Cell aggregates, or spheroids, have been used as building blocks to fabricate scaffold-free tissues that can closely mimic the native three-dimensional in vivo environment for broad applications including regenerative medicine and high throughput testing of drugs. The incorporation of magnetic nanoparticles (MNPs) into spheroids permits the manipulation of spheroids into desired shapes, patterns, and tissues using magnetic forces. Current strategies incorporating MNPs often involve cellular uptake, and should therefore be avoided because it induces adverse effects on cell activity, viability, and phenotype. Here, we report a Janus structure of magnetic cellular spheroids (JMCS) with spatial control of MNPs to form two distinct domains: cells and extracellular MNPs. This separation of cells and MNPs within magnetic cellular spheroids was successfully incorporated into cellular spheroids with various cellular and extracellular compositions and contents. The amount of cells that internalized MNPs was quantified and showed that JMCSs resulted in significantly lower internalization (35%) compared to uptake spheroids (83%, p < 0.05). Furthermore, the addition of MNPs to cellular spheroids using the Janus method has no adverse effects on cellular viability up to seven weeks, with spheroids maintaining at least 82% viability over 7 weeks when compared to control spheroids without MNPs. By safely incorporating MNPs into cellular spheroids, results demonstrated that JMCSs were capable of magnetic manipulation, and that magnetic forces used during magnetic force assembly mediate fusion into controlled patterns and complex tissues. Finally, JMCSs were assembled and fused into a vascular tissue construct 5 mm in diameter using magnetic force assembly.

Despite a cost of approximately $1 billion to develop a new cancer drug, about 90% of drugs that enter clinical trials fail. A tremendous opportunity exists to streamline the drug selection and testing process, and innovative approaches promise to reduce the burdensome cost of health care for those suffering from cancer. There is great potential for 3D models of human tumors to complement more traditional testing methods; however, the shift from 2D to 3D assays at early stages of the drug discovery and development process is far from widely accepted. 3D platforms range from simple tumor spheroids to more complex microfluidic hydrogels that better mimic the tumor microenvironment. While several companies have developed and patented advanced high-throughput 3D platforms for drug screening, their cost and complexity have limited their adoption as an industry standard. In this review, we will highlight the various tumor platforms that have been developed, emphasizing the approaches that have successfully led to commercial products. We will then consider potential directions toward more relevant tumor models, advantages of the adoption of such platforms within the drug development and screening process, and new opportunities in personalized medicine that such platforms will uniquely enable.

Peripherally inserted central catheters (PICCs) are hollow polymeric tubes that transport nutrients, blood and medications to neonates. To determine proper PICC placement, frequent X-ray imaging of neonates is performed. Because X-rays pose severe health risks to neonates, safer alternatives are needed. We hypothesize that near infrared (NIR) polymer composites can be fabricated into catheters by incorporating a fluorescent dye (IRDye 800CW) and visualized using NIR imaging. To fabricate catheters, polymer and dye are dry mixed and pressed, sectioned, and extruded to produce hollow tubes. We analyzed surface roughness, stiffness, dye retention, NIR contrast intensity, and biocompatibility. The extrusion process did not significantly alter the mechanical properties of the polymer composites. Over a period of 23 days, only 6.35 ± 5.08% dye leached out of catheters. The addition of 0.025 wt% dye resulted in a 14-fold contrast enhancement producing clear PICC images at 1 cm under a tissue equivalent. The addition of IRDye 800CW did not alter the biocompatibility of the polymer and did not increase adhesion of cells to the surface. We successfully demonstrated that catheters can be imaged without the use of harmful radiation and still maintain the same properties as the unaltered medical grade equivalent.

Current chemotherapy treatments are limited by poor drug solubility, rapid drug clearance and systemic side effects. Additionally, drug penetration into solid tumors is limited by physical diffusion barriers [e.g., extracellular matrix (ECM)]. Nanoparticle (NP) blood circulation half-life, biodistribution and ability to cross extracellular and cellular barriers will be dictated by NP composition, size, shape and surface functionality. Here, we investigated the effect of surface charge of poly(lactide)-poly(ethylene glycol) NPs on mediating cellular interaction. Polymeric NPs of equal sizes were used that had two different surface functionalities: negatively charged carboxyl (COOH) and neutral charged methoxy (OCH3). Cellular uptake studies showed significantly higher uptake in human brain cancer cells compared to noncancerous human brain cells, and negatively charged COOH NPs were uptaken more than neutral OCH3 NPs in 2D culture. NPs were also able to load and control the release of paclitaxel (PTX) over 19 days. Toxicity studies in U-87 glioblastoma cells showed that PTX-loaded NPs were effective drug delivery vehicles. Effect of surface charge on NP interaction with the ECM was investigated using collagen in a 3D cellular uptake model, as collagen content varies with the type of cancer and the stage of the disease compared to normal tissues. Results demonstrated that NPs can effectively diffuse across an ECM barrier and into cells, but NP mobility is dictated by surface charge. In vivo biodistribution of OCH3 NPs in intracranial tumor xenografts showed that NPs more easily accumulated in tumors with less collagen. These results indicate that a robust understanding of NP interaction with various tumor environments can lead to more effective patient-tailored therapies.

Gold-gold sulfide nanoparticles are of interest for drug delivery, biomedical imaging, and photothermal therapy applications due to a facile synthesis method resulting in small particles with high near-infrared (NIR) absorption efficiency. Previous studies suggest that the NIR sensitivity of these nanoparticles was due to hexagonally shaped metal-coated dielectric nanoparticles that consist of a gold sulfide core and gold shell. Here, we illustrate that the conventional synthesis procedure results in the formation of polydisperse samples of icosahedral gold particles, gold nanoplates, and small gold spheres. Importantly, through compositional analysis, via UV/vis absorption spectrophotometry, transmission electron microscopy (TEM), and energy dispersive x-ray spectroscopy (EDS), we show that all of the nanoparticles exhibit identical face center cubic (FCC) gold crystalline structures, thus suggesting that sulfide is not present in the final fabricated nanoparticles. We show that icosahedrally shaped nanoparticles result in a blue-shifted absorbance, with a peak in the visible range. Alternatively, the nanoplate nanoparticles result in the characteristic NIR absorbance peak. Thus, we report that the NIR-contributing species in conventional gold-gold sulfide formulations are nanoplates that are comprised entirely of gold. Furthermore, polydisperse gold nanoparticle samples produced by the traditional one-step reduction of HAuCl4 by sodium thiosulfate show increased in vitro toxicity, compared to isolated and more homogeneous constituent samples. This result exemplifies the importance of developing monodisperse nanoparticle formulations that are well characterized in order to expedite the development of clinically beneficial nanomaterials.