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1.  Ultrasound-Mediated Gene and Drug Delivery Using a Microbubble-Liposome Particle System 
Theranostics  2014;4(11):1133-1144.
Theranostic agents present a promising clinical approach for cancer detection and treatment. We herein introduce a microbubble and liposome complex (MB-Lipo) developed for ultrasound (US) imaging and activation. The MB-Lipo particles have a hybrid structure consisting of a MB complexed with multiple Lipos. The MB components are used to generate high echo signals in US imaging, while the Lipos serve as a versatile carrier of therapeutic materials. MB-Lipo allows high contrast US imaging of tumor sites. More importantly, the application of high acoustic pressure bursts MBs, which releases therapeutic Lipos and further enhances their intracellular delivery through sonoporation effect. Both imaging and drug release could thus be achieved by a single US modality, enabling in situ treatment guided by real-time imaging. The MB-Lipo system was applied to specifically deliver anti-cancer drug and genes to tumor cells, which showed enhanced therapeutic effect. We also demonstrate the clinical potential of MB-Lipo by imaging and treating tumor in vivo.
PMCID: PMC4165777  PMID: 25250094
Microbubble; Liposome; Ultrasound imaging; Drug and gene delivery; Theranostics.
2.  Recent advances in photoacoustic endoscopy 
Imaging based on photoacoustic effect relies on illuminating with short light pulses absorbed by tissue absorbers, resulting in thermoelastic expansion, giving rise to ultrasonic waves. The ultrasonic waves are then detected by detectors placed around the sample. Photoacoustic endoscopy (PAE) is one of four major implementations of photoacoustic tomography that have been developed recently. The prototype PAE was based on scanning mirror system that deflected both the light and the ultrasound. A recently developed mini-probe was further miniaturized, and enabled simultaneous photoacoustic and ultrasound imaging. This PAE-endoscopic ultrasound (EUS) system can offer high-resolution vasculature information in the gastrointestinal (GI) tract and display differences between optical and mechanical contrast compared with single-mode EUS. However, PAE for endoscopic GI imaging is still at the preclinical stage. In this commentary, we describe the technological improvements in PAE for possible clinical application in endoscopic GI imaging. In addition, we discuss the technical details of the ultrasonic transducer incorporated into the photoacoustic endoscopic probe.
PMCID: PMC3831195  PMID: 24255745
Photoacoustic techniques; Tomography; Endoscopy; Endosonography; Gastrointestinal neoplasm
3.  Recent advances in targeted endoscopic imaging: Early detection of gastrointestinal neoplasms 
Molecular imaging has emerged as a new discipline in gastrointestinal endoscopy. This technology encompasses modalities that can visualize disease-specific morphological or functional tissue changes based on the molecular signature of individual cells. Molecular imaging has several advantages including minimal damage to tissues, repetitive visualization, and utility for conducting quantitative analyses. Advancements in basic science coupled with endoscopy have made early detection of gastrointestinal cancer possible. Molecular imaging during gastrointestinal endoscopy requires the development of safe biomarkers and exogenous probes to detect molecular changes in cells with high specificity anda high signal-to-background ratio. Additionally, a high-resolution endoscope with an accurate wide-field viewing capability must be developed. Targeted endoscopic imaging is expected to improve early diagnosis and individual therapy of gastrointestinal cancer.
PMCID: PMC3309894  PMID: 22442742
Autofluorescence endoscopy; Confocal endomicroscopy; Endoscopy; Molecular imaging; Molecular probes, Near-infrared fluorescence imaging; Targeted endoscopic imaging
4.  Miniaturized Nuclear Magnetic Resonance Platform for Detection and Profiling of Circulating Tumor Cells 
Lab on a chip  2013;14(1):10.1039/c3lc50621e.
Accurate detection and profiling of circulating tumor cells (CTCs) is a highly sought after technology to improve cancer management. Such “liquid biopsies” could offer a non-invasive, repeatable window into each patient’s tumor, facilitating early cancer diagnosis and treatment monitoring. The rarity of CTCs, approximated at 1 CTC for every billion peripheral blood cells, however, poses significant challenges to sensitive and reliable detection. We have recently developed a new biosensor platform, namely a micro-nuclear magnetic resonance (µNMR). Through the synergistic integration of microfabrication, nanosensors, and novel chemistries, the µNMR platform offers high detection sensitivity and point-of-care operation, overcoming technical barriers in CTC research. We herein review the µNMR technology with emphasis on its application on CTC detection. Recent advances in the sensing technology will be summarized, followed by the description on the dynamic interplay between preclinical and clinical CTC studies.
PMCID: PMC3844052  PMID: 23835814
5.  Trastuzumab-Conjugated Liposome-Coated Fluorescent Magnetic Nanoparticles to Target Breast Cancer 
Korean Journal of Radiology  2014;15(4):411-422.
To synthesize mesoporous silica-core-shell magnetic nanoparticles (MNPs) encapsulated by liposomes (Lipo [MNP@m-SiO2]) in order to enhance their stability, allow them to be used in any buffer solution, and to produce trastuzumab-conjugated (Lipo[MNP@m-SiO2]-Her2Ab) nanoparticles to be utilized in vitro for the targeting of breast cancer.
Materials and Methods
The physiochemical characteristics of Lipo[MNP@m-SiO2] were assessed in terms of size, morphological features, and in vitro safety. The multimodal imaging properties of the organic dye incorporated into Lipo[MNP@m-SiO2] were assessed with both in vitro fluorescence and MR imaging. The specific targeting ability of trastuzumab (Her2/neu antibody, Herceptin®)-conjugated Lipo[MNP@m-SiO2] for Her2/neu-positive breast cancer cells was also evaluated with fluorescence and MR imaging.
We obtained uniformly-sized and evenly distributed Lipo[MNP@m-SiO2] that demonstrated biological stability, while not disrupting cell viability. Her2/neu-positive breast cancer cell targeting by trastuzumab-conjugated Lipo[MNP@m-SiO2] was observed by in vitro fluorescence and MR imaging.
Trastuzumab-conjugated Lipo[MNP@m-SiO2] is a potential treatment tool for targeted drug delivery in Her2/neu-positive breast cancer.
PMCID: PMC4105802  PMID: 25053899
Breast cancer; Drug delivery; Iron oxide nanoparticles; Magnetic resonance imaging; Trastuzumab
7.  Mechanism of Magnetic Relaxation Switching Sensing 
ACS nano  2012;6(8):6821-6828.
Magnetic relaxation switching (MRSw) assays that employ target-induced aggregation (or disaggregation) of magnetic nanoparticles (MNPs) can be used to detect a wide range of biomolecules. The precise working mechanisms, however, remain poorly understood, often leading to confounding interpretation. We herein present a systematic and comprehensive characterization of MRSw sensing. By using different types of MNPs with varying physical properties, we analyzed the nature and transverse relaxation modes for MRSw detection. The study found that clustered MNPs are universally in a diffusion-limited fractal state (dimension of ~2.4). Importantly, a new model for transverse relaxation was constructed, that accurately recapitulates observed MRSw phenomena, and predicts the MRSw detection sensitivities and dynamic ranges.
PMCID: PMC3429660  PMID: 22762250
Magnetic Relaxation Switching; Magnetic Nanoparticles; NMR; Biosensors
8.  Recent Developments in Nanoparticle-Based siRNA Delivery for Cancer Therapy 
BioMed Research International  2013;2013:782041.
RNA interference (RNAi) is a gene regulation mechanism initiated by RNA molecules that enables sequence-specific gene silencing by promoting degradation of specific mRNAs. Molecular therapy using small interfering RNA (siRNA) has shown great therapeutic potential for diseases caused by abnormal gene overexpression or mutation. The major challenges to application of siRNA therapeutics include the stability and effective delivery of siRNA in vivo. Important progress in nanotechnology has led to the development of efficient siRNA delivery systems. In this review, the authors discuss recent advances in nanoparticle-mediated siRNA delivery and the application of siRNA in clinical trials for cancer therapy. This review will also offer perspectives on future applications of siRNA therapeutics.
PMCID: PMC3703404  PMID: 23844368
11.  Magnetic Nanoparticles and microNMR for Diagnostic Applications 
Theranostics  2012;2(1):55-65.
Sensitive and quantitative measurements of clinically relevant protein biomarkers, pathogens and cells in biological samples would be invaluable for disease diagnosis, monitoring of malignancy, and for evaluating therapy efficacy. Biosensing strategies using magnetic nanoparticles (MNPs) have recently received considerable attention, since they offer unique advantages over traditional detection methods. Specifically, because biological samples have negligible magnetic background, MNPs can be used to obtain highly sensitive measurements in minimally processed samples. This review focuses on the use of MNPs for in vitro detection of cellular biomarkers based on nuclear magnetic resonance (NMR) effects. This detection platform, termed diagnostic magnetic resonance (DMR), exploits MNPs as proximity sensors to modulate the spin-spin relaxation time of water molecules surrounding the molecularly-targeted nanoparticles. With new developments such as more effective MNP biosensors, advanced conjugational strategies, and highly sensitive miniaturized NMR systems, the DMR detection capabilities have been considerably improved. These developments have also enabled parallel and rapid measurements from small sample volumes and on a wide range of targets, including whole cells, proteins, DNA/mRNA, metabolites, drugs, viruses and bacteria. The DMR platform thus makes a robust and easy-to-use sensor system with broad applications in biomedicine, as well as clinical utility in point-of-care settings.
PMCID: PMC3263516  PMID: 22272219
biosensor; diagnostics; magnetic nanoparticle; microfluidics; nuclear magnetic resonance.
12.  Aerosol Delivery of Small Hairpin Osteopontin Blocks Pulmonary Metastasis of Breast Cancer in Mice 
PLoS ONE  2010;5(12):e15623.
Metastasis to the lung may be the final step in the breast cancer-related morbidity. Conventional therapies such as chemotherapy and surgery are somewhat successful, however, metastasis-related breast cancer morbidity remains high. Thus, a novel approach to prevent breast tumor metastasis is needed.
Methodology/Principal Finding
Aerosol of lentivirus-based small hairpin osteopontin was delivered into mice with breast cancer twice a week for 1 or 2 months using a nose-only inhalation system. The effects of small hairpin osteopontin on breast cancer metastasis to the lung were evaluated using near infrared imaging as well as diverse molecular techniques. Aerosol-delivered small hairpin osteopontin significantly decreased the expression level of osteopontin and altered the expression of several important metastasis-related proteins in our murine breast cancer model.
Aerosol-delivered small hairpin osteopontin blocked breast cancer metastasis. Our results showed that noninvasive targeting of pulmonary osteopontin or other specific genes responsible for cancer metastasis could be used as an effective therapeutic regimen for the treatment of metastatic epithelial tumors.
PMCID: PMC3008732  PMID: 21203518
13.  Magnetic nanoparticles for biomedical NMR-based diagnostics 
Rapid and accurate measurements of protein biomarkers, pathogens and cells in biological samples could provide useful information for early disease diagnosis, treatment monitoring, and design of personalized medicine. In general, biological samples have only negligible magnetic susceptibility. Thus, using magnetic nanoparticles for biosensing not only enhances sensitivity but also effectively reduces sample preparation needs. This review focuses on the use of magnetic nanoparticles for in vitro detection of biomolecules and cells based on magnetic resonance effects. This detection platform, termed diagnostic magnetic resonance (DMR), exploits magnetic nanoparticles as proximity sensors, which modulate the spin–spin relaxation time of water molecules surrounding molecularly-targeted nanoparticles. By developing more effective magnetic nanoparticle biosensors, DMR detection limits for various target moieties have been considerably improved over the last few years. Already, a library of magnetic nanoparticles has been developed, in which a wide range of targets, including DNA/mRNA, proteins, small molecules/drugs, bacteria, and tumor cells, have been quantified. More recently, the capabilities of DMR technology have been further advanced with new developments such as miniaturized nuclear magnetic resonance detectors, better magnetic nanoparticles and novel conjugational methods. These developments have enabled parallel and sensitive measurements to be made from small volume samples. Thus, the DMR technology is a highly attractive platform for portable, low-cost, and efficient biomolecular detection within a biomedical setting.
PMCID: PMC3045933  PMID: 21977404
biosensor; diagnostics; magnetic nanoparticle; microfluidics; nuclear magnetic resonance
14.  Ultrasensitive detection of bacteria using core-shell nanoparticles and a NMR-filter system** 
PMCID: PMC2453069  PMID: 19554581
nanoparticles; biosensors; nanotechnology; NMR; microfluidics
15.  Monocyte Subset Dynamics in Human Atherosclerosis Can Be Profiled with Magnetic Nano-Sensors 
PLoS ONE  2009;4(5):e5663.
Monocytes are circulating macrophage and dendritic cell precursors that populate healthy and diseased tissue. In humans, monocytes consist of at least two subsets whose proportions in the blood fluctuate in response to coronary artery disease, sepsis, and viral infection. Animal studies have shown that specific shifts in the monocyte subset repertoire either exacerbate or attenuate disease, suggesting a role for monocyte subsets as biomarkers and therapeutic targets. Assays are therefore needed that can selectively and rapidly enumerate monocytes and their subsets. This study shows that two major human monocyte subsets express similar levels of the receptor for macrophage colony stimulating factor (MCSFR) but differ in their phagocytic capacity. We exploit these properties and custom-engineer magnetic nanoparticles for ex vivo sensing of monocytes and their subsets. We present a two-dimensional enumerative mathematical model that simultaneously reports number and proportion of monocyte subsets in a small volume of human blood. Using a recently described diagnostic magnetic resonance (DMR) chip with 1 µl sample size and high throughput capabilities, we then show that application of the model accurately quantifies subset fluctuations that occur in patients with atherosclerosis.
PMCID: PMC2680949  PMID: 19461894
16.  Use of Magnetic Nanoparticles to Visualize Threadlike Structures Inside Lymphatic Vessels of Rats 
A novel application of fluorescent magnetic nanoparticles was made to visualize a new tissue which had not been detectable by using simple stereomicroscopes. This unfamiliar threadlike structure inside the lymphatic vessels of rats was demonstrated in vivo by injecting nanoparticles into lymph nodes and applying magnetic fields on the collecting lymph vessels so that the nanoparticles were taken up by the threadlike structures. Confocal laser scanning microscope images of cryosectioned specimens exhibited that the nanoparticles were absorbed more strongly by the threadlike structure than by the lymphatic vessels. Further examination using a transmission electron microscope revealed that the nanoparticles had been captured between the reticular fibers in the extracellular matrix of the threadlike structures. The emerging technology of nanoparticles not only allows the extremely elusive threadlike structures to be visualized but also is expected to provide a magnetically controllable means to investigate their physiological functions.
PMCID: PMC1810370  PMID: 17342244
acupuncture meridian; Bonghan duct; lymph; nanoparticle; transmission electron microscope
17.  Cellular uptake of magnetic nanoparticle is mediated through energy-dependent endocytosis in A549 cells 
Journal of Veterinary Science  2006;7(4):321-326.
Biocompatible silica-overcoated magnetic nanoparticles containing an organic fluorescence dye, rhodamine B isothiocyanate (RITC), within a silica shell [50 nm size, MNP@SiO2(RITC)s] were synthesized. For future application of the MNP@SiO2(RITC)s into diverse areas of research such as drug or gene delivery, bioimaging, and biosensors, detailed information of the cellular uptake process of the nanoparticles is essential. Thus, this study was performed to elucidate the precise mechanism by which the lung cancer cells uptake the magnetic nanoparticles. Lung cells were chosen for this study because inhalation is the most likely route of exposure and lung cancer cells were also found to uptake magnetic nanoparticles rapidly in preliminary experiments. The lung cells were pretreated with different metabolic inhibitors. Our results revealed that low temperature disturbed the uptake of magnetic nanoparticles into the cells. Metabolic inhibitors also prevented the delivery of the materials into cells. Use of TEM clearly demonstrated that uptake of the nanoparticles was mediated through endosomes. Taken together, our results demonstrate that magnetic nanoparticles can be internalized into the cells through an energy-dependent endosomal-lysosomal mechanism.
PMCID: PMC3242138  PMID: 17106221
A549 cells; cellular uptake; endocytosis; magnetic nanoparticle

Results 1-17 (17)