Risk-Based Control Strategies of Recombinant Monoclonal Antibody Charge Variants.

Since the first approval of the anti-CD3 recombinant monoclonal antibody (mAb), muromonab-CD3, a mouse antibody for the prevention of transplant rejection, by the US Food and Drug Administration (FDA) in 1986, mAb therapeutics have become increasingly important to medical care. A wealth of information about mAbs regarding their structure, stability, post-translation modifications, and the relationship between modification and function has been reported. Yet, substantial resources are still required throughout development and commercialization to have appropriate control strategies to maintain consistent product quality, safety, and efficacy. A typical feature of mAbs is charge heterogeneity, which stems from a variety of modifications, including modifications that are common to many mAbs or unique to a specific molecule or process. Charge heterogeneity is highly sensitive to process changes and thus a good indicator of a robust process. It is a high-risk quality attribute that could potentially fail the specification and comparability required for batch disposition. Failure to meet product specifications or comparability can substantially affect clinical development timelines. To mitigate these risks, the general rule is to maintain a comparable charge profile when process changes are inevitably introduced during development and even after commercialization. Otherwise, new peaks or varied levels of acidic and basic species must be justified based on scientific knowledge and clinical experience for a specific molecule. Here, we summarize the current understanding of mAb charge variants and outline risk-based control strategies to support process development and ultimately commercialization.

Dual Wavelength-Triggered Gold Nanorods for Anticancer Treatment.

Gold nanomaterials with light-responsive properties can be exploited as light-triggered delivery vehicles to enhance the therapeutic efficacy of anticancer drugs. Additionally, different wavelengths of light can be utilized to achieve the combined effects of light-triggered release of therapeutics and light-induced localized heating, which results in improved anticancer efficacy. Herein, we describe methods to develop gold nanorod (AuNR) complexes that provide drug delivery or photothermal therapy when activated by ultraviolet (UV) or near-infrared (NIR) wavelengths of light, respectively. The surface functionalization of AuNRs with three key components is presented. The first component, cyclodextrin, serves to encapsulate drugs of interest. The second component, dextran-phenyl-azo-benzoic acid (DexAzo), serves as a capping agent that undergoes a conformational change upon UV light activation to expose the drugs for release. The third component is a folic acid-based targeting ligand that provides efficient delivery of the AuNR complexes to cancer cells. The dual wavelength activation of these drug-loaded AuNR complexes, which enables one to achieve highly efficient anticancer therapy through the combined effects of UV-triggered drug release and NIR-induced hyperthermia, is also described.

Transformable liquid-metal nanomedicine.

To date, numerous inorganic nanocarriers have been explored for drug delivery systems (DDSs). However, the clinical application of inorganic formulations has often been hindered by their toxicity and failure to biodegrade. We describe here a transformable liquid-metal nanomedicine, based on a core-shell nanosphere composed of a liquid-phase eutectic gallium-indium core and a thiolated polymeric shell. This formulation can be simply produced through a sonication-mediated method with bioconjugation flexibility. The resulting nanoparticles loaded with doxorubicin (Dox) have an average diameter of 107 nm and demonstrate the capability to fuse and subsequently degrade under a mildly acidic condition, which facilitates release of Dox in acidic endosomes after cellular internalization. Equipped with hyaluronic acid, a tumour-targeting ligand, this formulation displays enhanced chemotherapeutic inhibition towards the xenograft tumour-bearing mice. This liquid metal-based DDS with fusible and degradable behaviour under physiological conditions provides a new strategy for engineering theranostic agents with low toxicity.

A dual wavelength-activatable gold nanorod complex for synergistic cancer treatment.

A multifunctional gold nanorod (AuNR) complex is described with potential utility for theranostic anticancer treatment. The AuNR was functionalized with cyclodextrin for encapsulation of doxorubicin, with folic acid for targeting, and with a photo-responsive dextran-azo compound for intracellular controlled drug release. The interaction of a AuNR complex with HeLa cells was facilitated via a folic acid targeting ligand as displayed in the dark-field images of cells. Enhanced anticancer efficacy was demonstrated through the synergistic combination of promoted drug release upon ultraviolet (UV) light irradiation and photothermal therapy upon infrared (IR) irradiation. This multifunctional AuNR-based system represents a novel theranostic strategy for spatiotemporal delivery of anticancer therapeutics.

Programmable nanomedicine: synergistic and sequential drug delivery systems.

Recent developments in nanomedicine for the cancer therapy have enabled programmable delivery of therapeutics by exploiting the stimuli-responsive properties of nanocarriers. These therapeutic systems were designed with the relevant chemical and physical properties that respond to different triggers for enhanced anticancer efficacy, including the reduced development of drug-resistance, lower therapeutic dose, site-specific transport, and spatiotemporally controlled release. This minireview discusses the current advances in programmable nanocarriers for cancer therapy with particular emphasis on synergistic and sequential drug delivery systems.

A temperature microsensor for measuring laser-induced heating in gold nanorods.

Measuring temperature is an extensively explored field of analysis, but measuring a temperature change in a nanoparticle is a new challenge. Here, a microsensor is configured to measure temperature changes in gold nanorods in solution upon laser irradiation. The device consists of a silicon wafer coated with silicon nitride in which a microfabricated resistance temperature detector was embedded and attached to a digital multimeter. A polydimethylsiloxane mold served as a microcontainer for the sample attached on top of the silicon membrane. This enables laser irradiation of the gold nanorods and subsequent measurement of temperature changes. The results showed a temperature increase of 8 to 10 °C and good correlation with theoretical calculations and bulk sample direct temperature measurements. These results demonstrate the suitability of this simple temperature microsensor for determining laser-induced heating profiles of metallic nanomaterials; such measurements will be essential for optimizing therapeutic and catalytic applications.

Small-molecule detection in thiol-yne nanocomposites via surface-enhanced Raman spectroscopy.

Surface-enhanced Raman spectroscopy (SERS) is generally performed on planar surfaces, which can be difficult to prepare and may limit the interaction of the sensing surface with targets in large volume samples. We propose that nanocomposite materials can be configured that both include SERS probes and provide a high surface area-to-volume format, i.e., fibers. Thiol-yne nanocomposite films and fibers were fabricated using exposure to long-wave ultraviolet light after the inclusion of gold nanoparticles (AuNPs) functionalized with thiophenol. A SERS response was observed that was proportional to the aggregation of the AuNPs within the polymers and the amount of thiophenol present. Overall, this proof-of-concept fabrication of SERS active polymers indicated that thiol-yne nanocomposites may be useful as durable film or fiber SERS probes. Properties of the nanocomposites were evaluated using various techniques including UV-vis spectroscopy, µ-Raman spectroscopy, dynamic mechanical analysis, differential scanning calorimetry, thermogravimetric analysis, and transmission electron microscopy.

Self-folded redox/acid dual-responsive nanocarriers for anticancer drug delivery.

Self-folded redox/acid dual-responsive nanocarriers (RAD-NCs) are developed for physiologically triggered delivery of anticancer drugs. The evidenced redox/acid responsiveness, facile decoration of ligands, and active tumor-targeting capability of RAD-NCs suggest their potential as a promising formulation for tumor-targeted chemotherapy.

Interrogating the catalytic mechanism of nanoparticle mediated Stille coupling reactions employing bio-inspired Pd nanocatalysts.

To address issues concerning the global environmental and energy state, new catalytic technologies must be developed that translate ambient and efficient conditions to heavily used reactions. To achieve this, the structure/function relationship between model catalysts and individual reactions must be critically discerned to identify structural motifs responsible for the reactivity. This is especially true for nanoparticle-based systems where this level of information remains limited. Here we present evidence indicating that peptide-capped Pd nanoparticles drive Stille C-C coupling reactions via Pd atom leaching. Through a series of reaction studies, the materials are shown to be optimized for reactivity under ambient conditions where increases in temperature or catalyst concentration deactivate reactivity due to the leaching process. A quartz crystal microbalance analysis demonstrates that Pd leaching occurs during the initial oxidative addition step at the nanoparticle surface by aryl halides. Together, this suggests that peptide-based materials may be optimally suited for use as model systems to isolate structural motifs responsible for the generation of catalytically reactive materials under ambient synthetic conditions.

Biological surface effects of metallic nanomaterials for applications in assembly and catalysis.

Recent experimental evidence has suggested that bioinspired techniques represent promising avenues toward the production of functional nanomaterials that possess a high degree of activity. These materials are prepared under synthetically simple and efficient conditions, thus making them attractive alternatives to many traditional methods that employ hazardous and harsh conditions. Many biomimetic methods employ peptide and amino acid binding events on the surfaces of nanostructures to generate materials that are stable in solution. The basis of both the stability and activity of these materials is likely to be controlled by the biotic/abiotic interface, which is mediated by the bioligand binding process. Unfortunately, most readily available techniques are unable to be used to study this intrinsic process; however, very recent studies have begun to shed light on this important event. In this feature article, an overview of the understanding of peptide and amino acid binding events to nanomaterials and how these motifs can be exploited for activities in nanoparticle assembly and catalytic reactivity is discussed. From both 2D surface studies and computational modeling analyses, different biomolecule binding characteristics have been elucidated. These results indicate that the amino acid sequence and peptide secondary structure play important roles in the binding capability. Furthermore, these studies suggest that the peptides are able to form specific patterns and motifs once bound to the nanoparticle surface. This attribute could affect the nanoparticle electronics and can play a significant role in their activities to generate functional materials. From these binding motifs, the ability of reagents to interact with the metallic surface is possible, thus affecting many of the properties of these materials.

Employing high-resolution materials characterization to understand the effects of Pd nanoparticle structure on their activity as catalysts for olefin hydrogenation.

Recent developments in nanotechnology have led to the production of new materials with a wide array of applications, particularly in catalysis. Because of their small size, nanoparticles have a maximized surface-to-volume ratio, thus making them attractive targets for use as catalytic structures; however, the number of analytical techniques available to fully characterize materials on such a size scale is quite limited. As a result, a complete understanding of the entire nanoparticle structure remains unclear, especially when considering the active structural motif from which the specific activity arises. Metallic Pd materials have been widely studied due to their immense potential as catalysts for reactions such as olefin hydrogenation and C-C bond synthesis. These materials require surface passivants to act as ligands and stabilize the nanoparticles against aggregation and bulk formation. These ligands have the added value to function as gates that selectively allow reagents to reach the active surface of the Pd nanoparticles for chemical turnover. This accounts for the observed selectivities of the catalysts with the corresponding changes in the turnover frequency values. Here we present a broad overview of recent advances in the use of Pd nanoparticles for the industrially important hydrogenation reaction with a focus on characterizing and understanding the base structural effects that give rise to the catalytic activity.

Biomimetic synthesis of Pd nanocatalysts for the Stille coupling reaction.

Here we report on the biomimetic synthesis of Pd nanoparticles for use as models of green catalytic systems. The nanomaterials are synthesized using peptides isolated via phage-display techniques that are specific to Pd surfaces. Using this synthetic strategy, peptide-functionalized Pd nanoparticles of 1.9 +/- 0.3 nm in diameter are produced, which are soluble and stable in aqueous solutions. Once characterized, these biobased materials were then used as catalysts to drive the formation of C-C bonds using the Stille coupling reaction. Under the conditions of an aqueous solvent at room temperature, quantitative product yields were achieved within 24.0 h employing catalyst loadings of > or = 0.005 mol % of Pd. Additionally, high TOF values of 3207 +/- 269 mol product x (mol Pd x h)(-1) have been determined for these materials. The catalytic reactivity was then examined over a set of substrates with substitutions for both functional group and halide substituents, demonstrating that the peptide-based Pd nanoparticles are reactive toward a variety of functionalities. Taken together, these bioinspired materials represent unique model systems for catalytic studies to elucidate ecologically friendly reactive species and conditions.