultaneous cancer imaging and therapy.

Well-designed nanoparticle-mediated, image-guided cancer therapy has attracted interest for increasing the efficacy of cancer treatment. A new class of smart theragnostic nanoprobes employing cetuximab (CET)-conjugated polyethylene glycol (PEG)ylated gold nanorods (CET-PGNRs) is presented; these nanoprobes target epithelial cancer cells using near-infrared light. The cetyltrimethylammonium bromide bilayer on GNRs is replaced with heterobifunctional PEG (COOH-PEG-SH) to serve as a biocompatible stabilizer and to increase specificity. The carboxylated GNRs are further functionalized with CET using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide/N-hydroxysuccinimide (EDC-NHS) chemistry. To assess the potential of such GNRs, their optical properties, biocompatibility, colloidal stability, in vitro/in vivo binding affinities for cancer cells, absorption imaging, and photothermal therapy effects are investigated. CET-PGNRs exhibit excellent tumor targeting ability and strong potential for simultaneous absorption imaging and photothermal ablation of epithelial cancer cells.

We estimated the photothermal transduction efficiency of gold nanorod (GNR) solutions for different GNR concentrations and irradiation laser power. In particular, we verified that the degree of cell death area could be modulated by GNR concentration and irradiation laser power. The efficacy of GNR-produced photothermal ablation of cancer cells was evaluated by irradiating GNRs in the presence of MDA-MB-231 breast cancer cells with a near-infrared (NIR) laser at different laser power densities and irradiation times. GNR-induced photothermal ablation was applied successfully to cancer cells at various NIR laser power densities and irradiation times and was characterized with live-dead cell staining. Through these techniques, we established the system for not only verification of induced photothermal effect using NIR laser and thermocouple, but also identification of uptake efficiency for GNRs and cell viability using dark field and fluorescence imaging, respectively.

Well-designed photothermal nanostructures have attracted many scientists pursuing a better means to accurately diagnose cancer and assess the efficacy of treatment. Recently, gold-based nanostructures (nanoshells, nanorods and nanocages) have enabled photothermal ablation of cancer cells with near-infrared (NIR) light without damaging normal human tissues and in particular, animal studies and early clinical testing showed the great promise for these materials. In this review article, we first discuss the mechanism of the cellular death signaling by thermal stress and introduce the intrinsic properties of gold nanostructures as photothermal agent for cancer treatment. Then the overview follows for evolving researches for the synthesis of various types of gold nanostructures and for their biomedical applications. Finally we introduce the optimized therapeutic strategies involving nanoparticle surface modification and laser operation method for an enhanced accumulation of gold nanostructures to the target cancer as well as for an effective cancer cell ablation.

We obtained the diagnostic images of cancerous tumors by employing the THz molecular imaging (TMI) technique which measured the THz response change by surface plasmon resonance induced on the surface of nanoparticles with a irradiation of near-infrared (NIR) beam. To demonstrate the principle of the TMI technique, THz images of tissues with nanoprobes were observed and compared with THz only images. The sensitivity of TMI was further enhanced by adopting a THz differential measurement technique, which was realized by modulating the NIR beams. By employing this differential TMI technique, the diagnostic images of cancerous tumors were obtained ex vivo and in vivo in the preclinical stage. These images indicated the feasibility of applying the differential TMI technique in the clinical stage.

We fabricated hyaluronan-modified magnetic nanoclusters (HA-MNCs) for detection of CD44-overexpressing breast cancer using magnetic resonance (MR) imaging. CD44 is closely associated with cancer growth, including proliferation, metastasis, invasion, and angiogenesis. Hence, pyrenyl hyaluronan (Py-HA) conjugates were synthesized as CD44-targetable surfactants with hyaluronan (HA) and 1-pyrenylbutyric acid (Py) to modify hyaluronan on hydrophobic magnetic nanocrystals. Subsequently, HA-MNCs were fabricated using the nano-emulsion method; magnetic nanocrystals were simultaneously self-assembled with Py-HA conjugates, and their physical and magnetic properties depended on the degree of substitution (DS) of Py in Py-HA conjugates. HA-MNCs exhibited superior targeting efficiency with MR sensitivity as well as excellent biocompatibility through in vitro/in vivo studies. This suggests that HA-MNCs can be a potent cancer specific molecular imaging agent via targeted detection of CD44 with MR imaging.

Well-designed photothermal nanomaterials have attractedthe interest of many scientists pursuing a better means toaccurately diagnose cancer and assess the efficacy of treat-ment, because these materials enable therapies in which thetumor region is pin-pointed with a laser-guided light sourcewithout surgical intervention.

We investigated the synergism between shRNAs against Bcl-xL and doxorubicin (DOX) using aptamer-conjugated polyplexes (APs) in combination cancer therapy. Synergistic and selective cancer cell death was achieved by AP-mediated co-delivery of very small amounts of DOX and Bcl-xL-specific shRNA, which simultaneously activated an intrinsic apoptotic pathway. A branched polyethyleneimine (PEI) was grafted to polyethylene glycol (PEI-PEG) to serve as a vehicle for shRNA delivery, and its surface was further conjugated with an anti-PSMA aptamer (APT) for the selective delivery of APs to prostate cancer cells that express prostate-specific membrane antigens (PSMA) on their cell surface. The APs were finally obtained after intercalation of DOX to form shRNA/PEI-PEG-APT/DOX conjugates. Cell viability assays and FACS analysis of GFP expression against PC3 (PSMA deficient) and LNCaP (PSMA overexpressed) cells demonstrated that the synthesized APs inhibited the growth of PSMA-abundant prostate cancer cells with strong cell selectivity. Consequently, IC(50) values of APs loaded with both DOX and shRNA were approximately 17-fold less than those for the simple mixture of shRNA plus drug (shRNA/Lipofectamine + DOX). These results suggest that AP-mediated co-delivery of an anti-cancer drug and shRNA against Bcl-xL may widen the therapeutic window and allow for the selective destruction of cancer cells.

For efficient labeling and tracking via magnetic resonance (MR) imaging of human mesenchymal stem cells (h-MSCs), magnetic labeling agents must be responsive to an external magnetic field. Thus, we developed ultrasensitive magnetoplex as a magnetic labeling agent composed of PEGylated MnFe2O4 nanocrystals (PMNCs) and polycationics (poly-l-lysine, PLL) for efficient labeling of the h-MSCs and monitoring of the transplanted h-MSCs for a long term. PMNCs were prepared by nanoemulsion methods composed of MnFe2O4 nanocrystals (MNCs) and amphiphilic polymers (mPEG–dodecanoic acid). The prepared PMNCs exhibited excellent biocompatibility and their polycationic complexes (PMNCs/PLL) demonstrated remarkable sensitivity compared with magnetic iron oxide nanoparticles (MION)/PLL or Ferumoxides/PLL. Furthermore, PMNCs demonstrated the potentials for novel diagnostic and therapeutic strategies with potential applications in various biomedical fields.

Novel bifunctional fluorescent magneto polymeric nanoprobes (FMPNs) were synthesized to provide simultaneous diagnostic information via magnetic resonance imaging (MRI) and optical imaging. FMPNs consist of ultra-sensitive magnetic nanocrystals that function as MR probes combined with Nile Red, which functions as a fluorescent probe. FMPNs were encapsulated by a nano-emulsion method in polyvinyl alcohol (PVA, 87-89% hydrolyzed) through a matrix of polymethyl methacrylate (PMMA). FMPNs exhibited excellent colloidal stability and monodispersity. The production of MR and optical images demonstrated that FMPNs have potential as dual-mode imaging agents.

Cetuximab conjugated fluorescent magnetic nanohybrids (CET-FMNHs) were synthesized for detection of human epithelial cancer via magnetic resonance (MR) and optical imaging. Spherical FMNHs consist of MnFe 2 O 4 magnetic nanocrystals encapsulated in pyrene-labeled PCL- b -PMAA as a surfactant prepared by a nano-emulsion method. FMNHs demonstrated excellent colloidal stability and biocompatibility for biomedical application. Antibody conjugated fluorescent magnetic nanohybrids (CET-FMNHs) served as effective agents for both magnetic resonance (MR) and fluorescence optical imaging of cancer cell lines.

Novel multifunctional magnetic gold nanocomposites (MGNCs) were synthesized for synchronous cancer therapy and diagnosis via magnetic resonance imaging (MRI). The MGNCs consist of magnetic kernels (aggregates of ultra-sensitive MnFe 2 O 4 magnetic nanocrystals wrapped in polymer) as effective MR contrast agents and silica-gold nanocomposites as hyperthermal therapeutic agents. A therapeutic antibody, Erbitux (ERB), was conjugated for specific tumor cell targeting both to localize the near-IR laser beam and to image their events through MRI. ERB-conjugated MGNCs selectively recognize the target cancer cell lines. Fluorescence images and MRI analysis show that the MGNCs are effectively taken up by the cells. ERB-conjugated MGNCs have an excellent synchronous therapeutic efficacy as a result of the therapeutic antibody and near-IR laser-induced surface plasmon resonance. Consequently, MGNCs clearly demonstrate selective imaging and treatment of human epithelial cancer simultaneously.

Nanoparticles have the potential to revolutionize current bio-medical diagnostic and therapeutic methods. For example, magnetic nanoparticles with unique superparamagnetism are emerging as next-generation probes for high performance magnetic resonance (MR) imaging. Their enhanced properties and nanoscale controllability in terms of size, composition, surface states, and magnetic spin structure have allowed for the highly sensitive and target-specific MR imaging of various biological systems including cancer detection, cell trafficking, and angiogenesis. On the other hand, viruses can be utilized as excellent delivery vehicles due to their facile cellular transfection and gene expression efficacies within their target cells. Such excellent properties of viruses offer promising prospects for gene therapy of genetic diseases and cancers, as well as for the genetic engineering of cells. Despite these prospects, a lack of understanding of their biological behaviors including in vivo migration, molecular recognition, gene delivery, and ultimate fate following their desired biofunctional applications limits their further development. There have been previous studies in the development of nanoparticle probing systems for viruses including virus-gold and virus-quantum dot nanoparticle systems. However, their utilization in the probing of viral gene delivery has not been investigated so far. Recently, Gd-based MR contrast agent-coated viruses were developed, but their functional behaviors including targetrecognition, cellular transfection, and gene delivery capabilities have not been demonstrated partly due to the intrinsically low sensitivity of Gd-based MR contrast agents. Our strategy is to hybridize the virus with magnetic nanoparticles into a single nanoparticle system with the dual-functional capabilities of target-specific MR imaging and gene delivery. Specifically, we fabricate hybrid nanoparticles of “enhanced green fluorescent protein (eGFP) promoter genecontaining adenovirus” and “manganese-doped magnetism engineered iron oxide (abbreviated as MnMEIO) nanoparticle”. As the viral gene delivery vector, we selected adenoviruses. Adenoviruses are known to be highly effective for transferring double-stranded DNAs to various cell types. Along with a gene delivery capability, adenoviruses possess targetspecificity to the cells with overexpression of Coxsackievirus B adenovirus receptor (CAR) which is known to facilitate the binding and intrusion of adenoviruses to the host cells. As the magnetic nanoparticle component we selected manganese-doped magnetism-engineered iron oxide (MnFe2O4, MnMEIO) nanoparticles, since it is known that MnMEIO exhibits exceptional MR contrast effects (R2 (=1/T2) value of 358 sec mM) and therefore is advantageous as probes for ultra-sensitive MR imaging. Briefly, the thermal reaction of manganese chloride (MnCl2) and iron tris(2,4-pentadionate) in hot organic solvents containing oleic acid and oleylamine capping molecules yielded hydrophobically capped MnMEIO nanoparticles. Their water-solubility and biocompatibility were attained by introducing 2,3-dimercaptosuccinic acids to the nanoparticle surface. Nanoparticles obtained were 12 nm with a high sizemonodispersity (r < 7%) and possessed single crystallinity, and a saturation magnetization value of 110 emu g (Mn+Fe). Hybridization of adenoviruses with MnMEIO nanoparticles was performed through a slight modification of a literature method, as follows. First, the capsid lysine residues of the adenoviruses were converted to maleimide groups by reacting them with sulfo-succinimidyl(4-N-maleimidomethyl)cyclohexane-1-carboxylate (sulfo-SMCC) cross-linkers. These groups were allowed to react with a large stoichiometric amount of MnMEIO nanoparticles, which resulted in the formation of adenovirus-MnMEIO hybrid nanoparticles by way of the nucleophilic addition of a surface thiol group of MnMEIO to the C O M M U N IC A IO N

The nano-sized magnetite and the magnetic nanospheres (MNS) were synthesized for biomedical applications by co-precipitation method and emulsion solvent evaporation method, respectively. The prepared magnetite and the MNS (∼250 nm) exhibited superparamagnetic behaviors with the saturation of magnetization of 52.6 and 38.7 emu/g, respectively. The size, distribution and morphology were investigated by light scattering and electron microscopy. The motions of the MNS under the magnetic field in rectangular microchannel were investigated by using the particle tracking velocimetry (PTV) method. The particle motions due to both the fluid flow and the magnetic field were calculated and the experimentally observed data were in good agreement with theoretical model.

Diagnosis of cancer in the early stages requires sensitive magnetic resonance (MR) probes to detect low concentrations of magnetic substances. In this study, ultrasensitive magnetic resonance contrast agents (UMRCAs) composed of magnetic nanocrystals and amphiphilic block copolymers were synthesized for cancer detection using polyethylene glycol and fatty acid. The chemical structures and the compositions of PEGylated magnetic nanoparticles were analyzed. UMRCAs displayed remarkable colloidal stability and high sensitivity as MR probes. Furthermore, UMRCAs exhibited low cytotoxicity and excellent cancer detection ability in an in vivo animal model.

Successful development of ultra-sensitive molecular imaging nanoprobes for the detection of targeted biological objects is a challenging task. Although magnetic nanoprobes have the potential to perform such a role, the results from probes that are currently available have been far from optimal. Here we used artificial engineering approaches to develop innovative magnetic nanoprobes, through a process that involved the systematic evaluation of the magnetic spin, size and type of spinel metal ferrites. These magnetism-engineered iron oxide (MEIO) nanoprobes, when conjugated with antibodies, showed enhanced magnetic resonance imaging (MRI) sensitivity for the detection of cancer markers compared with probes currently available. Also, we successfully visualized small tumors implanted in a mouse. Such high-performance, nanotechnology-based molecular probes could enhance the ability to visualize other biological events critical to diagnostics and therapeutics.

The unique optical, magnetic, and electronic properties of nanocrystals enable them to be key probes and vectors in the next generation of biomedical applications. Semiconductor quantum dots have been demonstrated as excellent fluorescent probes. However, they suffer from the intrinsic limitations of optical imaging systems such as low penetration depth and large background fluorescence. Magnetic nanocrystals are now emerging in biomedical applications with new possibilities. We have demonstrated the production of high quality water-soluble iron oxide (WSIO) nanocrystals by thermal decomposition method. One of the current challenges now is how to develop well-defined magnetic nanocrystals with optimal nanoscale magnetism, high bio-stability to withstand harsh biological conditions, Conjugation of biologically functional molecules to nanocrystals produce nanohybrids that have multi-functionality such as detection, diagnosis, and therapeutics. However, further development of in vivo imaging applications of these molecules has been very limited with very few successful in vivo demonstrations. In addition to therapeutic antibody, the ability to incorporate genes or drugs into detectable site-targeted nanosystems may represent a whole new paradigm in therapeutics. The application for molecular and cellar imaging in nanoscience have not been fully developed. However, it has enormous potential for development and nanocrystals will bring improvement in bio-medical sciences.

Telomerase has attracted much attention as a universal cancer biomarker because telomerase is overexpressed in more than 85% of human cancer cells while suppressed in normal somatic cells. Since a strong association exists between telomerase activity and human cancers, the development of effective telomerase activity assay is critically important. Here, a nanogap-rich Au nanowire (NW) surface-enhanced Raman scattering (SERS) sensor is reported for detection of telomerase activity in various cancer cells and tissues. The nanogap-rich Au NWs are constructed by deposition of nanoparticles on single-crystalline Au NWs and provided highly reproducible SERS spectra. The telomeric substrate (TS) primer-attached nanogap-rich Au NWs can detect telomerase activity through SERS measurement after the elongation of TS primers, folding into G-quadruplex structures, and intercalation of methylene blue. This sensor enables us to detect telomerase activity from various cancer cell lines with a detection limit of 0.2 cancer cells mL−1. Importantly, the nanogap-rich Au NW sensor can diagnose gastric and breast cancer tissues accurately. The nanogap-rich Au NW sensors show strong SERS signals only in the presence of tumor tissues excised from 16 tumor-bearing mice, while negligible signals in the presence of heated tumor tissues or normal tissues. It is anticipated that nanogap-rich Au NW SERS sensors can be used for a universal cancer diagnosis and further biomedical applications including a diverse biomarker sensing.

Correction for ‘Stent containing CD44-targeting polymeric prodrug nanoparticles that release paclitaxel and gemcitabine in a time interval-controlled manner for synergistic human biliary cancer therapy’ by Dayeon Yun et al., J. Mater. Chem. B, 2017, 5, 6317–6324.