Eunji Jang

Delivery of Cancer Therapeutics Using Nanotechnology

Nanoparticles have been investigated as drug carriers, because they provide a great opportunity due to their advantageous features: (i) various formulations using organic/inorganic materials, (ii) easy modification of targeting molecules, drugs or other molecules on them, (iii) effective delivery to target sites, resulting in high therapeutic efficacy and (iv) controlling drug release by external/internal stimuli. Because of these features, therapeutic efficacy can be improved and unwanted side effects can be reduced. Theranostic nanoparticles have been developed by incorporating imaging agents in drug carriers as all-in-one system, which makes it possible to diagnose and treat cancer by monitoring drug delivery behavior simultaneously. Recently, stimuli-responsive, activatable nanomaterials are being applied that are capable of producing chemical or physical changes by external stimuli. By using these nanoparticles, multiple tasks can be carried out simultaneously, e.g., early and accurate diagnosis, efficient cataloguing of patient groups of personalized therapy and real-time monitoring of disease progress. In this paper, we describe various types of nanoparticles for drug delivery systems, as well as theranostic systems.

Gold Nanostructures as Photothermal Therapy Agent for Cancer

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.

A biodegradable polymersome containing Bcl-xL siRNA and doxorubicin as a dual delivery vehicle for a synergistic anticancer effect.

Combined cancer treatment via co-delivery of siRNAs and an anticancer drug can be a promising strategy due to the synergistic effect of simultaneously minimizing gene/drug administration. In this study, Bcl-xL siRNA and doxorubicin (DOX) are encapsulated into designed methoxy-poly(ethylene glycol)-block-poly(D,L-lactic acid) (mPEG-b-PLA) block copolymer polymersomes (PSomes). A study of the cytotoxicity of Bcl-xL siRNA and DOX co-encapsulated PSomes (CPSomes) shows more inhibited proliferation of MKN-45 and MKN-28 human gastric cancer cell lines than only gene- and drug-loaded ones. Consequently, these results demonstrate that co-delivery of genes and drugs using PSomes results in a synergistic efficacy and indicates the potential of PSomes as efficient nanocarriers for combined cancer therapy.

Microfluidic bioassay system based on microarrays of hydrogel sensing elements entrapping quantum dot-enzyme conjugates.

This paper presents a simple method to fabricate a microfluidic biosensor that is able to detect substrates for H(2)O(2)-generating oxidase. The biosensor consists of three components (quantum dot-enzyme conjugates, hydrogel microstructures, and a set of microchannels) that were hierarchically integrated into a microfluidic device. The quantum dot (QD)-enzyme conjugates were entrapped within the poly(ethylene glycol) (PEG)-based hydrogel microstructures that were fabricated within the microchannels by a photopatterning process. Glucose oxidase (GOX) and alcohol oxidase (AOX) were chosen as the model oxidase enzymes, conjugated to carboxyl-terminated CdSe/ZnS QDs, and entrapped within the hydrogel microstructures, which resulted in a fluorescent hydrogel microarray that was responsive to glucose or alcohol. The hydrogel-entrapped GOX and AOX were able to perform enzyme-catalyzed oxidation of glucose and alcohol, respectively, to produce H(2)O(2), which subsequently quenched the fluorescence of the conjugated QDs. The fluorescence intensity of the hydrogel microstructures decreased as the glucose and alcohol concentrations increased, and the detection limits of this system were found to be 50 μM of glucose and 70 μM of alcohol. Because each microchannel was able to carry out different assays independently, the simultaneous detection of glucose and alcohol was possible using our novel microfluidic device composed of multiple microchannels.

Dextran-coated magnetic nanoclusters as highly sensitive contrast agents for magnetic resonance imaging of inflammatory macrophages

We fabricated dextran-coated magnetic nanoclusters (Dex-MNCs) for targeted magnetic resonance (MR) imaging of inflammatory macrophages. Dex-MNCs were prepared through encapsulation of hydrophobic magnetic nanocrystals (MNCs) by pyrenyl dextran in order that MNCs could achieve increased colloidal stability in aqueous phase as well as strongly interact with macrophages. Dex-MNCs exhibited biocompatibility and sufficient targeting efficiency against macrophages with strengthened MR contrast effect from in vitro/in vivo studies. Considering these results, we confirmed that Dex-MNCs could accurately detect inflammatory macrophagevia MR imaging.

Mutiscale substrates based on hydrogel-incorporated silicon nanowires for protein patterning and microarray-based immunoassays

Here, protein micropatterns were prepared on micropatterned nanostructures for potential applications in microarray-based multiplex bioassays with enhanced protein-loading capacity and detection sensitivity. Vertically-aligned silicon nanowires (SiNWs) that were about 8 μm in height and 150 nm in diameter were prepared using an etching process and were surface-modified with aminopropyltriethoxysilane (APTES) to allow them to covalently immobilize proteins. The SiNW substrate was then overlaid with a micropattern of poly(ethylene glycol) (PEG) hydrogel to create defined arrays of microwells consisting of APTES-modified SiNW on the bottom of the wells, with hydrogel on the walls of the wells. Due to the non-adhesiveness of PEG hydrogels toward proteins, proteins were selectively immobilized on the surface-modified SiNW regions to create protein micropatterns. The increase in surface area increased the protein loading capacity of the SiNWs by more than 10 times the capacity of a planar silicon substrate. Immunobinding assays between IgG and anti-IgG and between IgM and anti-IgM that were performed on micropatterned SiNWs emitted stronger fluorescent signals and showed higher sensitivity than assays performed on planar silicon substrates. Finally, microfluidic channels were successfully integrated into the micropatterned SiNWs to enable the simultaneous performance of multiple immunoassays on a single microarray platform.

Aptamer-modified magnetic nanoprobe for molecular MR imaging of VEGFR2 on angiogenic vasculature

Nucleic acid-based aptamers have been developed for the specific delivery of diagnostic nanoprobes. Here, we introduce a new class of smart imaging nanoprobe, which is based on hybridization of a magnetic nanocrystal with a specific aptamer for specific detection of the angiogenic vasculature of glioblastoma via magnetic resonance (MR) imaging. The magnetic nanocrystal imaging core was synthesized using the thermal decomposition method and enveloped by carboxyl polysorbate 80 for water solubilization and conjugation of the targeting moiety. Subsequently, the surface of the carboxylated magnetic nanocrystal was modified with amine-functionalized aptamers that specifically bind to the vascular growth factor receptor 2 (VEGFR2) that is overexpressed on angiogenic vessels. To assess the targeted imaging potential of the aptamer-conjugated magnetic nanocrystal for VEGFR2 markers, the magnetic properties and MR imaging sensitivity were investigated using the orthotopic glioblastoma mouse model. In in vivo tests, the aptamer-conjugated magnetic nanocrystal effectively targeted VEGFR2 and demonstrated excellent MR imaging sensitivity with no cytotoxicity.

Self-fabricated dextran-coated gold nanoparticles using pyrenyl dextran as a reducible stabilizer and their application as CT imaging agents for atherosclerosis

A facile method to produce dextran-coated gold nanoparticles (DGNPs) for atherosclerosis detection using computed tomography (CT) imaging is developed. DGNPs are prepared using only pyrenyl dextran as a reducible stabilizer chemically conjugated with hydroxyl groups of dextran and carboxyl groups of pyrenyl molecules, which can reduce gold ions to gold particles and stably form gold nanoparticles in the aqueous phase. The physical properties of DGNPs can be controlled by the reaction time. DGNPs, where gold particles were stably covered with dextran, exhibit targeting ability against inflammatory macrophages with the help of strong interactions between dextran on their surface and scavenger receptors in the macrophages with good biocompatibility without cell damage. From the in vivo studies, DGNPs can be used to accurately detect atherosclerosis via CT imaging.

π-Hyaluronan nanocarriers for CD44-targeted and pH-boosted aromatic drug delivery

Molecular targeted delivery of therapeutic agents and their stimuli-responsive release are some of the major issues for modern medical administration, particularly in cancer chemotherapy. In this study, we developed a π-hyaluronan nanocarrier (πHNC) for CD44-targeted and pH-boosted delivery of an aromatic anticancer drug to cancer cells. Amphiphilic π-hyaluronan (pyrenyl hyaluronan, πHA) was synthesized using EDC chemistry, and self-assembled to form πHNC, the structure of which was obviously micellar but was convincingly effective to function; (i) a π-rich pyrenyl core of πHNC, a loading aromatic drug (doxorubicin, DOX) by π-stacking attraction, showed a rapid release profile under low pH conditions which is a notable characteristic of the cancer microenvironment as well as the endolysosomal state after uptake into the target cell and (ii) the hydrophilic hyaluronan shell of πHNC acted as a ligand for CD44 resulting in the localization of πHNC into the target cell by CD44-mediated endocytosis, without cytotoxicity. With its targeted and stimulated delivery of aromatic drugs to the target cells, DOX-loaded πHNC (πHNC/DOX) provided effectual therapeutic activity in both in vitro and in vivo models of CD44-positive human gastric cancer, which is suitable as a facile and efficient drug delivery platform.

Metal-enhanced fluorescence using silver nanoparticles-embedded polyelectrolyte multilayer films for microarray-based immunoassays

Metal-enhanced fluorescence (MEF) of quantum dots (QDs) and its potential application in microarray-based immunoassays was investigated using silver nanoparticles (AgNPs) prepared by the in situ photoreduction of Ag+ inside a multilayer film consisting of poly(ethyleneimine) (PEI) and hyaluronic acid (HA). UV–Vis spectroscopy, X-ray diffraction, atomic force microscopy, scanning electron microscopy, and transmission electron microscopy confirmed the formation of well-dispersed AgNPs within the multilayer films, the thickness and the amount of which depended on the number of HA layers. Using AgNPs-containing hybrid multilayered films, it was possible to observe the MEF effect of adsorbed QDs, which could be tuned by the thickness of interlayer spacer film prepared of the layer-by-layer assembly of PEI and poly(styrene sulfonate). When the MEF-inducing hybrid film was used as a platform for immunoassay, a significant improvement in the fluorescence signal and sensitivity of the biosensing were observed in the presence of AgNPs in comparison with films that did not contain the nanoparticles.