Kwan Hyi Lee

State-of-the-art in design rules for drug delivery platforms: Lessons learned from FDA-approved nanomedicines

The ability to efficiently deliver a drug to a tumor site is dependent on a wide range of physiologically imposed design constraints. Nanotechnology provides the possibility of creating delivery vehicles where these design constraints can be decoupled, allowing new approaches for reducing the unwanted side effects of systemic delivery, increasing targeting efficiency and efficacy. Here we review the design strategies of the two FDA-approved antibody-drug conjugates (Brentuximab vedotin and Trastuzumab emtansine) and the four FDA-approved nanoparticle-based drug delivery platforms (Doxil, DaunoXome, Marqibo, and Abraxane) in the context of the challenges associated with systemic targeted delivery of a drug to a solid tumor. The lessons learned from these nanomedicines provide an important insight into the key challenges associated with the development of new platforms for systemic delivery of anti-cancer drugs.

CuInSe/ZnS Core/Shell NIR Quantum Dots for Biomedical Imaging

A current challenge in biomedical imaging is the synthesis of water-soluble quantum dots (QDs) with emission wavelengths in the near-IR, a high quantum yield, stability in water, and relatively small sizes. Ideally the synthesis should be relatively straightforward and not involve toxic elements. The optimum wavelength for in-vivo optical imaging, taking into account the absorbance from melanin in the epidermis, hemoglobin in blood, and water in tissue, is in the range of 700-900 nm.[1,2] To achieve emission in this optical window requires a QD with a bandgap of around 1.3–1.7 eV.[3] Semiconductor QDs that emit in the NIR—such as CdTe, PbS, InAs, InP—have been synthesized[4-8] and explored for biomedical imaging.[9-12] High quantum yield is important to optimize the signal-to-noise ratio for imaging, and stability in aqueous solutions is key to avoid aggregation and degradation during imaging. At the same time, it is thought that a hydrodynamic diameter less than about 15 nm is necessary to ensure renal clearance and to avoid accumulation in other organs.[13] In addition, due to concerns over toxicity if QDs are not cleared from the body, it is desirable to avoid elements such as cadmium, lead, and arsenic. Thus there remains a need for the development of QD systems that satisfy all of these requirements.

Nanoscale bacteriophage biosensors beyond phage display

Bacteriophages are traditionally used for the development of phage display technology. Recently, their nanosized dimensions and ease with which genetic modifications can be made to their structure and function have put them in the spotlight towards their use in a variety of biosensors. In particular, the expression of any protein or peptide on the extraluminal surface of bacteriophages is possible by genetically engineering the genome. In addition, the relatively short replication time of bacteriophages offers researchers the ability to generate mass quantities of any given bacteriophage-based biosensor. Coupled with the emergence of various biomarkers in the clinic as a means to determine pathophysiological states, the development of current and novel technologies for their detection and quantification is imperative. In this review, we categorize bacteriophages by their morphology into M13-based filamentous bacteriophages and T4- or T7-based icosahedral bacteriophages, and examine how such advantages are utilized across a variety of biosensors. In essence, we take a comprehensive approach towards recent trends in bacteriophage-based biosensor applications and discuss their outlook with regards to the field of biotechnology.

A systematic in-vivo toxicity evaluation of nanophosphor particles via zebrafish models

Lanthanide ion-doped nanophosphors are an emerging group of nanomaterials with excellent optical properties, and have been suggested as alternatives to quantum dots. In this letter, we determine the in-vitro and in-vivo toxicity of β-NaYF4:Ce,Tb nanophosphors using Capan-1 cells and embryonic zebrafish, respectively. In particular, we are the first to report on the in-vivo toxicity of β-phase nanophosphors and examine phenotypic developmental abnormalities (growth retardation, heart deformity, and bent tail), apoptotic cell death, and changes in heart function due to the nanophosphors. This study suggests the use of β-NaYF4:Ce,Tb nanophosphors as alternatives for QDs in a wide variety of biomedical imaging applications.

Quantitative molecular profiling of biomarkers for pancreatic cancer with functionalized quantum dots

UNLABELLEDnApplications in nanomedicine, such as diagnostics and targeted therapeutics, rely on the detection and targeting of membrane biomarkers. In this article we demonstrate absolute quantitative profiling, spatial mapping, and multiplexing of cancer biomarkers using functionalized quantum dots (QDs). We demonstrate highly selective targeting molecular markers for pancreatic cancer with extremely low levels of nonspecific binding. We confirm that we have saturated all biomarkers on the cell surface, and, in conjunction with control experiments, extract absolute quantitative values for the biomarker density in terms of the number of molecules per square micron on the cell surface. We show that we can obtain quantitative spatial information of biomarker distribution on a single cell, important because tumors cell populations are inherently heterogeneous. We validate our quantitative measurements (number of molecules per square micron) using flow cytometry and demonstrate multiplexed quantitative profiling using color-coded QDs.nnnFROM THE CLINICAL EDITORnThis paper demonstrates a nice example for quantum dot-based molecular targeting of pancreatic cancer cells for advanced high sensitivity diagnostics and potential future selective therapeutic purposes.

Think Modular: A Simple Apoferritin-Based Platform for the Multifaceted Detection of Pancreatic Cancer

The generation of nanosized probes often requires time-intensive and application-specific optimization processes that involve conjugating a nanoconstruct to a targeting moiety. Herein, we genetically modify apoferritin and generate a universal interface system composed of protein G and 6×His-tag. The resulting construct, conferred with modularity and high targeting efficiency, is applied toward two distinct applications in the detection of a pancreatic cancer biomarker and used to demonstrate its potential in the facile exchange of nanoprobe components.

Electrical signaling of enzyme-linked immunosorbent assays with an ion-sensitive field-effect transistor.

Optical laboratory-based immunoassays, such as enzyme-linked immunosorbent assay (ELISA) give a high sensitivity and specificity of various fatal diseases. However, these assays are no longer efficient in on-spot diagnostics of wide-spreading and contagious infections. At this point in time, portable and handhold devices play a pivotal role in infectious diseases with quick diagnostics at or near the site of the disease propagation. In this paper, we demonstrated a novel electrical immunoassay of ELISA that was not based on optical signaling but on electrical signaling. This was done by combining an ion-sensitive field-effect transistor (ISFET) with ELISA. By harnessing the catalytic reaction of alkaline phosphatase that precipitated silver particles, we effectively overcame the chronic Debye screening length issue of the ISFET. Ultimately, small signal ranging from 1 pg/mL to 10 ng/mL was immensely amplified with the ALP label, regardless of buffer conditions. The sensor platform herein surpassed a sensing capability of conventional ELISA that is considered to have a LOD on the order of ~1 ng/mL. The results were compared with those of horseradish peroxidase label, which is generally used for optical analyses in ELISA. Our newly developed ISFET-based portable sensor holds a large potential for point-of-care tools in a variety of diseases, without being limited by the need for expensive equipment such as spectrophotometers.

Immunomagnetic nanoparticle-based assays for detection of biomarkers

The emergence of biomarkers as key players in the paradigm shift towards preventative medicine underscores the need for their detection and quantification. Advances made in the field of nanotechnology have played a crucial role in achieving these needs, and have contributed to recent advances in the field of medicine. Nanoparticle-based immunomagnetic assays, in particular, offer numerous advantages that utilize the unique physical properties of magnetic nanoparticles. In this review, we focus on recent developments and trends with regards to immunomagnetic assays used for detection of biomarkers. The various immunomagnetic assays are categorized into the following: particle-based multiplexing, signal control, microfluidics, microarray, and automation. Herein, we analyze each category and discuss their advantages and disadvantages.

Quantitative characterization of the lipid encapsulation of quantum dots for biomedical applications

UNLABELLEDnThe water solubilization of nanoparticles is key for many applications in biomedicine. Despite the importance of surface functionalization, progress has been largely empirical and very few systematic studies have been performed. Here we report on the water solubilization of quantum dots using lipid encapsulation. We systematically evaluate the monodispersity, zeta potential, stability, and quantum yield for quantum dots encapsulated with single and double acyl-chain lipids, pegylated double acyl-chain lipids, and single alkyl-chain surfactant molecules with charged head groups. We show that charged surfactants and pegylated lipids are important to obtain monodisperse suspensions with high yield and excellent long-term stability.nnnFROM THE CLINICAL EDITORnThis study reports on solubilization of nanoparticles in water, a key, but often neglected aspect for biomedical applications. The authors demonstrate that charged surfactants and PEGylated lipids are important to obtain monodisperse suspensions with high yield and long-term stability.

Microwave Annealing Effect for Highly Reliable Biosensor: Dual-Gate Ion-Sensitive Field-Effect Transistor Using Amorphous InGaZnO Thin-Film Transistor

We used a microwave annealing process to fabricate a highly reliable biosensor using amorphous-InGaZnO (a-IGZO) thin-film transistors (TFTs), which usually experience threshold voltage instability. Compared with furnace-annealed a-IGZO TFTs, the microwave-annealed devices showed superior threshold voltage stability and performance, including a high field-effect mobility of 9.51 cm(2)/V·s, a low threshold voltage of 0.99 V, a good subthreshold slope of 135 mV/dec, and an outstanding on/off current ratio of 1.18 × 10(8). In conclusion, by using the microwave-annealed a-IGZO TFT as the transducer in an extended-gate ion-sensitive field-effect transistor biosensor, we developed a high-performance biosensor with excellent sensing properties in terms of pH sensitivity, reliability, and chemical stability.