Magnetic nanoparticle-based therapeutic agents for thermo-chemotherapy treatment of cancer

Magnetic nanoparticles have been widely investigated for their great potential as mediators of heat for localised hyperthermia therapy. Nanocarriers have also attracted increasing attention due to the possibility of delivering drugs at specific locations, therefore limiting systematic effects. The enhancement of the anti-cancer effect of chemotherapy with application of concurrent hyperthermia was noticed more than thirty years ago. However, combining magnetic nanoparticles with molecules of drugs in the same nanoformulation has only recently emerged as a promising tool for the application of hyperthermia with combined chemotherapy in the treatment of cancer. The main feature of this review is to present the recent advances in the development of multifunctional therapeutic nanosystems incorporating both magnetic nanoparticles and drugs, and their superior efficacy in treating cancer compared to either hyperthermia or chemotherapy as standalone therapies. The principle of magnetic fluid hyperthermia is also presented

In vitro exploration of the synergistic effect of alternating magnetic field mediated thermo-chemotherapy with doxorubicin loaded dual pH- and thermo-responsive magnetic nanocomposite carriers

Nanoparticle induced hyperthermia has been considered as a promising approach for cancer treatment for decades. The local heating ability and drug delivery potential highlight a diversified possibility in clinical application, therefore a variety of nanoparticles has been developed accordingly. However, currently, only a few of them are translated into the clinical stage indicating a 'medically underexplored nanoparticles' situation, which encourages their comprehensive biomedical exploration. This study presents a thorough biological evaluation of previous well-developed dual pH- and thermo-responsive magnetic doxorubicin-nanocarriers (MNC-DOX) in multiple cancer cell lines. The cytotoxicity of the nanocomposites has been determined by the MTT assay on primary cell lines. Histology and fluorescence microscopy imaging revealed the efficiency of cellular uptake of nanocarriers in different cell lines. The IC50 of MNC-DOX is significantly higher than that of free DOX without an alternating magnetic field (AMF), which implied the potential to lower the systemic cytotoxicity in clinical research. The concurrent thermo-chemotherapy generated by this platform has been successfully achieved under an AMF. Promising effective synergistic results have been demonstrated through in vitro study in multi-model cancer cell lines via both trypan blue exclusion and bioluminescence imaging methods. Furthermore, the two most used magnetic hyperthermia modalities, namely intracellular and extracellular treatments, have been compared on the same nanocarriers in all 3 cell lines, which showed that treatment after internalization is not required but preferable. These results lead to the conclusion that this dual responsive nanocarrier has extraordinary potential to serve as a novel broad-spectrum anticancer drug and worth pursuing for potential clinical applications

In vitro exploration of the synergistic effect of alternating magnetic field mediated thermo-chemotherapy with doxorubicin loaded dual pH- and thermo-responsive magnetic nanocomposite carriers

Nanoparticle induced hyperthermia has been considered as a promising approach for cancer treatment for decades. The local heating ability and drug delivery potential highlight a diversified possibility in clinical application, therefore a variety of nanoparticles has been developed accordingly. However, currently, only a few of them are translated into the clinical stage indicating a 'medically underexplored nanoparticles' situation, which encourages their comprehensive biomedical exploration. This study presents a thorough biological evaluation of previous well-developed dual pH- and thermo-responsive magnetic doxorubicin-nanocarriers (MNC-DOX) in multiple cancer cell lines. The cytotoxicity of the nanocomposites has been determined by the MTT assay on primary cell lines. Histology and fluorescence microscopy imaging revealed the efficiency of cellular uptake of nanocarriers in different cell lines. The IC50 of MNC-DOX is significantly higher than that of free DOX without an alternating magnetic field (AMF), which implied the potential to lower the systemic cytotoxicity in clinical research. The concurrent thermo-chemotherapy generated by this platform has been successfully achieved under an AMF. Promising effective synergistic results have been demonstrated through in vitro study in multi-model cancer cell lines via both trypan blue exclusion and bioluminescence imaging methods. Furthermore, the two most used magnetic hyperthermia modalities, namely intracellular and extracellular treatments, have been compared on the same nanocarriers in all 3 cell lines, which showed that treatment after internalization is not required but preferable. These results lead to the conclusion that this dual responsive nanocarrier has extraordinary potential to serve as a novel broad-spectrum anticancer drug and worth pursuing for potential clinical applications

Doxorubicin loaded dual pH- and thermo-responsive magnetic nanocarrier for combined magnetic hyperthermia and targeted controlled drug delivery applications

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 tumou

Polyol synthesis, functionalisation, and biocompatibility studies of superparamagnetic iron oxide nanoparticles as potential MRI contrast agents

Iron oxide nanoparticles (IONPs) of low polydispersity were obtained through a simple polyol synthesis in high pressure and high temperature conditions. The control of the size and morphology of the nanoparticles was studied by varying the solvent used, the amount of iron precursor and the reaction time. Compared with conventional synthesis methods such as thermal decomposition or co-precipitation, this process yields nanoparticles with a narrow particle size distribution in a simple, reproducible and cost effective manner without the need for an inert atmosphere. For example, IONPs with a diameter of ca. 8 nm could be made in a reproducible manner and with good crystallinity as evidenced by X-ray diffraction analysis and high saturation magnetization value (84.5 emu g(-1)). The surface of the IONPs could be tailored post synthesis with two different ligands which provided functionality and stability in water and phosphate buffer saline (PBS). Their potential as a magnetic resonance imaging (MRI) contrast agent was confirmed as they exhibited high r1 and r2 relaxivities of 7.95 mM(-1) s(-1) and 185.58 mM(-1) s(-1) respectively at 1.4 T. Biocompatibility and viability of IONPs in primary human mesenchymal stem cells (hMSCs) was studied and confirmed

Particle interactions in liquid magnetic colloids by zero field cooled measurements: effects on heating efficiency

The influence of magnetic interactions in assemblies formed by either aggregated or disaggregated uniform gamma-Fe_2O_3 particles are investigated as a function of particle size, concentration, and applied field. Hyperthermia and magnetization measurements are performed in the liquid phase of colloids consisting of 8 and 13 nm uniform gamma-Fe_2O_3 particles dispersed in water and hexane. Although hexane allows the disagglomerated obtaining particle system; aggregation is observed in the case of water colloids. The zero field cooled (ZFC) curves show a discontinuity in the magnetization values associated with the melting points of water and hexane. Additionally, for 13 nm gamma-Fe_2O_3 dispersed in hexane, a second magnetization jump is observed that depends on particle concentration and shifts toward lower temperature by increasing applied field. This second jump is related to the strength of the magnetic interactions as it is only present in disagglomerated particle systems with the largest size, i.e., is not observed for 8 nm superparamagnetic particles, and surface effects can be discarded. The specific absorption rate (SAR) decreases with increasing concentration only for the hexane colloid, whereas for aqueous colloids, the SAR is almost independent of particle concentration. Our results suggest that, as a consequence of the magnetic interactions, the dipolar field acting on large particles increases with concentration, leading to a decrease of the SAR

Magnetic carbon nanostructures and study of their transport in microfluidic devices for hyperthermia

Cancer incidence and mortality are growing worldwide at an alarming pace, emphasizing the urgent need for new strategies to combat this disease. One of the frontiers of cancer research is currently focused on the design of multifunctional magnetic nanoparticles capable to achieve the synergistic cancer theranostics (both diagnosis and therapy). Although the potentiality that these multifunctional nanosystems represents to nanomedicine, cancer treatment and diagnostic, there are still many challenges that must be addressed in a near future before this approach became a reality. The development of efficient multifunctional magnetic nanosystems able to selectively destroy cancer cells in detriment of healthy ones, is one of the main challenges that have damped the spread of this technology into clinical applications. The limited biological and biophysical studies between the biomedical nanosystems and cells/tissues/organs is another challenge that has to be addressed. With these two main challenges in mind, the present Ph.D. work was focused in the development of: (1) Multifunctional magnetic carbon nanostructures as multifunctional nanosystems for the treatment of cancer, and (2) New advanced microfluidic devices capable to give new insights over the developed nanosystems and human cells.The successful accomplishment of the multidisciplinary tasks considered in this Ph.D. work, was supported by important collaborations that were strengthened at different stages in the frame of this Ph.D. project, namely INL -International Iberian Nanotechnology Laboratory (Braga, Portugal); CeRiCol -Centro Ricerche Colorobbia Consulting (Vinci, Italy); CIMO -Centro de Investigacao da Montanha (Braganca, Portugal) and Harvard-MIT Division of Health Sciences and Technology (Cambridge, USA).R.O. Rodrigues acknowledge the Ph.D. scholarship SFRH/BD/97658/2013 granted by Fundacao para a Ciencia e a Tecnologia (FCT), as well as a Fulbright Research Grant 2017, granted by Fulbright Portugal