Cameron W. Evans

Green chemistry and the health implications of nanoparticles

Until recently the spectacular developments in nanotechnology have been with little regard to their potential effect on human health and the environment. There are no specific regulations on nanoparticles except existing regulations covering the same material in bulk form. Difficulties abound in devising such regulations, beyond self-imposed regulations by responsible companies, because of the likelihood of different properties exhibited by any one type of nanoparticle, which are tuneable by changing their size, shape and surface characteristics. Green chemistry metrics need to be incorporated into nanotechnologies at the source. This review scopes this issue in the context of potential health effects of nanoparticles, along with medical applications of nanoparticles including imaging, drug delivery, disinfection, and tissue repair. Nanoparticles can enter the human body through the lungs, the intestinal tract, and to a lesser extent the skin, and are likely to be a health issue, although the extent of effects on health are inconclusive. Nanoparticles can be modified to cross the brain blood barrier for medical applications, but this suggests other synthetic nanoparticles may unintentionally cross this barrier.

Multimodal analysis of PEI-mediated endocytosis of nanoparticles in neural cells.

Polymer nanoparticles are widely used as a highly generalizable tool to entrap a range of different drugs for controlled or site-specific release. However, despite numerous studies examining the kinetics of controlled release, the biological behavior of such nanoparticles remains poorly understood, particularly with respect to endocytosis and intracellular trafficking. We synthesized polyethylenimine-decorated polymer nanospheres (ca. 100-250 nm) of the type commonly used for drug release and used correlated electron microscopy, fluorescence spectroscopy and microscopy, and relaxometry to track endocytosis in neural cells. These capabilities provide insight into how polyethylenimine mediates the entry of nanoparticles into neural cells and show that polymer nanosphere uptake involves three distinct steps, namely, plasma membrane attachment, fluid-phase as well as clathrin- and caveolin-independent endocytosis, and progressive accumulation in membrane-bound intracellular vesicles. These findings provide detailed insight into how the intracellular delivery of nanoparticles is mediated by polyethylenimine, which is presently the most commonly used nonviral gene transfer agent. This fundamental knowledge may also assist in the preparation of next-generation nonviral vectors.

In vivo Imaging and Biodistribution of Multimodal Polymeric Nanoparticles Delivered to the Optic Nerve

The use of nanoparticles for targeted delivery of therapeutic agents to sites of injury or disease in the central nervous system (CNS) holds great promise. However, the biodistribution of nanoparticles following in vivo administration is often unknown, and concerns have been raised regarding potential toxicity. Using poly(glycidyl methacrylate) (PGMA) nanoparticles coated with polyethylenimine (PEI) and containing superparamagnetic iron oxide nanoparticles as a magnetic resonance imaging (MRI) contrast agent and rhodamine B as a fluorophore, whole animal MRI and fluorescence analyses are used to demonstrate that these nanoparticles (NP) remain close to the site of injection into a partial injury of the optic nerve, a CNS white matter tract. In addition, some of these NP enter axons and are transported to parent neuronal somata. NP also remain in the eye following intravitreal injection, a non-injury model. Considerable infiltration of activated microglia/macrophages occurs in both models. Using magnetic concentration and fluorescence visualization of tissue homogenates, no dissemination of the NP into peripheral tissues is observed. Histopathological analysis reveals no toxicity in organs other than at the injection sites. Multifunctional nanoparticles may be a useful mechanism to deliver therapeutic agents to the injury site and somata of injured CNS neurons and thus may be of therapeutic value following brain or spinal cord trauma.

Sequential microfluidic flow synthesis of CePO4 nanorods decorated with emission tunable quantum dots

CePO(4) nanorods decorated with QDs (QDs@CePO(4)) can be prepared in a sequential, aqueous procedure under continuous flow using a rotating tube processor and a narrow channel reactor. The emission from the QD@CePO(4) is tunable from green to red by simply adjusting the feeding rate, which in turn regulates the particle size of the QDs. The Ce(3+) ions in the QDs@CePO(4) serve as an efficient fluorescence resonance energy transfer (FRET) donor, effectively enlarging the Stokes shift of the QDs.

Multimodal and multifunctional stealth polymer nanospheres for sustained drug delivery

We report the preparation of fluorescent and magnetic PMMA nanospheres, and a corresponding PEGylated ‘stealth’ analogue prepared using a block copolymer. The nanospheres contain encapsulated magnetite nanoparticles and fluorescent BODIPY dyes, including a new such dye with pH-sensitive fluorescent emission. The new dye could potentially be used as an indicator of the immediate physiological environment. The nanospheres were non-toxic at up to 500 μg ml−1 in PC12 cells. Lomerizine, a lipophilic calcium channel blocker, was also encapsulated in the nanospheres and displayed sustained, pH-dependent release characteristics. The nanospheres may be of use to release lomerizine and other water-insoluble drugs at central nervous system injury sites.

The potential for nanotechnology to improve delivery of therapy to the acute ischemic heart

Treatment of acute cardiac ischemia remains an area in which there are opportunities for therapeutic improvement. Despite significant advances, many patients still progress to cardiac hypertrophy and heart failure. Timely reperfusion is critical in rescuing vulnerable ischemic tissue and is directly related to patient outcome, but reperfusion of the ischemic myocardium also contributes to damage. Overproduction of reactive oxygen species, initiation of an inflammatory response and deregulation of calcium homeostasis all contribute to injury, and difficulties in delivering a sufficient quantity of drug to the affected tissue in a controlled manner is a limitation of current therapies. Nanotechnology may offer significant improvements in this respect. Here, we review recent examples of how nanoparticles can be used to improve delivery to the ischemic myocardium, and suggest some approaches that may lead to improved therapies for acute cardiac ischemia.

Nanosized luminescent superparamagnetic hybrids

The combination of fluorescent and magnetic properties in single nanosystems is of current interest for applications in the biomedical and biological sciences, including drug delivery, and cell separation and labelling procedures. These nanocomposite particles are generally synthesised using high-temperature procedures, and many involve encapsulation in a silica or polymer coating. The resulting large particle size may limit the use of these nanocomposites in biological work. We demonstrate an aqueous self-assembly route to fabricate nanohybrids combining cadmium telluride quantum dots and magnetite nanoparticles. The entire procedure is conducted under aqueous conditions to improve sustainability and physiological compatibility. The resulting nanocomposite displays strong fluorescent emission, and superparamagnetic behaviour.

Sensitizing basal-like breast cancer to chemotherapy using nanoparticles conjugated with interference peptide

Basal-like breast cancers are highly aggressive malignancies associated with very poor prognosis. Although these cancers may initially respond to first-line treatment, they become highly resistant to standard chemotherapy in the metastatic setting. Chemotherapy resistance in basal-like breast cancers is associated with highly selective overexpression of the homeobox transcription factor Engrailed 1 (EN1). Herein, we propose a novel therapeutic strategy using poly(glycidyl methacrylate) nanoparticles decorated with poly(acrylic acid) that enable dual delivery of docetaxel and interference peptides designed to block or inhibit EN1 (EN1-iPep). We demonstrate that EN1-iPep is highly selective in inducing apoptotic cell death in basal-like cancer cells with negligible effects in a non-neoplastic human mammary epithelial cell line. Furthermore, we show that treatment with EN1-iPep results in a highly synergistic pharmacological interaction with docetaxel in inhibiting cancer cell growth. The incorporation of these two agents in a single nanoformulation results in greater anticancer efficacy than current nanoparticle-based treatments used in the clinical setting.

Nanoparticle-mediated internalisation and release of a calcium channel blocker

Lomerizine is a calcium channel blocker that selectively blocks L- and T-type Ca2+ channels, but it is effectively insoluble under physiological conditions. Herein we show that lomerizine can be released from a nanoparticle-based carrier by intracellular protonation in PC12 cells, suppressing Ca2+ influx in these cells in response to glutamate.

Multifunctional nanoadditives for the thermodynamic and kinetic stabilization of enzymes

Stabilization of enzymes has become a major focus in the quest to improve the activity, sustainability and recyclability of enzymes for their successful integration into both industry and medicine. Here, we describe the kinetic and thermodynamic stabilization of a variety of enzymes in the presence of cationic multifunctional polymeric nanoparticles.