Hyperthermia, the mild elevation of temperature to 40–43°C, can induce cancer cell death and enhance the effects of radiotherapy and chemotherapy. However, achievement of its full potential as a clinically relevant treatment modality has been restricted by its inability to effectively and preferentially heat malignant cells. The limited spatial resolution may be circumvented by the intravenous administration of cancer-targeting magnetic nanoparticles that accumulate in the tumor, followed by the application of an alternating magnetic field to raise the temperature of the nanoparticles located in the tumor tissue. This targeted approach enables preferential heating of malignant cancer cells whilst sparing the surrounding normal tissue, potentially improving the effectiveness and safety of hyperthermia. Despite promising results in preclinical studies, there are numerous challenges that must be addressed before this technique can progress to the clinic. This review discusses these challenges and highlights the current understanding of targeted magnetic hyperthermia.

A detailed study of the aqueous synthesis of composite 50-150 nm magnetite-gold core-shell nanoparticles with the ability to engineer the coverage of gold on the magnetite particle surface is presented. This method utilizes polyethyleneimine for the dual functions of attaching 2 nm gold nanoparticle seeds onto magnetite particles as well as preventing the formation of large aggregates. Saturation of the magnetite surface with gold seeds facilitates the subsequent overlaying of gold to form magnetically responsive core-shell particles, which exhibit surface plasmon resonance. In-depth characterization and quantification of the gold-shell formation process was performed using transmission electron microscopy, X-ray photoelectron spectroscopy, energy-dispersive spectroscopy, and inductively coupled plasma optical emission spectroscopy. Dynamic light scattering studies also showed that PEI coating of synthesized particles served as an excellent barrier against aggregation. The ability of the gold shell to protect the magnetite cores was tested by subjecting the particles to a magnetite-specific dissolution procedure. Elemental analysis of dissolved species revealed that the gold coating of magnetite cores imparts remarkable resistance to iron dissolution. The ability to engineer gold coverage on particle surfaces allows for controlled biofunctionalization, whereas their resistance to dissolution ensures applicability in harsh environments.

Upon contact with plasma or other protein-containing biological fluids, the surface of nanoparticles is immediately decorated with proteins forming a biologically active protein corona. The biological fates and functions of nanoparticles are determined by physiological responses toward these nanoparticleprotein corona complexes as the effective biological unit of nanoparticles. In this article, we review representative studies on the effects of particle physicochemical characteristics along with the protein profiles in the biological medium on the formation of protein corona and importantly, how the dynamic nature and protein fingerprints of the formed corona govern the biological responses toward nanoparticles. The biological effects arising from the presence of protein corona can be both beneficial and unfavourable to the biomedical applications of nanoparticles. The protein corona-cell interactions open up the feasibility of targeted delivery and cell-specific uptake of therapeutic nanoparticles and in other circumstances, engineering of nanoparticles as adjuvants for vaccine development as well as mitigation of the unintentional cytotoxic effects of nanoparticles. On the other hand, the protein corona-cell interactions could induce rapid clearance of nanoparticles from in vivo circulation as well as activating unwanted inflammatory responses. Taken together, the knowledge on the formation and biological effects of protein corona enables tailored tuning of the physicochemical characteristics of nanoparticles, unique to their intended biological activity.

The development of drug delivery systems (DDSs) using near infrared (NIR) light and upconversion nanoparticles (UCNPs) has generated intensive interest over the past five years. These NIR‐initiated DDSs not only offer a high degree of spatial and temporal determination of therapeutic release but also provide precise control over the released dosage. Furthermore, these nanoplatforms confer several advantages over conventional light‐based DDSs—NIR offers better tissue penetration depth and a reduced risk of cellular photo‐damage caused by exposure to light at high‐energy wavelengths (e.g., ultraviolet light, <400 nm). The development of DDSs that can be activated by low intensity NIR illumination is highly desirable to avoid exposing living tissues to excessive heat that can limit the in vivo application of these DDSs. This encompasses research in three directions: (i) enhancing the quantum yield of the UCNPs; (ii) incorporation of photo‐responsive materials with red‐shifted absorptions into the UCNPs; and (iii) tuning the UCNPs excitation wavelength. This review focuses on recent advances in the development of NIR‐initiated DDS, with emphasis on the use of photo‐responsive compounds and polymeric materials conjugated onto UCNPs. The challenges that limit UCNPs clinical applications, alongside with the aforementioned techniques that have emerged to overcome these limitations, are highlighted.

Exposure to fetal bovine serum (FBS) is shown herein to reduce the aggregate size of titanium dioxide (TiO(2)) nanoparticles, affecting uptake and consequent effect on A549 and H1299 human lung cell lines. Initially, the cellular uptake of the FBS-treated TiO(2) was lower than that of non-FBS-treated TiO(2). Expulsion of particles was then observed, followed by a second phase of uptake of FBS-treated TiO(2), resulting in an increase in the cellular content of FBS-treated TiO(2), eventually exceeding the amount by cells exposed to non-FBS-treated TiO(2). Surface adsorbed vitronectin and the clathrin-mediated endocytosis pathway were shown to regulate the uptake of TiO(2) into A549 cells, while the endocytosis mechanism responsible remains elusive for H1299. Intriguingly, nystatin treatment was shown to have the unexpected effect of increasing nanoparticle uptake into the A549 cells via an alternate endocytic pathway. The surface adsorbed serum components were found to provide some protection from the cytotoxic effect of endocytosed TiO(2) nanoparticles.

Magnetic nanocarriers have attracted increasing attention for multimodal cancer therapy due to the possibility to deliver heat and drugs locally. The present study reports the development of magnetic nanocomposites (MNCs) made of an iron oxide core and a pH- and thermo-responsive polymer shell, that can be used as both hyperthermic agent and drug carrier. The conjugation of anticancer drug doxorubicin (DOX) to the pH- and thermo-responsive MNCs via acid-cleavable imine linker provides advanced features for the targeted delivery of DOX molecules via the combination of magnetic targeting, and dual pH- and thermo-responsive behaviour which offers spatial and temporal control over the release of DOX. The iron oxide cores exhibit a superparamagnetic behaviour with a saturation magnetization around 70 emu g(-1). The MNCs contained 8.1 wt% of polymer and exhibit good heating properties in an alternating magnetic field. The drug release experiments confirmed that only a small amount of DOX was released at room temperature and physiological pH, while the highest drug release of 85.2% was obtained after 48 h at acidic tumour pH under hyperthermia conditions (50 °C). The drug release kinetic followed Korsmeyer-Peppas model and displayed Fickian diffusion mechanism. From the results obtained it can be concluded that this smart magnetic nanocarrier is promising for applications in multi-modal cancer therapy, to target and efficiently deliver heat and drug specifically to the tumour.

The use of a nonviral magnetic vector, comprised of magnetic iron oxide nanoparticles (MNP), polyethylenimine (PEI), and plasmid DNA, for transfection of BHK21 cells under a magnetic field is presented. Four different vector configurations were studied by systematically varying the mixing order of MNP, PEI, and DNA. The assembly of the vector has significant effects on its vector size, surface charge, cellular uptake, and level of gene expression. Mixing MNP with PEI first improved MNP stability, giving a narrow aggregate size distribution and positive surface charge at physiological pH, which in turn facilitated DNA binding onto MNP. The presence of serum in culture media improves vector dispersion and alters the surface charge of all vectors to negative charge, indicating serum protein adsorption. Cellular uptake was greater for larger vectors than the smaller vectors due to enhanced gravitational and magnetic aided sedimentation onto the cells. High MNP uptake by the cells, however, does not inevitably lead to increase gene expression efficiency. It can be shown that besides vector uptake, gene expression is affected by extracellular factors such as premature DNA release from MNP and DNA degradation by serum as well as intracellular factors such as vector lysosomal degradation, inability of DNA to detach from MNP, and cytotoxic effects of MNP at high uptake. Some of these extra- and intracellular properties are shown to be mediated by the presence of PEI.

A facile method of stabilizing magnetic iron oxide nanoparticles (MNPs) in biological media (RPMI-1640) via surface modification with fetal bovine serum (FBS) is presented herein. Dynamic light scattering (DLS) shows that the size of the MNP aggregates can be maintained at 190 ± 2 nm for up to 16 h in an RPMI 1640 culture medium containing ≥4 vol % FBS. Under transmission electron microscopy (TEM), a layer of protein coating is observed to cover the MNP surface following treatment with FBS. The adsorption of proteins is further confirmed by X-ray photoelectron spectroscopy (XPS). Gel electrophoresis and LC-MS/MS studies reveal that complement factor H, antithrombin, complement factor I, α-1-antiproteinase, and apolipoprotein E are the proteins most strongly attached to the surface of an MNP. These surface-adsorbed proteins serve as a linker that aids the adsorption of other serum proteins, such as albumin, which otherwise adsorb poorly onto MNPs. The size stability of FBS-treated MNPs in biological media is attributed to the secondary adsorbed proteins, and the size stability in biological media can be maintained only when both the surface-adsorbed proteins and the secondary adsorbed proteins are present on the particle's surface.