Magnetic nanoparticles (MNPs) have unique properties suitable for numerous biomedical applications. Here, the utility of MNPs for drug delivery applications were examined through two features: magnetic capture and hyperthermia-triggered release. Magnetic localization of the nanoparticles was investigated using iron oxide nanoparticles in simulated blood flow, with the effectiveness of magnetic capture tested as a function of field strength, vessel diameter, flow rate, and the presence of blood proteins. The dispersion quality and viscosity also impact capture. After localization, drug release can be triggered using MNPs imbedded in thermosensitive hydrogels. The tuning of the lower critical solution temperature in poly(N-isopropylacrylamide-co-acrylamide) gels allows triggering to release a drug when mild heating is applied. Thermally modulated release showed that 5-fluorouracil, an anticancer agent, could be effectively squeezed from gels containing 90% NIPAAm upon heating. Additionally, MNPs were successfully dispersed into hydrogels with minimal visible agglomerations, and were largely retained within the hydrogel structure despite their size of less than 10 nm. Magnetic heating of hydrogels with imbedded MNPs was demonstrated. The materials described herein provide a reasonable foundation for the design of magnetothermally responsive gels, which have the potential for triggered drug release using a magnetic field applied from outside of the body.

Magnetic iron oxide nanoparticles (MNPs) have been developed for magnetic fluid hyperthermia (MFH) cancer therapy, where cancer cells are treated through the heat generated by application of a high frequency magnetic field. This heat has also been proposed as a mechanism to trigger release of chemotherapy agents. In each of these cases, MNPs with optimal heating performance can be used to maximize therapeutic effect while minimizing the required dosage of MNPs. In this study, the heating efficiencies (or specific absorption rate, SAR) of two types of MNPs were evaluated experimentally and then predicted from their magnetic properties. MNPs were also incorporated in the core of poly(ethylene glycol-b-caprolactone) micelles, co-localized with rhodamine B fluorescent dye attached to polycaprolactone to monitor local, nanoscale temperatures during magnetic heating. Despite a relatively high SAR produced by these MNPs, no significant temperature rise beyond that observed in the bulk solution was measured by fluorescence in the core of the magnetic micelles. MNPs were also incorporated into a macro-scale agarose gel system that mimicked a tumor targeted by MNPs and surrounded by healthy tissues. The agarose-based tumor models showed that targeted MNPs can reach hyperthermia temperatures inside a tumor with a sufficient MNP concentration, while causing minimal temperature rise in the healthy tissue surrounding the tumor.

Single‐use bioprocessing bags are gaining popularity due to ease of use, lower risk of contamination, and ease of process scale‐up. Bis(2,4‐di‐tert‐butylphenyl)phosphate (bDtBPP), a degradant of tris(2,4‐di‐tert‐butylphenyl)phosphite, marketed as Irgafos 168®, which is an antioxidant stabilizer added to resins, has been identified as a potentially toxic leachate which may impact the performance of single‐use, multilayer bioprocessing bags. In this study, the toxicity of bDtBPP was tested on CHO‐K1 cells grown as adherent or suspended cells. The EC50 (effective concentration to cause 50% cell death) for adherent cells was found to be one order of magnitude higher than that for suspended CHO‐K1 cells. While CHO‐K1 cells had good cell viability when exposed to moderate concentrations of bDtBPP, the degradant was shown to impact the viable cell density (VCD) at much lower concentrations. Hence, in developing an industry‐standard assay for testing the cytotoxicity of leachates, suspended cells (as commonly used in the bioprocessing industry) would likely be most sensitive, particularly when reporting EC50 values based on VCD. The effects of mixing, cell culture volume, and exposure duration were also evaluated for suspended CHO‐K1 cells. It was found that the sensitivity of cell culture to leachates from single‐use plastic bags was enhanced for suspended cells cultured for longer exposure times and when the cells were subjected to continuous agitation, both of which are important considerations in the production of biopharmaceuticals. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:1318–1323, 2016

Heating of nanoparticles (NPs) using an AC magnetic field depends on several factors, and optimization of these parameters can improve the efficiency of heat generation for effective cancer therapy while administering a low NP treatment dose. This study investigated magnetic field strength and frequency, NP size, NP concentration, and solution viscosity as important parameters that impact the heating efficiency of iron oxide NPs with magnetite (Fe3O4) and maghemite (γ-Fe2O3) crystal structures. Heating efficiencies were determined for each experimental setting, with specific absorption rates (SARs) ranging from 3.7 to 325.9 W/g Fe. Magnetic heating was conducted on iron oxide NPs synthesized in our laboratories (with average core sizes of 8, 11, 13, and 18 nm), as well as commercially-available iron oxides (with average core sizes of 8, 9, and 16 nm). The experimental magnetic coil system made it possible to isolate the effect of magnetic field parameters and independently study the effect on heat generation. The highest SAR values were found for the 18 nm synthesized particles and the maghemite nanopowder. Magnetic field strengths were applied in the range of 15.1–47.7 kA/m, with field frequencies ranging from 123 to 430 kHz. The best heating was observed for the highest field strengths and frequencies tested, with results following trends predicted by the Rosensweig equation. An increase in solution viscosity led to lower heating rates in nanoparticle solutions, which can have significant implications for the application of magnetic fluid hyperthermia in vivo.

The inclusion of magnetic nanoparticles into block copolymer micelles was studied towards the development of a targeted, magnetically triggered drug delivery system for cancer therapy. Herein, we report the synthesis of magnetic nanoparticles and poly(ethylene glycol-b-caprolactone) block copolymers, and experimental verification of magnetic heating of the nanoparticles, self-assembly of the block copolymers to form magnetic micelles, and thermally-enhanced drug release. The semicrystalline core of the micelles melted at temperatures just above physiological conditions, indicating that they could be used to release a chemotherapy agent from a thermoresponsive polymer system. The magnetic nanoparticles were shown to heat effectively in high frequency magnetic fields ranging from 30-70 kA/m. Magnetic micelles also showed heating properties, that when combined with a chemotherapeutic agent and a targeting ligand could be developed for localized, triggered drug delivery. During the magnetic heating experiments, a time lag was observed in the temperature profile for magnetic micelles, likely due to the heat of fusion of melting of polycaprolactone micelle cores before bulk solution temperatures increased. Doxorubicin, incorporated into the micelles, released faster when the micelles were heated above the core melting point.

Iron oxide (IO) nanoparticles hold great promise as diagnostic and therapeutic agents in oncology. Their intrinsic physical properties make IO nanoparticles particularly interesting for simultaneous drug delivery, molecular imaging, and applications such as localized hyperthermia. Multiple non-targeted IO nanoparticle preparations have entered clinical trials, but more exciting, new tumortargeted IO nanoparticle preparations are currently being tested in preclinical settings. This paper will analyze the challenges faced by this new theranostic modality, with a specific focus on the interactions of IO nanoparticles with the innate and adaptive immune systems, and their effect on nanoparticle biodistribution and tumor targeting. Next, we will review the critical need for innovative surface chemistry solutions and strategies to overcome the immune interactions that prevent existing tumor-targeted IO preparations from entering clinical trials. Finally, we will provide an outlook for the future role of IO nanoparticles in oncology, which have the promise of becoming significant contributors to improved diagnosis and treatment of cancer patients.

Interest in the use of poly(ethylene glycol)-b-polycaprolactone diblock copolymers in a targeted, magnetically triggered drug delivery system has led to this study of the phase behavior of the polycaprolactone core. Four different diblock copolymers were prepared by the ring-opening polymerization of caprolactone from the alcohol terminus of poly(ethylene glycol) monomethylether, M(n) ≈ 2000. The critical micelle concentration depended on the degree of polymerization for the polycaprolactone block and was in the range of 2.9 to 41 mg/L. Differential scanning calorimetry curves for polymer solutions with a concentration above the critical micelle concentration showed a melting endotherm in the range of 40 to 45 °C, indicating the polycaprolactone core was semicrystalline. Pyrene was entrapped in the micelle core without interfering with the ability of the polycaprolactone to crystallize. When the polymer solution was heated above the melting point of the micelle core, the pyrene was free to leave the core. Temperature-dependent measurements of the critical micelle concentration and temperature-dependent dynamic light scattering showed that the micelles remain intact at temperatures above the melting point of the polycaprolactone core.

One successfully demonstrated application of ionic liquids (ILs) is to produce flexible polymeric materials, i.e., as plasticizers. However, the use of ILs as plasticizers, especially in medical plastics and children's toys, requires a thorough toxicological investigation. This is particularly important considering the safety concerns associated with leaching of many traditional plasticizers. This paper encompasses cellular biology and engineering aspects of the application of ILs as novel plasticizers by analyzing the cytotoxic effects of a variety of ILs on Drosophila melanogaster (fruit fly) S2 cell culture. While the effects observed have been correlated with previous observations, the cytotoxicity of ILs was found to depend on the selection of specific cations, anions, exposure time, concentration and solubility of the ILs in the culture media, and the toxicity of the parent chemicals used to synthesize the ILs.