Publications by authors named "Leu-Wei Lo"

44 Publications

Annealing-modulated nanoscintillators for nonconventional X-ray activation of comprehensive photodynamic effects in deep cancer theranostics.

Theranostics 2020 20;10(15):6758-6773. Epub 2020 May 20.

Institute of Biomedical Engineering and Nanomedicine Research, National Health Research Institutes, 35 Keyan Road, Zhunan 350, Taiwan.

Photodynamic therapy (PDT), which involves the generation of reactive oxygen species (ROS) through interactions of a photosensitizer (PS) with light and oxygen, has been applied in oncology. Over the years, PDT techniques have been developed for the treatment of deep-seated cancers. However, (1) the tissue penetration limitation of excitation photon, (2) suppressed efficiency of PS due to multiple energy transfers, and (3) insufficient oxygen source in hypoxic tumor microenvironment still constitute major challenges facing the clinical application of PDT for achieving effective treatment. We present herein a PS-independent, ionizing radiation-induced PDT agent composed of yttrium oxide nanoscintillators core and silica shell (YO:[email protected]) with an annealing process. Our results revealed that annealed YO:[email protected] could directly induce comprehensive photodynamic effects under X-ray irradiation without the presence of PS molecules. The crystallinity of YO:[email protected] was demonstrated to enable the generation of electron-hole (e-h) pairs in YO under ionizing irradiation, giving rise to the formation of ROS including superoxide, hydroxyl radical and singlet oxygen. In particular, combining YO:[email protected] with fractionated radiation therapy increased radio-resistant tumor cell damage. Furthermore, photoacoustic imaging of tumors showed re-distribution of oxygen saturation (O) and reoxygenation of the hypoxia region. The results of this study support applicability of the integration of fractionated radiation therapy with YO:[email protected], achieving synchronously in-depth and oxygen-insensitive X-ray PDT. Furthermore, we demonstrate YO:[email protected] exhibited radioluminescence (RL) under X-ray irradiation and observed the virtually linear correlation between X-ray-induced radioluminescence (X-RL) and the YO:[email protected] concentration . With the pronounced X-RL for imaging and dosimetry, it possesses significant potential for utilization as a precision theranostics producing highly efficient X-ray PDT for deep-seated tumors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7150/thno.41752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295068PMC
May 2021

Biodegradable Polymers for Gene-Delivery Applications.

Int J Nanomedicine 2020 30;15:2131-2150. Epub 2020 Mar 30.

Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Zhunan 35053, Taiwan.

Gene-based therapies have emerged as a new modality for combating a myriad of currently incurable diseases. However, the fragile nature of gene therapeutics has significantly hampered their biomedical applications. Correspondingly, the development of gene-delivery vectors is of critical importance for gene-based therapies. To date, a variety of gene-delivery vectors have been created and utilized for gene delivery. In general, they can be categorized into viral- and non-viral vectors. Due to safety issues associated with viral vectors, non-viral vectors have recently attracted much more research focus. Of these non-viral vectors, polymeric vectors, which have been preferred due to their low immunogenicity, ease of production, controlled chemical composition and high chemical versatility, have constituted an ideal alternative to viral vectors. In particular, biodegradable polymers, which possess advantageous biocompatibility and biosafety, have been considered to have great potential in clinical applications. In this context, the aim of this review is to introduce the recent development and progress of biodegradable polymers for gene delivery applications, especially for their chemical structure design, gene delivery capacity and additional biological functions. Accordingly, we first define and categorize biodegradable polymers, followed by describing their corresponding degradation mechanisms. Various types of biodegradable polymers resulting from natural and synthetic polymers will be introduced and their applications in gene delivery will be examined. Finally, a future perspective regarding the development of biodegradable polymer vectors will be given.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/IJN.S222419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7125329PMC
June 2020

Precision control of the large-scale green synthesis of biodegradable gold nanodandelions as potential radiotheranostics.

Biomater Sci 2019 Nov 9;7(11):4720-4729. Epub 2019 Sep 9.

Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Zhunan, Miaoli 35053, Taiwan.

Herein, we report a new type of biodegradable, high surface-area gold nanodandelions (GNDs). This report possesses important features and some are the first of its kind: (1) the large scale green synthesis of GNDs with high monodispersity and a circa 100% yield with consistent chemistry, manufacturing and controls (CMC); (2) cellular/physiological degradability of GNDs leading to its disassembly into debris, which is indicative of the potential for possible body clearance; (3) precision control of the chemicophysical properties of the GNDs including shape, petal number and size, all can be judiciously fine-tuned by the synthetic parameters; (4) highly efficient radiotheranostics of GNDs encompassing better enhanced computed tomography (CT) contrast and pronounced X-ray induced reactive oxygen species (ROS) generation than conventional spherical gold nanoparticles (AuNP). It is noteworthy that the GNDs demonstrate a unique combinational effect of radiosensitization (production of superoxide anions and hydroxyl radicals) and type II photodynamic interaction (generation of singlet oxygen). Given the above, our reported GNDs are promising in clinical translation as radiotheranostics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/c9bm00897gDOI Listing
November 2019

Seeing Better and Going Deeper in Cancer Nanotheranostics.

Int J Mol Sci 2019 Jul 16;20(14). Epub 2019 Jul 16.

Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Zhunan 350, Taiwan.

Biomedical imaging modalities in clinical practice have revolutionized oncology for several decades. State-of-the-art biomedical techniques allow visualizing both normal physiological and pathological architectures of the human body. The use of nanoparticles (NP) as contrast agents enabled visualization of refined contrast images with superior resolution, which assists clinicians in more accurate diagnoses and in planning appropriate therapy. These desirable features are due to the ability of NPs to carry high payloads (contrast agents or drugs), increased in vivo half-life, and disease-specific accumulation. We review the various NP-based interventions for treatments of deep-seated tumors, involving "seeing better" to precisely visualize early diagnosis and "going deeper" to activate selective therapeutics in situ.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms20143490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678689PMC
July 2019

Highly sensitive electron paramagnetic resonance nanoradicals for quantitative intracellular tumor oxymetric images.

Int J Nanomedicine 2019 29;14:2963-2971. Epub 2019 Apr 29.

Department of Radiology, University of Chicago, Chicago, IL 60637 USA.

Tumor oxygenation is a critical parameter influencing the efficacy of cancer therapy. Low levels of oxygen in solid tumor have been recognized as an indicator of malignant progression and metastasis, as well as poor response to chemo- and radiation therapy. Being able to measure oxygenation for an individual's tumor would provide doctors with a valuable way of identifying optimal treatments for patients. Electron paramagnetic resonance imaging (EPRI) in combination with an oxygen-measuring paramagnetic probe was performed to measure tumor oxygenation in vivo. Triarylmethyl (trityl) radical exhibits high specificity, sensitivity, and resolution for quantitative measurement of O concentration. However, its in vivo applications in previous studies have been limited by the required high dosage, its short half-life, and poor intracellular permeability. To address these limitations, we developed high-capacity nanoformulated radicals that employed fluorescein isothiocyanate-labeled mesoporous silica nanoparticles (FMSNs) as trityl radical carriers. The high surface area nanostructure and easy surface modification of physiochemical properties of FMSNs enable efficient targeted delivery of highly concentrated, nonself-quenched trityl radicals, protected from environmental degradation and dilution. We successfully designed and synthesized a tumor-targeted nanoplatform as a carrier for trityl. In addition, the nanoformulated trityl does not affect oxygen-sensing capacity by a self-relaxation or broadening effect. The FMSN-trityl exhibited high sensitivity/response to oxygen in the partial oxygen pressure range from 0 to 155 mmHg. Furthermore, MSN-trityl displayed outstanding intracellular oxygen mapping in both in vitro and in vivo animal studies. The highly sensitive nanoformulated trityl spin probe can profile intracellular oxygen distributions of tumor in a real-time and quantitative manner using in vivo EPRI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/IJN.S194779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6503311PMC
July 2019

Microwave-Synthesized Platinum-Embedded Mesoporous Silica Nanoparticles as Dual-Modality Contrast Agents: Computed Tomography and Optical Imaging.

Int J Mol Sci 2019 Mar 28;20(7). Epub 2019 Mar 28.

Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Zhunan, Miaoli County 35053, Taiwan.

Nanoparticle-based imaging contrast agents have drawn tremendous attention especially in multi-modality imaging. In this study, we developed mesoporous silica nanoparticles (MSNs) for use as dual-modality contrast agents for computed tomography (CT) and near-infrared (NIR) optical imaging (OI). A microwave synthesis for preparing naked platinum nanoparticles (nPtNPs) on MSNs (MSNs-Pt) was developed and characterized with physicochemical analysis and imaging systems. The high density of nPtNPs on the surface of the MSNs could greatly enhance the CT contrast. Inductively coupled plasma mass spectrometry (ICP-MS) revealed the MSNs-Pt compositions to be ~14% Pt by weight and TEM revealed an average particle diameter of ~50 nm and covered with ~3 nm diameter nPtNPs. To enhance the OI contrast, the NIR fluorescent dye Dy800 was conjugated to the MSNs-Pt nanochannels. The fluorescence spectra of MSNs-Pt-Dy800 were very similar to unconjugated Dy800. The CT imaging demonstrated that even modest degrees of Pt labeling could result in substantial X-ray attenuation. In vivo imaging of breast tumor-bearing mice treated with PEGylated MSNs-Pt-Dy800 (PEG-MSNs-Pt-Dy800) showed significantly improved contrasts in both fluorescence and CT imaging and the signal intensity within the tumor retained for 24 h post-injection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms20071560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6480439PMC
March 2019

A novel mouse model of sporadic colon cancer induced by combination of conditional Apc genes and chemical carcinogen in the absence of Cre recombinase.

Carcinogenesis 2019 11;40(11):1376-1386

Department of Medicine, The University of Chicago, Chicago, IL, USA.

Although valuable insights into colon cancer biology have been garnered from human colon cancer cell lines and primary colonic tissues, and animal studies using human colon cancer xenografts, immunocompetent mouse models of spontaneous or chemically induced colon cancer better phenocopy human disease. As most sporadic human colon tumors present adenomatous polyposis coli (APC) gene mutations, considerable effort has gone into developing mice that express mutant Apc alleles that mimic human colon cancer pathogenesis. A serious limitation of many of these Apc-mutant murine models, however, is that these mice develop numerous tumors in the small intestine but few, if any, in the colon. In this work, we examined three spontaneous mouse models of colon tumorigenesis based upon the widely used multiple intestinal neoplasia (Min) mouse: mice with either constitutive or conditional Apc mutations alone or in combination with caudal-related homeobox transcription factor CDX2P-Cre transgene - either with or without exposure to the potent colon carcinogen azoxymethane. Using the CDX2 promoter to drive Cre recombinase transgene expression effectively inactivated Apc in colonocytes, creating a model with earlier tumor onset and increased tumor incidence/burden, but without the Min mouse model's small intestine tumorigenesis and susceptibility to intestinal perforation/ulceration/hemorrhage. Most significantly, azoxymethane-treated mice with conditional Apc expression, but absent the Cre recombinase gene, demonstrated nearly 50% tumor incidence with two or more large colon tumors per mouse of human-like histology, but no small intestine tumors - unlike the azoxymethane-resistant C57BL/6J-background Min mouse model. As such this model provides a robust platform for chemoprevention studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/carcin/bgz050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6875902PMC
November 2019

Evolution of Nanoparticle-Mediated Photodynamic Therapy: From Superficial to Deep-Seated Cancers.

Molecules 2019 Jan 31;24(3). Epub 2019 Jan 31.

Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Zhunan 350, Taiwan.

Enthusiasm for photodynamic therapy (PDT) as a potential therapeutic intervention for cancer has increased exponentially in recent decades. Photodynamic therapy constitutes a clinically approved, minimally invasive treatment modality that uses a photosensitizer (light absorbing molecule) and light to kill cancer cells. The principle of PDT is, when irradiated with a light of a suitable wavelength, a photosensitizer absorbs the light energy and generates cytotoxic free radicals through various mechanisms. The overall efficiency of PDT depends on characteristics of activation light and in-situ dosimetry, including the choice of photosensitizer molecule, wavelength of the light, and tumor location and microenvironment, for instance, the use of two-photon laser or an X-ray irradiator as the light source increases tissue-penetration depth, enabling it to achieve deep PDT. In this mini-review, we discuss the various designs and strategies for single, two-photon, and X-ray-mediated PDT for improved clinical outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/molecules24030520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6385004PMC
January 2019

Pollen-Structured Gold Nanoclusters for X-ray Induced Photodynamic Therapy.

Materials (Basel) 2018 Jul 9;11(7). Epub 2018 Jul 9.

Institute of New Drug Development, China Medical University, Taichung 40402, Taiwan.

Photodynamic therapy (PDT) is a cancer treatment that employs the production of cytotoxic reactive oxygen species (ROS), subsequently triggering tumor apoptosis and tumor size reduction. However, this approach suffers from insufficient light penetration depth. In order to mitigate this issue, pollen-structured gold clusters (PSGCs) were designed for mediating X-ray-induced PDT for radiotherapy enhancement. The structure of PSGCs provides a large surface area that is able to generate ROS upon X-ray irradiation. The synthesized PSGCs were exposed to different X-ray doses and the generated ROS was then quantified by dihydroethidium (DHE) assay. Furthermore, at the cellular level, the PDT efficacy of PSGCs was evaluated via immunofluorescence staining with γ-H2AX and comet assay. The results demonstrated that PSGCs possess a significantly high ROS-generating capacity and a remarkable PDT efficacy in the treatment of breast cancer cells, thus showing potential clinical uses in deep-tissue cancer treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ma11071170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6073926PMC
July 2018

Sensitivity evaluation and selective plane imaging geometry for x-ray-induced luminescence imaging.

Med Phys 2017 Oct 4;44(10):5367-5377. Epub 2017 Sep 4.

Department of Radiology, The University of Chicago, Chicago, IL, 60637, USA.

Purpose: X-ray-induced luminescence (XIL) is a hybrid x-ray/optical imaging modality that employs nanophosphors that luminescence in response to x-ray irradiation. X-ray-activated phosphorescent nanoparticles have potential applications in radiation therapy as theranostics, nanodosimeters, or radiosensitizers. Extracting clinically relevant information from the luminescent signal requires the development of a robust imaging model that can determine nanophosphor distributions at depth in an optically scattering environment from surface radiance measurements. The applications of XIL in radiotherapy will be limited by the dose-dependent sensitivity at depth in tissue. We propose a novel geometry called selective plane XIL (SPXIL), and apply it to experimental measurements in optical gel phantoms and sensitivity simulations.

Methods: An imaging model is presented based on the selective plane geometry which can determine the detected diffuse optical signal for a given x-ray dose and nanophosphor distribution at depth in a semi-infinite, optically homogenous material. The surface radiance in the model is calculated using an analytical solution to the extrapolated boundary condition. Y O :Eu nanoparticles are synthesized and inserted into various optical phantom in order to measure the luminescent output per unit dose for a given concentration of nanophosphors and calibrate an imaging model for XIL sensitivity simulations. SPXIL imaging with a dual-source optical gel phantom is performed, and an iterative Richardson-Lucy deconvolution using a shifted Poisson noise model is applied to the measurements in order to reconstruct the nanophosphor distribution.

Results: Nanophosphor characterizations showed a peak emission at 611 nm, a linear luminescent response to tube current and nanoparticle concentration, and a quadratic luminescent response to tube voltage. The luminescent efficiency calculation accomplished with calibrated bioluminescence mouse phantoms determines 1.06 photons were emitted per keV of x-ray radiation absorbed per g/mL of nanophosphor concentration. Sensitivity simulations determined that XIL could detect a concentration of 1 mg/mL of nanophosphors with a dose of 1 cGy at a depth ranging from 2 to 4 cm, depending on the optical parameters of the homogeneous diffuse optical environment. The deconvolution applied to the SPXIL measurements could resolve two sources 1 cm apart up to a depth of 1.75 cm in the diffuse phantom.

Conclusions: We present a novel imaging geometry for XIL in a homogenous, diffuse optical environment. Basic characterization of Y O :Eu nanophosphors are presented along with XIL/SPXIL measurements in optical gel phantoms. The diffuse optical imaging model is validated using these measurements and then calibrated in order to execute initial sensitivity simulations for the dose-depth limitations of XIL imaging. The SPXIL imaging model is used to perform a deconvolution on a dual-source phantom, which successfully reconstructs the nanophosphor distributions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mp.12470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5646227PMC
October 2017

Lectin-functionalized mesoporous silica nanoparticles for endoscopic detection of premalignant colonic lesions.

Nanomedicine 2017 Aug 29;13(6):1941-1952. Epub 2017 Mar 29.

Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes Zhunan, Miaoli, Taiwan. Electronic address:

Colorectal cancer (CRC) is one of the leading causes of cancer-deaths worldwide. Methods for the early in situ detection of colorectal adenomatous polyps and their precursors - prior to their malignancy transformation into CRC - are urgently needed. Unfortunately at present, the primary diagnostic method, colonoscopy, can only detect polyps and carcinomas by shape/morphology; with sessile polyps more likely to go unnoticed than polypoid lesions. Here we describe our development of polyp-targeting, fluorescently-labeled mesoporous silica nanoparticles (MSNs) that serve as targeted endoscopic contrast agents for the early detection of colorectal polyps and cancer. In vitro cell studies, ex vivo histopathological analysis, and in vivo colonoscopy and endoscopy of murine colorectal cancer models, demonstrate significant binding specificity of our nanoconstructs to pathological lesions via targeting aberrant α-L-fucose expression. Our findings strongly suggest that lectin-functionalized fluorescent MSNs could serve as a promising endoscopic contrast agent for in situ diagnostic imaging of premalignant colonic lesions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nano.2017.03.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5673680PMC
August 2017

Depicting Binding-Mediated Translocation of HIV-1 Tat Peptides in Living Cells with Nanoscale Pens of Tat-Conjugated Quantum Dots.

Sensors (Basel) 2017 Feb 10;17(2). Epub 2017 Feb 10.

Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Zhunan 350, Taiwan.

Cell-penetrating peptides (CPPs) can translocate across cell membranes, and thus have great potential for the cellular delivery of macromolecular cargoes. However, the mechanism of this cellular uptake process is not yet fully understood. In this study, a time-lapse single-particle light-sheet microscopy technique was implemented to obtain a parallel visualization of the translocating process of individual human immunodeficiency virus 1 (HIV-1) transactivator of transcription (Tat) peptide conjugated quantum dots (TatP-QDs) in complex cellular terrains. Here, TatP-QDs served as nanoscale dynamic pens, which depict remarkable trajectory aggregates of TatP-QDs on the cell surface. Spectral-embedding analysis of the trajectory aggregates revealed a manifold formed by isotropic diffusion and a fraction of directed movement, possibly caused by interaction between the Tat peptides and heparan sulfate groups on the plasma membrane. Further analysis indicated that the membrane deformation induced by Tat-peptide attachment increased with the disruption of the actin framework in cytochalasin D (cyto D)-treated cells, yielding higher interactions on the TatP-QDs. In native cells, the Tat peptides can remodel the actin framework to reduce their interaction with the local membrane environment. Characteristic hot spots for interaction were detected on the membrane, suggesting that a funnel passage may have formed for the Tat-coated particles. This finding offers valuable insight into the cellular delivery of nanoscale cargo, suggesting an avenue for direct therapeutic delivery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/s17020315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5335923PMC
February 2017

Synthesis of Polylactide-Based Core-Shell Interface Cross-Linked Micelles for Anticancer Drug Delivery.

Macromol Biosci 2017 03 28;17(3). Epub 2016 Sep 28.

Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Zhunan, 35053, Taiwan.

Well-defined poly(ethylene glycol)-b-allyl functional polylactide-b-polylactides (PEG-APLA-PLAs) are synthesized through sequential ring-opening polymerization. PEG-APLA-PLAs that have amphiphilic properties and reactive allyl side chains on their intermediate blocks are successfully transferred to core-shell interface cross-linked micelles (ICMs) by micellization and UV-initiated irradiation. ICMs have demonstrated enhanced colloidal stability in physiological-mimicking media. Hydrophobic molecules such as Nile Red or doxorubicin (Dox) are readily loaded into ICMs; the resulting drug-ICM formulations possess slow and sustained drug release profiles under physiological-mimicking conditions. ICMs exhibit negligible cytotoxicity in human uterine sarcoma cancer cells by using biodegradable aliphatic polyester as the hydrophobic segments. Relative to free Dox, Dox-loaded ICMs show a reduced cytotoxicity due to the late intracellular release of Dox from ICMs. Overall, ICMs represent a new type of biodegradable cross-linked micelle and can be employed as a promising platform for delivering a broad variety of hydrophobic drugs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mabi.201600191DOI Listing
March 2017

Exploring in vivo cholesterol-mediated interactions between activated EGF receptors in plasma membrane with single-molecule optical tracking.

BMC Biophys 2016 24;9. Epub 2016 Jun 24.

Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, 35, Keyan Road, Zhunan, Taiwan.

Background: The first step in many cellular signaling processes occurs at various types of receptors in the plasma membrane. Membrane cholesterol can alter these signaling pathways of living cells. However, the process in which the interaction of activated receptors is modulated by cholesterol remains unclear.

Methods: In this study, we measured single-molecule optical trajectories of epidermal growth factor receptors moving in the plasma membranes of two cancerous cell lines and one normal endothelial cell line. A stochastic model was developed and applied to identify critical information from single-molecule trajectories.

Results: We discovered that unliganded epidermal growth factor receptors may reside nearby cholesterol-riched regions of the plasma membrane and can move into these lipid domains when subjected to ligand binding. The amount of membrane cholesterol considerably affects the stability of correlated motion of activated epidermal growth factor receptors.

Conclusions: Our results provide single-molecule evidence of membrane cholesterol in regulating signaling receptors. Because the three cell lines used for this study are quite diverse, our results may be useful to shed light on the mechanism of cholesterol-mediated interaction between activated receptors in live cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13628-016-0030-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4919887PMC
June 2016

Dynamic In Vivo SPECT Imaging of Neural Stem Cells Functionalized with Radiolabeled Nanoparticles for Tracking of Glioblastoma.

J Nucl Med 2016 Feb 12;57(2):279-84. Epub 2015 Nov 12.

The Brain Tumor Center, The University of Chicago, Chicago, Illinois

Unlabelled: There is strong clinical interest in using neural stem cells (NSCs) as carriers for targeted delivery of therapeutics to glioblastoma. Multimodal dynamic in vivo imaging of NSC behaviors in the brain is necessary for developing such tailored therapies; however, such technology is lacking. Here we report a novel strategy for mesoporous silica nanoparticle (MSN)-facilitated NSC tracking in the brain via SPECT.

Methods: (111)In was conjugated to MSNs, taking advantage of the large surface area of their unique porous feature. A series of nanomaterial characterization assays was performed to assess the modified MSN. Loading efficiency and viability of NSCs with (111)In-MSN complex were optimized. Radiolabeled NSCs were administered to glioma-bearing mice via either intracranial or systemic injection. SPECT imaging and bioluminescence imaging were performed daily up to 48 h after NSC injection. Histology and immunocytochemistry were used to confirm the findings.

Results: (111)In-MSN complexes show minimal toxicity to NSCs and robust in vitro and in vivo stability. Phantom studies demonstrate feasibility of this platform for NSC imaging. Of significance, we discovered that decayed (111)In-MSN complexes exhibit strong fluorescent profiles in preloaded NSCs, allowing for ex vivo validation of the in vivo data. In vivo, SPECT visualizes actively migrating NSCs toward glioma xenografts in real time after both intracranial and systemic administrations. This is in agreement with bioluminescence live imaging, confocal microscopy, and histology.

Conclusion: These advancements warrant further development and integration of this technology with MRI for multimodal noninvasive tracking of therapeutic NSCs toward various brain malignancies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2967/jnumed.115.163006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5831675PMC
February 2016

Unraveling the impact of lipid domains on the dimerization processes of single-molecule EGFRs of live cells.

Biochim Biophys Acta 2015 Mar 30;1848(3):886-93. Epub 2014 Dec 30.

Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Zhunan, Miaoli 350, Taiwan, ROC.

Epidermal growth factor receptor (EGFR/ErbB1) is a transmembrane protein that can drive cell growth and survival via the ligand-induced dimerization of receptors. Because dimerization is a common mechanism for signal transduction, it is important to improve our understanding of how the dimerization process and membrane structure regulate signal transduction. In this study, we examined the effect of lipid nanodomains on the dimerization process of EGFR molecules. We discovered that after ligand binding, EGFR molecules may move into lipid nanodomains. The lipid nanodomains surrounding two liganded EGFRs can merge during their correlated motion. The transition rates between different diffusion states of liganded EGFR molecules are regulated by the lipid domains. Our method successfully captures both the sensitivity of single-molecule processes and statistic accuracy of data analysis, providing insight into the connection between the mobile clustering process of receptors and the hierarchical structure of plasma membrane.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbamem.2014.12.019DOI Listing
March 2015

Energetic modeling and single-molecule verification of dynamic regulation on receptor complexes by actin corrals and lipid raft domains.

J Chem Phys 2014 Dec;141(21):215102

Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Zhunan, Miaoli 350, Taiwan.

We developed an energetic model by integrating the generalized Langevin equation with the Cahn-Hilliard equation to simulate the diffusive behaviors of receptor proteins in the plasma membrane of a living cell. Simulation results are presented to elaborate the confinement effects from actin corrals and protein-induced lipid domains. Single-molecule tracking data of epidermal growth factor receptors (EGFR) acquired on live HeLa cells agree with the simulation results and the mechanism that controls the diffusion of single-molecule receptors is clarified. We discovered that after ligand binding, EGFR molecules move into lipid nanodomains. The transition rates between different diffusion states of liganded EGFR molecules are regulated by the lipid domains. Our method successfully captures dynamic interactions of receptors at the single-molecule level and provides insight into the functional architecture of both the diffusing EGFR molecules and their local cellular environment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1063/1.4902985DOI Listing
December 2014

Radioluminescence characterization of x-ray nanodosimeters: Potential real-time monitors and modulators of external beam radiation therapy.

Appl Phys Lett 2014 Nov 20;105(20):203110. Epub 2014 Nov 20.

Department of Radiology, The University of Chicago , Chicago, Illinois 60637, USA.

Europium-doped yttrium oxide (YO:Eu) has garnered considerable interest recently for its use as a highly efficient, red phosphor in a variety of lighting applications that include fluorescent lamps, plasma, and field emission display panels, light emitting diodes (LEDs), and lasers. In the present work, we describe the development of YO:Eu nanoparticles for a very different application: , x-ray dosimetry. Spectroscopic analyses of these nanoparticles during x-ray irradiation reveal surprisingly bright and stable radioluminescence at near-infrared wavelengths, with markedly linear response to changes in x-ray flux and energy. Monte Carlo modeling of incident flux and broadband, wide-field imaging of mouse phantoms bearing both YO:Eu nanoparticles and calibrated LEDs of similar spectral emission demonstrated significant transmission of radioluminescence, in agreement with spectroscopic studies; with approximately 15 visible photons being generated for every x-ray photon incident. Unlike the dosimeters currently employed in clinical practice, these nanodosimeters can sample both dose and dose rate rapidly enough as to provide real-time feedback for x-ray based external beam radiotherapy (EBRT). The technique's use of remote sensing and absence of supporting structures enable perturbation-free dosing of the targeted region and complete sampling from any direction. With the conjugation of pathology-targeting ligands onto their surfaces, these nanodosimeters offer a potential paradigm shift in the real-time monitoring and modulation of delivered dose in the EBRT of cancer .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1063/1.4900962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4240777PMC
November 2014

Enhanced plasmonic resonance energy transfer in mesoporous silica-encased gold nanorod for two-photon-activated photodynamic therapy.

Theranostics 2014 30;4(8):798-807. Epub 2014 May 30.

1. Institute of Biomedical Engineering and Nanomedicine (I-BEN), National Health Research Institutes, Zhunan, Miaoli 350, Taiwan.

The unique optical properties of gold nanorods (GNRs) have recently drawn considerable interest from those working in in vivo biomolecular sensing and bioimaging. Especially appealing in these applications is the plasmon-enhanced photoluminescence of GNRs induced by two-photon excitation at infrared wavelengths, owing to the significant penetration depth of infrared light in tissue. Unfortunately, many studies have also shown that often the intensity of pulsed coherent irradiation of GNRs needed results in irreversible deformation of GNRs, greatly reducing their two-photon luminescence (TPL) emission intensity. In this work we report the design, synthesis, and evaluation of mesoporous silica-encased gold nanorods (MS-GNRs) that incorporate photosensitizers (PSs) for two-photon-activated photodynamic therapy (TPA-PDT). The PSs, doped into the nano-channels of the mesoporous silica shell, can be efficiently excited via intra-particle plasmonic resonance energy transfer from the encased two-photon excited gold nanorod and further generates cytotoxic singlet oxygen for cancer eradication. In addition, due to the mechanical support provided by encapsulating mesoporous silica matrix against thermal deformation, the two-photon luminescence stability of GNRs was significantly improved; after 100 seconds of 800 nm repetitive laser pulse with the 30 times higher than average power for imaging acquisition, MS-GNR luminescence intensity exhibited ~260% better resistance to deformation than that of the uncoated gold nanorods. These results strongly suggest that MS-GNRs with embedded PSs might provide a promising photodynamic therapy for the treatment of deeply situated cancers via plasmonic resonance energy transfer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7150/thno.8934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4063978PMC
February 2015

Nanoparticle-facilitated functional and molecular imaging for the early detection of cancer.

Front Mol Biosci 2014 17;1:15. Epub 2014 Oct 17.

Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes Zhunan, Taiwan.

Cancer detection in its early stages is imperative for effective cancer treatment and patient survival. In recent years, biomedical imaging techniques, such as magnetic resonance imaging, computed tomography and ultrasound have been greatly developed and have served pivotal roles in clinical cancer management. Molecular imaging (MI) is a non-invasive imaging technique that monitors biological processes at the cellular and sub-cellular levels. To achieve these goals, MI uses targeted imaging agents that can bind targets of interest with high specificity and report on associated abnormalities, a task that cannot be performed by conventional imaging techniques. In this respect, MI holds great promise as a potential therapeutic tool for the early diagnosis of cancer. Nevertheless, the clinical applications of targeted imaging agents are limited due to their inability to overcome biological barriers inside the body. The use of nanoparticles has made it possible to overcome these limitations. Hence, nanoparticles have been the subject of a great deal of recent studies. Therefore, developing nanoparticle-based imaging agents that can target tumors via active or passive targeting mechanisms is desirable. This review focuses on the applications of various functionalized nanoparticle-based imaging agents used in MI for the early detection of cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fmolb.2014.00015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4428449PMC
May 2015

Deciphering the catalysis-associated conformational changes of human adenylate kinase 1 with single-molecule spectroscopy.

J Phys Chem B 2013 Nov 1;117(45):13947-55. Epub 2013 Nov 1.

Department of Photonics, Chiao Tung University , Hsinchu, Taiwan.

Human adenylate kinase isoenzyme 1 (AK1) is the key enzyme in maintaining the cellular energy homeostasis. The catalysis-associated conformational changes of AK1 involve large-amplitude rearrangements. To decipher the conformational changes of AK1 at the single-molecule level, we tagged AK1 with two identical fluorophores, one near the substrate-binding site and the other at the boundary of the core domain. We found that magnesium ion binding to AK1 increases the structural heterogeneity of AK1, whereas ADP binding reduces the structural heterogeneity. We exploited the hidden Markov model to extract the underlying catalysis-associated conformational dynamics and determined thermodynamic parameters of the multiple catalytic pathways. The third-order correlation difference calculated from photon fluctuation traces reveals the irreversible nature of the conformational motions, suggesting that single-molecule AK1 is in a nonequilibrium steady state. This discovery offers a fresh viewpoint to look into the molecular mechanisms of cellular biochemistry.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jp4019537DOI Listing
November 2013

Nanoparticle-programmed self-destructive neural stem cells for glioblastoma targeting and therapy.

Small 2013 Dec 21;9(24):4123-9. Epub 2013 Jul 21.

The Brain Tumor Center, The University of Chicago, Chicago, Illinois, USA.

A 3-step glioblastoma-tropic delivery and therapy method using nanoparticle programmed self-destructive neural stem cells (NSCs) is demonstrated in vivo: 1) FDA-approved NSCs for clinical trials are loaded with pH-sensitive MSN-Dox; 2) the nanoparticle conjugates provide a delayed drug-releasing mechanism and allow for NSC migration towards a distant tumor site; 3) NSCs eventually undergo cell death and release impregnated MSN-Dox, which subsequently induces toxicity towards surrounding glioma cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/smll.201301111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3879136PMC
December 2013

In-situ formation and assembly of gold nanoparticles by gum arabic as efficient photothermal agent for killing cancer cells.

Macromol Biosci 2013 Oct 16;13(10):1314-20. Epub 2013 Jul 16.

Center for Nanomedicine Research, Division of Medical Engineering Research, National Health Research Institutes, 35 Keyan Road, Zhunan, 35053, Taiwan.

Gold nanoparticles (AuNPs) have been established to sufficiently eradicate tumors by means of heat production for photothermal therapy. However, the translation of the AuNPs from bench to the clinic still remains to be solved until realizing high bioclearance after treatment. Herein, we developed a simple strategy for simultaneous formation and assembly of small-size gold nanoparticles (Au-SNPs) to form a novel nanocomposite in the presence of gum arabic (GA) by synchrotron X-ray irradiation in an aqueous solution within 5 min. GA, a porous polysaccharide, can not only provide a confined space in which to produce uniform Au-SNPs (1.6 ± 0.7 nm in diameter), but can also facilitate the formation of [email protected] (diameter ≈ 40 nm) after irradiating synchrotron X-rays. Specifically, the [email protected] possesses high thermal stability and a strong photothermal effect for killing cancer cells. Importantly, a bioclearance study demonstrated that the [email protected] can be gradually excreted by the renal and hepatobiliary system, which might be due to the breakdown and oxidation of GA under irradiating synchrotron X-rays. Thus, the novel gold nanocomposite can be promising photothermal agents for cancer treatment at the therapeutic level, minimizing toxicity concerns regarding long-term accumulation in vivo.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mabi.201300162DOI Listing
October 2013

Theranostic applications of mesoporous silica nanoparticles and their organic/inorganic hybrids.

J Mater Chem B 2013 Jul 16;1(25):3128-3135. Epub 2013 May 16.

Division of Medical Engineering Research, National Health Research Institutes, Zhunan, Taiwan, R. O. C..

Mesoporous silica nanoparticles (MSNs), with their intrinsically large and easily functionalized surface areas and pore volumes, are particularly well-suited to efficient conveyance of a wide variety of therapeutic agents. When combined with other organic/inorganic nanomaterials, the resultant organic/inorganic-MSN hybrids demonstrate unique synergies and even greater versatility. In this paper, we describe the current status and future prospects of MSNs and organic/inorganic-MSN hybrids for combined therapeutic and diagnostic - theranostic - biomedical applications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/c3tb20249fDOI Listing
July 2013

Recent advances in nanoparticle-based Förster resonance energy transfer for biosensing, molecular imaging and drug release profiling.

Int J Mol Sci 2012 Dec 5;13(12):16598-623. Epub 2012 Dec 5.

Division of Medical Engineering Research, National Health Research Institutes, Zhunan 35053, Miaoli County, Taiwan.

Förster resonance energy transfer (FRET) may be regarded as a "smart" technology in the design of fluorescence probes for biological sensing and imaging. Recently, a variety of nanoparticles that include quantum dots, gold nanoparticles, polymer, mesoporous silica nanoparticles and upconversion nanoparticles have been employed to modulate FRET. Researchers have developed a number of "visible" and "activatable" FRET probes sensitive to specific changes in the biological environment that are especially attractive from the biomedical point of view. This article reviews recent progress in bringing these nanoparticle-modulated energy transfer schemes to fruition for applications in biosensing, molecular imaging and drug delivery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms131216598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3546710PMC
December 2012

Programmable cellular retention of nanoparticles by replacing the synergistic anion of transferrin.

ACS Nano 2013 Jan 10;7(1):365-75. Epub 2012 Dec 10.

Biochemistry Laboratory, Department of Applied Chemistry, National Chi Nan University, Puli, Nantou 54561, Taiwan.

The ability to program the intracellular retention of nanoparticles (NPs) would increase their applicability for imaging and therapeutic applications. To date, there has been no efficient method developed to control the fate of NPs once they enter cells. Existing approaches to manipulate the intracellular retention of NPs are mostly "passive" and particle size-dependent. Different sized particles hold distinct cellular responses. The adverse effect of particle size may limit the utility of nanodelivery systems. Therefore, the development of tunable/"active" NP intracellular retention systems with fixed particle sizes remains a considerable challenge. By replacing the synergistic anions of transferrin (Tf) immobilized on quantum dots (Tf-QDs, ca. 25 nm), we have examined the feasibility of this concept. Substitution of synergistic anions of Tf from carbonate (holo-Tf) to oxalate (oxa-Tf) significantly increased the intracellular accumulation of the oxa-Tf-QDs as a result of (i) a delay in cellular removal triggered by oxalate (oxa-Tf)-induced endosomal Tf iron-release retardation and (ii) enhanced recycling of Tf-QD/TfR (Tf receptor) complexes from early endosomes to the plasma membrane. This accumulation extended the intracellular NP retention interval. The half-maximum fluorescence intensity of the oxa-Tf-QDs in vivo was 4 times higher than that of the holo-Tf-QDs. Programming of the intracellular NP retention time was accomplished through manipulation of the ratio of holo- and oxa-Tfs on the surfaces of the QDs. Using this simple and efficient approach, it was possible to readily achieve a desirable intracellular retention interval for the NPs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/nn3043397DOI Listing
January 2013

Probing the dynamics of doxorubicin-DNA intercalation during the initial activation of apoptosis by fluorescence lifetime imaging microscopy (FLIM).

PLoS One 2012 18;7(9):e44947. Epub 2012 Sep 18.

Division of Medical Engineering Research, National Health Research Institutes, Zhunan, Taiwan.

Doxorubicin is a potent anthracycline antibiotic, commonly used to treat a wide range of cancers. Although postulated to intercalate between DNA bases, many of the details of doxorubicin's mechanism of action remain unclear. In this work, we demonstrate the ability of fluorescence lifetime imaging microscopy (FLIM) to dynamically monitor doxorubicin-DNA intercalation during the earliest stages of apoptosis. The fluorescence lifetime of doxorubicin in nuclei is found to decrease rapidly during the first 2 hours following drug administration, suggesting significant changes in the doxorubicin-DNA binding site's microenvironment upon apoptosis initiation. Decreases in doxorubicin fluorescence lifetimes were found to be concurrent with increases in phosphorylation of H2AX (an immediate signal of DNA double-strand breakage), but preceded activation of caspase-3 (a late signature of apoptosis) by more than 150 minutes. Time-dependent doxorubicin FLIM analyses of the effects of pretreating cells with either Cyclopentylidene-[4-(4-chlorophenyl)thiazol-2-yl)-hydrazine (a histone acetyltransferase inhibitor) or Trichostatin A (a histone deacetylase inhibitor) revealed significant correlation of fluorescence lifetime with the stage of chromatin decondensation. Taken together, our findings suggest that monitoring the dynamics of doxorubicin fluorescence lifetimes can provide valuable information during the earliest phases of doxorubicin-induced apoptosis; and implicate that FLIM can serve as a sensitive, high-resolution tool for the elucidation of intercellular mechanisms and kinetics of anti-cancer drugs that bear fluorescent moieties.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0044947PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3445590PMC
March 2013

Dynamic regulation on energy landscape evolution of single-molecule protein by conformational fluctuation.

Phys Rev E Stat Nonlin Soft Matter Phys 2012 Aug 31;86(2 Pt 1):021925. Epub 2012 Aug 31.

Department of Photonics and Institute of Electro-Optical Engineering, Chiao Tung University, Hsinchu 300, Taiwan, Republic of China.

We formalize a theory to help explore the effect of conformational fluctuation on the energy landscape evolution of single-molecule protein. Using this formalization, we investigate the photon emission from single photoactivated fluorescent protein. A bimodal regulation on the energy landscape evolution was discovered, and its origin was attributed to slow conformational fluctuations of the protein matrix.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1103/PhysRevE.86.021925DOI Listing
August 2012

Visualizing dynamics of sub-hepatic distribution of nanoparticles using intravital multiphoton fluorescence microscopy.

ACS Nano 2012 May 19;6(5):4122-31. Epub 2012 Apr 19.

Division of Medical Engineering Research, National Health Research Institutes, Zhunan, Miaoli 350, Taiwan.

Nanoparticles that do not undergo renal excretion or in vivo degradation into biocompatible debris often accumulate in the reticuloendothelial system, also know as the mononuclear phagocyte system, with undesired consequences that limit their clinical utility. In this work, we report the first application of intravital multiphoton fluorescence microscopy to dynamically track the hepatic metabolism of nanoparticles with subcellular resolution in real time. Using fluorescently labeled mesoporous silica nanoparticles (MSNs) in mice as a prototypical model, we observed significant hepatocyte uptake of positively charged, but not negatively charged, moieties. Conversely, in vivo imaging of negatively charged, but not positively charged, MSNs reveals an overwhelming propensity for the former's rapid uptake by Kupffer cells in liver sinusoids. Since the only prerequisite for these studies was that nanoparticles are fluorescently labeled and not of a specific composition or structure, the techniques we present can readily be extended to a wide variety of nanoparticle structures and surface modifications (e.g., shape, charge, hydrophobicity, PEGylation) in the preclinical assessment and tailoring of their hepatotoxicities and clearances.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/nn300558pDOI Listing
May 2012

Inorganic nanoparticles for enhanced photodynamic cancer therapy.

Curr Drug Discov Technol 2011 Sep;8(3):250-68

Division of Medical Engineering Research, National Health Research Institutes, Taiwan.

Photodynamic therapy (PDT) in cancer treatment uses photosensitizers to generate singlet oxygen followed by photoirradiation. The efficacy of PDT is greatly determined by the dosimetry of activation light and the photosensitizer (PS), modulating the photodynamic reaction at depth in diseased tissue. Development of nano-formulated photosensitizer has emerged as a promising field because of the biocompatibility and the accessibility for multi-functionalization of nanoparticles. In this review, we summarize the contemporary progress in use of inorganic nanoparticles for improvement of PDT in cancer therapeutics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/157016311796798982DOI Listing
September 2011
-->