Spatial Organization of Superparamagnetic Iron Oxide Nanoparticles in/on Nano/Microsized Carriers Modulates the Magnetic Resonance Signal.

Superparamagnetic iron oxide nanoparticles (SPIONs) are often encapsulated into drug-carrying nano/microsized particles for simultaneous magnetic resonance (MR) imaging and treatment of diseased tissues. Unfortunately, encapsulated SPIONs may have a limited ability to modulate the T2-weighted relaxation of water protons, but this insight has not been examined systematically. This study demonstrates that SPIONs immobilized on 200 nm diameter poly(lactic- co-glycolic acid) (PLGA) nanoparticles using Pickering emulsification present 18-fold higher relaxivity than encapsulated SPIONs and 1.5-fold higher relaxivity than free SPIONs. In contrast, the SPIONs immobilized on 10 µm diameter PLGA particles exhibit a minor increase in MR relaxivity. This interesting finding will significantly impact current efforts to synthesize and assemble advanced MR contrast agents.

Self-Assembled, Biodegradable Magnetic Resonance Imaging Agents: Organic Radical-Functionalized Diblock Copolymers.

We report the design, synthesis, and evaluation of biodegradable amphiphilic poly(ethylene glycol)-b-polycarbonate-based diblock copolymers containing pendant persistent organic radicals (e.g., PROXYL). These paramagnetic radical-functionalized polymers self-assemble into micellar nanoparticles in aqueous media, which preferentially accumulate in tumor tissue via the enhanced permeability and retention (EPR) effect. Through T1 relaxation NMR studies, as well as magnetic resonance imaging (MRI) studies on mice, we show that these nanomaterials are effective as metal-free, biodegradable MRI contrast agents. We also demonstrate anticancer drugs can be readily loaded into the nanoparticles, conferring therapeutic delivery properties in addition to their imaging properties making these materials potential theranostic agents in the treatment of cancer.

Worm-Like Superparamagnetic Nanoparticle Clusters for Enhanced Adhesion and Magnetic Resonance Relaxivity.

Nanosized bioprobes that can highlight diseased tissue can be powerful diagnostic tools. However, a major unmet need is a tool with adequate adhesive properties and contrast-to-dose ratio. To this end, this study demonstrates that targeted superparamagnetic nanoprobes engineered to present a worm-like shape and hydrophilic packaging enhance both adhesion efficiency to target substrates and magnetic resonance (MR) sensitivity. These nanoprobes were prepared by the controlled self-assembly of superparamagnetic iron oxide nanoparticles (SPIONs) into worm-like superstructures using glycogen-like amphiphilic hyperbranched polyglycerols functionalized with peptides capable of binding to defective vasculature. The resulting worm-like SPION clusters presented binding affinity to the target substrate 10-fold higher than that of spherical ones and T2 molar MR relaxivity 3.5-fold higher than that of conventional, single SPIONs. The design principles discovered for these nanoprobes should be applicable to a range of other diseases where improved diagnostics are needed.

Functionalized ultrathin palladium nanosheets as patches for HepG2 cancer cells.

Flexible, charged Pd nanosheets were prepared by using short chain thiolated carboxylic acids and amines. They could wrap around amine or hydroxyl functionalized micron-sized spheres driven by electrostatic interactions. Upon incubation with HepG2 cells, the positively charged cysteamine (CA) functionalized Pd nanosheets exhibited a much higher cytotoxicity, showing more than 80% cell death at 100 ppm than the negatively charged 3-mercaptopropionic acid (MPA) functionalized ones which caused 30% cell death. The results show through surface functionalization Pd nanosheets can be modified to interact differently with HepG2 cancerous cells, resulting in varied cytotoxicity.

Hydrophilic packaging of iron oxide nanoclusters for highly sensitive imaging.

Superparamagnetic iron oxide nanoparticles (SPIONs) are used as imaging probes to provide contrast in magnetic resonance images. Successful use of SPIONs in targeted applications greatly depends on their ability to generate contrast, even at low levels of accumulation, in the tissue of interest. In the present study, we report that SPION nanoclusters packaged to a controlled size by a hyperbranched polyglycerol (HPG) can target tissue defects and have a high relaxivity of 719 mM(-1) s(-1), which was close to their theoretical maximal limit. The resulting nanoclusters were able to identify regions of defective vasculature in an ischemic murine hindlimb using MRI with iron doses that were 5-10 fold lower than those typically used in preclinical studies. Such high relaxivity was attributed to the molecular architecture of HPG, which mimics that of the water retentive polysaccharide, glycogen. The results of this study will be broadly useful in sensitive imaging applications.

Tailoring polymersome bilayer permeability improves enhanced permeability and retention effect for bioimaging.

Self-assembled nanoparticles conjugated with various imaging contrast agents have been used for the detection and imaging of pathologic tissues. Inadvertently, these nanoparticles undergo fast, dilution-induced disintegration in circulation and quickly lose their capability to associate with and image the site of interest. To resolve this challenge, we hypothesize that decreasing the bilayer permeability of polymersomes can stabilize their structure, extend their lifetime in circulation, and hence improve the quality of bioimaging when the polymersome is coupled with an imaging probe. This hypothesis is examined by using poly(2-hydroxyethyl-co-octadecyl aspartamide), sequentially modified with methacrylate groups, to build model polymersomes. The bilayer permeability of the polymersome is decreased by increasing the packing density of the bilayer with methacrylate groups and is further decreased by inducing chemical cross-linking reactions between the methacrylate groups. The polymersome with decreased bilayer permeability demonstrates greater particle stability in physiological media and ultimately can better highlight tumors in mice over 2 days compared to those with higher bilayer permeability after labeling with a near-infrared (NIR) fluorescent probe. We envisage that the resulting nanoparticles will not only improve diagnosis but also further image-guided therapies.

Recapitulating cell-cell adhesion using N-cadherin biologically tethered to substrates.

Intercellular adhesion modulated by cadherin molecules plays an important role in diverse cellular functions including tissue morphogenesis, regeneration, and pathogenesis. However, it is a challenging task to decipher the effects of cell-cell adhesion in vitro because of difficulty in controlling the extent and numbers of cell-cell contacts. In this study, we hypothesize that tethering recombinant extracellular domains of neural cadherin with a C-terminal immunoglobulin Fc domain (N-Cad-Fc) to a substrate with an immobilized anti-Fc antibody (Fc-antibody) and a bifunctional polymer, which is reactive to both protein and substrate, would allow us to recapitulate cell-cell adhesion, independent of the number of cells plated on the substrate. To examine this hypothesis, we first immobilized Fc-antibody to a polyacrylamide hydrogel and a methacrylate-substituted glass using poly(amino-2-hydroxyethyl-co-2-methacryloxyethyl aspartamide)-g-poly(ethylene glycol)-N-hydroxysuccinimide ester (PHMAA-g-PEGNHS) and then incubated the gel in medium containing defined concentrations of the recombinant N-Cad-Fc. The resulting N-Cad-conjugated substrate enabled us to modulate adhesion of bone marrow stromal cells to the gel surface by varying the surface density of N-Cad-Fc. In contrast, direct chemical conjugation of N-Cad-Fc to the gel surface did not support cell adhesion. Additionally, the glass substrate biologically tethered with N-Cad-Fc promoted neuronal adhesion significantly more than substrates coated with poly-l-lysine. We suggest that this novel biological tethering method could be broadly applicable for modifying substrates with a variety of classical cadherins to enable the systematic study of the effects of cadherin-modulated cell-cell adhesion on cellular activities.

Cross-linkable liposomes stabilize a magnetic resonance contrast-enhancing polymeric fastener.

Liposomes are commonly used to deliver drugs and contrast agents to their target site in a controlled manner. One of the greatest obstacles in the performance of such delivery vehicles is their stability in the presence of serum. Here, we demonstrate a method to stabilize a class of liposomes that load gadolinium, a magnetic resonance (MR) contrast agent, as a model cargo on their surfaces. We hypothesized that the sequential adsorption of a gadolinium-binding chitosan fastener on the liposome surface followed by covalent cross-linking of the lipid bilayer would provide enhanced stability and improved MR signal in the presence of human serum. To investigate this hypothesis, liposomes composed of diyne-containing lipids were assembled and functionalized via chitosan conjugated with a hydrophobic anchor and diethylenetriaminepentaacetic acid (DTPA). This postadsorption cross-linking strategy served to stabilize the thermodynamically favorable association between liposome and polymeric fastener. Furthermore, the chitosan-coated, cross-linked liposomes proved more effective as delivery vehicles of gadolinium than uncross-linked liposomes due to the reduced liposome degradation and chitosan desorption. Overall, this study demonstrates a useful method to stabilize a broad class of particles used for systemic delivery of various molecular payloads.

A polymeric fastener can easily functionalize liposome surfaces with gadolinium for enhanced magnetic resonance imaging.

Common methods of loading magnetic resonance imaging (MRI) contrast agents into nanoparticles often suffer from challenges related to particle formation, complex chemical modification/purification steps, and reduced contrast efficiency. This study presents a simple, yet advanced process to address these issues by loading gadolinium, an MRI contrast agent, exclusively on a liposome surface using a polymeric fastener. The fastener, so named for its ability to physically link the two functional components together, consisted of chitosan substituted with diethylenetriaminepentaacetic acid (DTPA) to chelate gadolinium, as well as octadecyl chains to stabilize the modified chitosan on the liposome surface. The assembly strategy, mimicking the mechanisms by which viruses and proteins naturally anchor to a cell, provided greater T1 relaxivity than liposomes loaded with gadolinium in both the interior and outer leaflet. Gadolinium-coated liposomes were ultimately evaluated in vivo using murine ischemia models to highlight the diagnostic capability of the system. Taken together, this process decouples particle assembly and functionalization and, therefore, has considerable potential to enhance imaging quality while alleviating many of the difficulties associated with multifunctional particle fabrication.

Flow-mediated stem cell labeling with superparamagnetic iron oxide nanoparticle clusters.

This study presents a strategy to enhance the uptake of superparamagnetic iron oxide nanoparticle (SPIO) clusters by manipulating the cellular mechanical environment. Specifically, stem cells exposed to an orbital flow ingested almost a 2-fold greater amount of SPIO clusters than those cultured statically. Improvements in magnetic resonance (MR) contrast were subsequently achieved for labeled cells in collagen gels and a mouse model. Overall, this strategy will serve to improve the efficiency of cell tracking and therapies.

A liposome-based ion release impedance sensor for biological detection.

Low-cost detection of pathogens and biomolecules at the point-of-care promises to revolutionize medicine through more individualized monitoring and increased accessibility to diagnostics in remote and resource-limited areas. While many approaches to biosensing are still limited by expensive components or inadequate portability, we present here an ELISA-inspired lab-on-a-chip strategy for biological detection based on liposome tagging and ion-release impedance spectroscopy. Ion-encapsulating dipalmitoylphosphatidylcholine (DPPC) liposomes can be functionalized with antibodies and are stable in deionized water yet permeabilized for ion release upon heating, making them ideal reporters for electrical biosensing of surface-immobilized antigens. We demonstrate the quantification of these liposomes by real-time impedance measurements, as well as the qualitative detection of viruses as a proof-of-concept toward a portable platform for viral load determination which can be applied broadly to the detection of pathogens and other biomolecules.

Leukocyte-mimicking stem cell delivery via in situ coating of cells with a bioactive hyperbranched polyglycerol.

Since stem cells emerged as a new generation of medicine, there are increasing efforts to deliver stem cells to a target tissue via intravascular injection. However, the therapeutic stem cells lack the capacity to detect and adhere to the target tissue. Therefore, this study presents synthesis of a bioactive hyperbranched polyglycerol (HPG) that can noninvasively associate with stem cells and further guide them to target sites, such as inflamed endothelium. The overall process is analogous to the way in which leukocytes are mobilized to the injured endothelium.

A highly selective colorimetric aqueous sensor for mercury.

A new colorimetric mercury sensor is reported based on binding to terpyridine derivatives. It is able to selectively detect Hg II ions over a number of environmentally relevant ions including Ca II, Pb II, Zn II, Cd II, Ni II, Cu II, and others. The response time upon exposure to Hg II is instantaneous. By the "naked eye," the detection limit of Hg II is 2 ppm (25 microM) in solution. With a spectrometer, this detection limit is increased down to 2 ppb (25 nM), which is the current EPA standard for drinking water. The significant problem of mercury poisoning requires new methods of detection that are sensitive and selective. Here we report a new simple system that takes advantage of the unique optical properties generated by terpyiridine-Hg complexes.