Radio frequency plasma assisted surface modification of Fe3O4 nanoparticles using polyaniline/polypyrrole for bioimaging and magnetic hyperthermia applications.

Surface modification of superparamagnetic Fe3O4 nanoparticles using polymers (polyaniline/polypyrrole) was done by radio frequency (r.f.) plasma polymerization technique and characterized by XRD, TEM, TG/DTA and VSM. Surface-passivated Fe3O4 nanoparticles with polymers were having spherical/rod-shaped structures with superparamagnetic properties. Broad visible photoluminescence emission bands were observed at 445 and 580 nm for polyaniline-coated Fe3O4 and at 488 nm for polypyrrole-coated Fe3O4. These samples exhibit good fluorescence emissions with L929 cellular assay and were non-toxic. Magnetic hyperthermia response of Fe3O4 and polymer (polyaniline/polypyrrole)-coated Fe3O4 was evaluated and all the samples exhibit hyperthermia activity in the range of 42-45 °C. Specific loss power (SLP) values of polyaniline and polypyrrole-coated Fe3O4 nanoparticles (5 and 10 mg/ml) exhibit a controlled heat generation with an increase in the magnetic field.

Optimization of the Preparation of Magnetic Liposomes for the Combined Use of Magnetic Hyperthermia and Photothermia in Dual Magneto-Photothermal Cancer Therapy.

In this work, we aimed to develop liposomal nanocomposites containing citric-acid-coated iron oxide magnetic nanoparticles (CMNPs) for dual magneto-photothermal cancer therapy induced by alternating magnetic field (AMF) and near-infrared (NIR) lasers. Toward this end, CMNPs were encapsulated in cationic liposomes to form nano-sized magnetic liposomes (MLs) for simultaneous magnetic hyperthermia (MH) in the presence of AMF and photothermia (PT) induced by NIR laser exposure, which amplified the heating efficiency for dual-mode cancer cell killing and tumor therapy. Since the heating capability is directly related to the amount of entrapped CMNPs in MLs, while the liposome size is important to allow internalization by cancer cells, response surface methodology was utilized to optimize the preparation of MLs by simultaneously maximizing the encapsulation efficiency (EE) of CMNPs in MLs and minimizing the size of MLs. The experimental design was performed based on the central composite rotatable design. The accuracy of the model was verified from the validation experiments, providing a simple and effective method for fabricating the best MLs, with an EE of 87% and liposome size of 121 nm. The CMNPs and the optimized MLs were fully characterized from chemical and physical perspectives. In the presence of dual AMF and NIR laser treatment, a suspension of MLs demonstrated amplified heat generation from dual hyperthermia (MH)-photothermia (PT) in comparison with single MH or PT. In vitro cell culture experiments confirmed the efficient cellular uptake of the MLs from confocal laser scanning microscopy due to passive accumulation in human glioblastoma U87 cells originated from the cationic nature of MLs. The inducible thermal effects mediated by MLs after endocytosis also led to enhanced cytotoxicity and cumulative cell death of cancer cells in the presence of AMF-NIR lasers. This functional nanocomposite will be a potential candidate for bimodal MH-PT dual magneto-photothermal cancer therapy.

Targeted Dendrimer-Coated Magnetic Nanoparticles for Selective Delivery of Therapeutics in Living Cells.

Nanoparticles are widely used as theranostic agents for the treatment of various pathologies, including cancer. Among all, dendrimers-based nanoparticles represent a valid approach for drugs delivery, thanks to their controllable size and surface properties. Indeed, dendrimers can be easily loaded with different payloads and functionalized with targeting agents. Moreover, they can be used in combination with other materials such as metal nanoparticles for combinatorial therapies. Here, we present the formulation of an innovative nanostructured hybrid system composed by a metallic core and a dendrimers-based coating that is able to deliver doxorubicin specifically to cancer cells through a targeting agent. Its dual nature allows us to transport nanoparticles to our site of interest through the magnetic field and specifically increase internalization by exploiting the T7 targeting peptide. Our system can release the drug in a controlled pH-dependent way, causing more than 50% of cell death in a pancreatic cancer cell line. Finally, we show how the system was internalized inside cancer cells, highlighting a peculiar disassembly of the nanostructure at the cell surface. Indeed, only the dendrimeric portion is internalized, while the metal core remains outside. Thanks to these features, our nanosystem can be exploited for a multistage magnetic vector.

A mitochondria-targeting photothermogenic nanozyme for MRI-guided mild photothermal therapy.

Iridium complexes were used as a mitochondria-targeting agent to modify the surface of a photothermogenic nanozyme Fe3O4 nanoparticles (Ir@Fe3O4 NPs). Upon NIR irradiation, Ir@Fe3O4 NPs increase the localized temperature to 42 °C which accelerates the catalysis of ˙OH production from H2O2 resulting in excellent mild photothermal therapy.

Magnetically-responsive, multifunctional drug delivery nanoparticles for elastic matrix regenerative repair.

Arresting or regressing growth of abdominal aortic aneurysms (AAAs), localized expansions of the abdominal aorta are contingent on inhibiting chronically overexpressed matrix metalloproteases (MMPs)-2 and -9 that disrupt elastic matrix within the aortic wall, concurrent with providing a stimulus to augmenting inherently poor auto-regeneration of these matrix structures. In a recent study we demonstrated that localized, controlled and sustained delivery of doxycycline (DOX; a tetracycline-based antibiotic) from poly(lactic-co-glycolic acid) nanoparticles (PLGA NPs), enhances elastic matrix deposition and MMP-inhibition at a fraction of the therapeutically effective oral dose. The surface functionalization of these NPs with cationic amphiphiles, which enhances their arterial uptake, was also shown to have pro-matrix regenerative and anti-MMP effects independent of the DOX. Based on the hypothesis that the incorporation of superparamagnetic iron oxide NPs (SPIONs) within these PLGA NPs would enhance their targetability to the AAA site under an applied external magnetic field, we sought to evaluate the functional effects of NPs co-encapsulating DOX and SPIONs (DOX-SPION NPs) on elastic matrix regeneration and MMP synthesis/activity in vitro within aneurysmal smooth muscle cell (EaRASMC) cultures. The DOX-SPION NPs were mobile under an applied external magnetic field, while enhancing elastic matrix deposition 1.5-2-fold and significantly inhibiting MMP-2 synthesis and MMP-2 and -9 activities, compared to NP-untreated control cultures. These results illustrate that the multifunctional benefits of NPs are maintained following SPION co-incorporation. Additionally, preliminary studies carried out demonstrated enhanced targetability of SPION-loaded NPs within proteolytically-disrupted porcine carotid arteries ex vivo, under the influence of an applied external magnetic field. Thus, this dual-agent loaded NP system proffers a potential non-surgical option for treating small growing AAAs, via controlled and sustained drug release from multifunctional, targetable nanocarriers. STATEMENT OF SIGNIFICANCE: Proactive screening of high risk elderly patients now enables early detection of abdominal aortic aneurysms (AAAs). There are no established drug-based therapeutic alternatives to surgery for AAAs, which is unsuitable for many elderly patients, and none which can achieve restore disrupted and lost elastic matrix in the AAA wall, which is essential to achieve growth arrest or regression. We have developed a first generation design of polymer nanoparticles (NPs) for AAA tissue localized delivery of doxycycline, a modified tetracycline drug at low micromolar doses at which it provides both pro-elastogenic and anti-proteolytic benefits that can augment elastic matrix regenerative repair. The nanocarriers themselves are also uniquely chemically functionalized on their surface to also provide them pro-elastin-regenerative & anti-matrix degradative properties. To provide an active driving force for efficient uptake of intra-lumenally infused NPs to the AAA wall, in this work, we have rendered our polymer NPs mobile in an applied magnetic field via co-incorporation of super-paramagnetic iron oxide NPs. We demonstrate that such modifications significantly improve wall uptake of the NPs with no significant changes to their physical properties and regenerative benefits. Such NPs can potentially stimulate structural repair in the AAA wall following one time infusion to delay or prevent AAA growth to rupture. The therapy can provide a non-surgical treatment option for high risk AAA patients.

Multifunctional magnetic nanowires: A novel breakthrough for ultrasensitive detection and isolation of rare cancer cells from non-metastatic early breast cancer patients using small volumes of blood.

Circulating tumor cells (CTCs) are recognized as promising biomarkers for diagnosis and indication of the prognosis of several epithelial cancers. However, at present, CTC monitoring is available only for advanced-stage patients rather than for those at an early stage of cancer. This is because of the extraordinary rarity of CTCs and the limited sensitivity of current methods. Herein, we report the development of multifunctional magnetic nanowires for the efficient isolation and detection of CTCs from the blood of patients, especially those with non-metastatic early-stage cancer. The nanowires, which are equipped with a high density of magnetic nanoparticles and five different types of antibodies (Ab mixture_mPpyNWs), offer a significant improvement in cell-isolation efficiency, even from very small amounts of blood (250 µL-1 mL). Notably, CTCs were isolated and identified in 29 out of 29 patients (100%) with non-metastatic early breast cancer, indicating that this procedure allowed detection of CTCs with greater accuracy, sensitivity, and specificity. In addition, we demonstrated in situ "naked eye" identification of the captured cancer cells via a simple colorimetric immunoassay. Our results show that antibody-functionalized magnetic nanowires offer great potential for a broad range of practical clinical applications, including early detection, diagnosis, and treatment of cancer.

Investigating the effect of tumor vascularization on magnetic targeting in vivo using retrospective design of experiment.

Nanocarriers take advantages of the enhanced permeability and retention (EPR) to accumulate passively in solid tumors. Magnetic targeting has shown to further enhance tumor accumulation in response to a magnetic field gradient. It is widely known that passive accumulation of nanocarriers varies hugely in tumor tissues of different tumor vascularization. It is hypothesized that magnetic targeting is likely to be influenced by such factors. In this work, magnetic targeting is assessed in a range of subcutaneously implanted murine tumors, namely, colon (CT26), breast (4T1), lung (Lewis lung carcinoma) cancer and melanoma (B16F10). Passively- and magnetically-driven tumor accumulation of the radiolabeled polymeric magnetic nanocapsules are assessed with gamma counting. The influence of tumor vasculature, namely, the tumor microvessel density, permeability and diameter on passive and magnetic tumor targeting is assessed with the aid of the retrospective design of experiment (DoE) approach. It is clear that the three tumor vascular parameters contribute greatly to both passive and magnetically targeted tumor accumulation but play different roles when nanocarriers are targeted to the tumor with different strategies. It is concluded that tumor permeability is a rate-limiting factor in both targeting modes. Diameter and microvessel density influence passive and magnetic tumor targeting, respectively.

Magnetic Field-Induced Accentuation of Drug Release from Core/Shell Magnetic Mesoporous Silica Nanoparticles for Anticancer Treatment.

Drug (9-aminoacridine) loaded core/shell magnetic iron oxide-containing mesoporous silica nanoparticles (MMSN) were treated with HeLa cells and the drug carriers were agitated by expo- sure to magnetic field. Viability studies show the applicability of drug loaded magnetic material for anticancer treatment, which is enhanced upon stimulation with magnetic field. Confocal micrographs of fluorescein grafted MMSN-treated HeLa cells confirmed the ability of magnetic field to concentrate the synthesized material in the exposed area of the cells. The synthesized material and the applied drug delivery method may find application in magnetic field-responsive targeted treatment of cancer.

Breast Tumor Targetable Fe3O4 Embedded Thermo-Responsive Nanoparticles for Radiofrequency Assisted Drug Delivery.

Non-invasive radiofrequency (RF) frequency may be utilized as an energy source to activate thermo-responsive nanoparticles for the controlled local delivery of drugs to cancer cells. Herein, we demonstrate that 180 ± 20 nm sized curcumin encapsulated chitosan-graft-poly(N-vinyl caprolactam) nanoparticles containing iron oxide nanoparticles (Fe3O4-CRC-TRC-NPs) were selectively internalized in cancer cells in vivo. Using an RF treatment at 80 watts for 2 min, Fe3O4-CRC-TRC-NPs, dissipated heat energy of 42 degrees C, which is the lower critical solution temperature (LCST) of the chitosan-graft-poly(N-vinyl caprolactam), causing controlled curcumin release and apoptosis to cultured 4T1 breast cancer cells. Further, the tumor localization studies on orthotopic breast cancer model revealed that Fe3O4-CRC-TRC-NPs selectively accumulated at the primary tumor as confirmed by in vivo live imaging followed by ex vivo tissue imaging and HPLC studies. These initial results strongly support the development of RF assisted drug delivery from nanoparticles for improved tumor targeting for breast cancer treatment.

Real-time tracking of delayed-onset cellular apoptosis induced by intracellular magnetic hyperthermia.

AIM: To assess cell death pathways in response to magnetic hyperthermia. MATERIALS & METHODS: Human melanoma cells were loaded with citric acid-coated iron-oxide nanoparticles, and subjected to a time-varying magnetic field. Pathways were monitored in vitro in suspensions and in situ in monolayers using fluorophores to report on early-stage apoptosis and late-stage apoptosis and/or necrosis. RESULTS: Delayed-onset effects were observed, with a rate and extent proportional to the thermal-load-per-cell. At moderate loads, membranal internal-to-external lipid exchange preceded rupture and death by a few hours (the timeline varying cell-to-cell), without any measurable change in the local environment temperature. CONCLUSION: Our observations support the proposition that intracellular heating may be a viable, controllable and nonaggressive in vivo treatment for human pathological conditions.

Magnetorelaxometry procedures for quantitative imaging and characterization of magnetic nanoparticles in biomedical applications.

BACKGROUND: Quantitative knowledge about the spatial distribution and local environment of magnetic nanoparticles (MNPs) inside an organism is essential for guidance and improvement of biomedical applications such as magnetic hyperthermia and magnetic drug targeting. Magnetorelaxometry (MRX) provides such quantitative information by detecting the magnetic response of MNPs following a fast change in the applied magnetic field. METHODS: In this article, we review our MRX based procedures that enable both the characterization and the quantitative imaging of MNPs in a biomedical environment. RESULTS: MRX characterization supported the selection of an MNP system with colloidal stability and suitable cellular MNP uptake. Spatially resolved MRX, a procedure employing multi-channel MRX measurements allowed for in-vivo monitoring of the MNP distribution in a pre-clinical carcinoma animal model. Extending spatially resolved MRX by consecutive magnetization of distinct parts of the sample led to a demonstration of MRX tomography. With this tomography, we reconstructed the three dimensional MNP distribution inside animal sized phantoms with a sensitivity of milligrams of MNPs per cm3. In addition, the targeting efficiency of MNPs in whole blood was assessed using a flow phantom and MRX quantification. CONCLUSION: These MRX based measurement and analysis procedures have substantially supported the development of MNP based biomedical applications.

Magnetic nanoparticles for magnetic drug targeting.

Nanomedicine and superparamagnetic iron oxide nanoparticles (SPIONs) are thought to have an important impact on medicine in the future. Especially in cancer therapy, SPIONs offer the opportunity of improving the effectivity of the treatment and reduce side effects by magnetic accumulation of SPION-bound chemotherapeutics in the tumor area. Although still some challenges have to be overcome, before the new treatment concept of magnetic drug targeting will reach the patients, substantial progress has been made, and promising results were shown in the last years.

Means to increase the therapeutic efficiency of magnetic heating of tumors.

The treatment of tumors via hyperthermia has gained increased attention in the last years. Among the different modalities available so far, magnetic hyperthermia has the particular advantage of offering the possibility of depositing the heating source directly into the tumor. In this study, we summarized the present knowledge we gained on how to improve the therapeutic efficiency of magnetic hyperthermia using magnetic nanoparticles (MNPs), with particular consideration of the intratumoral infiltration of the magnetic material. We found that (1) MNPs will be mainly immobilized at the tumor area and that this aspect has to be considered when estimating the heating potential of MNPs, (2) the intratumoral distribution patterns via slow infiltration might well be modulated by specific MNP coating and magnetic targeting, (3) imaging of the nanoparticle depositions within the tumor might allow to correct the distribution pattern via multiple applications, (4) multiple therapeutic sessions are feasible because MNPs are not delivered from the tumor site during the heating process, (5) the utilization of MNPs that internalize into cells will favor the production of intracellular heating spots rather than extracellular ones, (6) utilization of MNPs functionalized with chemotherapeutic agents will allow us to exploit the additive effects of both therapeutic modalities, and (7) distinct cytopathological and histopathological alterations in target tissues are induced as a result of magnetic hyperthermia. However, the accumulation at the tumor via intravenous application remains a matter of challenge.

Computational evaluation of amplitude modulation for enhanced magnetic nanoparticle hyperthermia.

Magnetic nanoparticles (MNPs) can interact with alternating magnetic fields (AMFs) to deposit localized energy for hyperthermia treatment of cancer. Hyperthermia is useful in the context of multimodality treatments with radiation or chemotherapy to enhance disease control without increased toxicity. The unique attributes of heat deposition and transfer with MNPs have generated considerable attention and have been the focus of extensive investigations to elucidate mechanisms and optimize performance. Three-dimensional (3D) simulations are often conducted with the finite element method (FEM) using the Pennes' bioheat equation. In the current study, the Pennes' equation was modified to include a thermal damage-dependent perfusion profile to improve model predictions with respect to known physiological responses to tissue heating. A normal distribution of MNPs in a model liver tumor was combined with empirical nanoparticle heating data to calculate tumor temperature distributions and resulting survival fraction of cancer cells. In addition, calculated spatiotemporal temperature changes were compared among magnetic field amplitude modulations of a base 150-kHz sinusoidal waveform, specifically, no modulation, sinusoidal, rectangular, and triangular modulation. Complex relationships were observed between nanoparticle heating and cancer tissue damage when amplitude modulation and damage-related perfusion profiles were varied. These results are tantalizing and motivate further exploration of amplitude modulation as a means to enhance efficiency of and overcome technical challenges associated with magnetic nanoparticle hyperthermia (MNH).

Fluid mechanics aspects of magnetic drug targeting.

Experiments and numerical simulations using a flow phantom for magnetic drug targeting have been undertaken. The flow phantom is a half y-branched tube configuration where the main tube represents an artery from which a tumour-supplying artery, which is simulated by the side branch of the flow phantom, branches off. In the experiments a quantification of the amount of magnetic particles targeted towards the branch by a magnetic field applied via a permanent magnet is achieved by impedance measurement using sensor coils. Measuring the targeting efficiency, i.e. the relative amount of particles targeted to the side branch, for different field configurations one obtains targeting maps which combine the targeting efficiency with the magnetic force densities in characteristic points in the flow phantom. It could be shown that targeting efficiency depends strongly on the magnetic field configuration. A corresponding numerical model has been set up, which allows the simulation of targeting efficiency for variable field configuration. With this simulation good agreement of targeting efficiency with experimental data has been found. Thus, the basis has been laid for future calculations of optimal field configurations in clinical applications of magnetic drug targeting. Moreover, the numerical model allows the variation of additional parameters of the drug targeting process and thus an estimation of the influence, e.g. of the fluid properties on the targeting efficiency. Corresponding calculations have shown that the non-Newtonian behaviour of the fluid will significantly influence the targeting process, an aspect which has to be taken into account, especially recalling the fact that the viscosity of magnetic suspensions depends strongly on the magnetic field strength and the mechanical load.

Magnetic nanoparticle-based drug delivery for cancer therapy.

Nanoparticles have belonged to various fields of biomedical research for quite some time. A promising site-directed application in the field of nanomedicine is drug targeting using magnetic nanoparticles which are directed at the target tissue by means of an external magnetic field. Materials most commonly used for magnetic drug delivery contain metal or metal oxide nanoparticles, such as superparamagnetic iron oxide nanoparticles (SPIONs). SPIONs consist of an iron oxide core, often coated with organic materials such as fatty acids, polysaccharides or polymers to improve colloidal stability and to prevent separation into particles and carrier medium [1]. In general, magnetite and maghemite particles are those most commonly used in medicine and are, as a rule, well-tolerated. The magnetic properties of SPIONs allow the remote control of their accumulation by means of an external magnetic field. Conjugation of SPIONs with drugs, in combination with an external magnetic field to target the nanoparticles (so-called "magnetic drug targeting", MDT), has additionally emerged as a promising strategy of drug delivery. Magnetic nanoparticle-based drug delivery is a sophisticated overall concept and a multitude of magnetic delivery vehicles have been developed. Targeting mechanism-exploiting, tumor-specific attributes are becoming more and more sophisticated. The same is true for controlled-release strategies for the diseased site. As it is nearly impossible to record every magnetic nanoparticle system developed so far, this review summarizes interesting approaches which have recently emerged in the field of targeted drug delivery for cancer therapy based on magnetic nanoparticles.

Magnetic iron oxide nanoparticles: Recent trends in design and synthesis of magnetoresponsive nanosystems.

Recent developments in nanotechnology and application of magnetic nanoparticles, in particular in magnetic iron oxide nanosystems, offer exciting possibilities for nanomedicine. Facile and precise synthesis procedures, high magnetic response, tunable morphologies and multiple bio-functionalities of single- and multi-core magnetic particles designed for nanomedicine applications are thoroughly appraised. This review focuses on the structural and magnetic characterization of the cores, the synthesis of single- and multicore iron oxide NPs, especially the design of the latter, as well as their protection, stabilization and functionalization by desired coating in order to protect against the corrosion of core, to prevent non-specific protein adsorption and particle aggregation in biological media, and to provide binding sites for targeting and therapeutic agents.

The possibility of using magnetic nanoparticles to increase the therapeutic efficiency of Herceptin antibody.

INTRODUCTION: Herceptin is an expensive humanized antibody used for the treatment of early-stage breast cancers. This antibody can cause cardiotoxicity in some patients. In this study, we evaluated the possibility of increasing the therapeutic efficacy of Herceptin by combining magnetic nanoparticles and a permanent magnet for more accumulation in the tumor site. METHODS: Herceptin magnetic nanoparticles (HMNs) were synthesized and some of their characteristics, such as stability, magnetization, particle size by transmission electron microscopy (TEM), and dynamic light scattering (DLS) technique, were measured. The biodistribution study was checked in mice bearing breast tumor with and without a permanent magnet on the position of the tumor. The therapeutic effects of HMNs were considered in this condition. RESULTS: The size distribution of HMNs determined by the DLS technique was 182±7 nm and the average size by TEM was 100±10 nm. The reductions of 81% and 98% in the mean tumor volume for the group that received HMNs with magnetic field were observed at 42 and 45 days after injection, respectively. CONCLUSION: The good results in mice indicated that Herceptin-loaded iron oxide nanoparticles with external magnetic field have good potential for use in humans as a targeted drug delivery that needs more investigation.

Magnetic nanoparticles adapted for specific biomedical applications.

Magnetic nanoparticles (MNPs) are used in different biomedical applications, whereby each application requires specific particle properties. To fulfill these requirements, particle properties have to be optimized by means of variation of crystal structure, particle size, and size distribution. To this aim, improved aqueous precipitation procedures for magnetic iron oxide nanoparticle synthesis were developed. One procedure focused on the cyclic growth of MNPs without nucleation of new particle cores during precipitation. The second novel particle type are magnetic multicore nanoparticles, which consist of single cores of approximately 10 nm forming dense clusters in the size range from 40 to 80 nm. Their highest potential features these multicore particles in hyperthermia application. In our in vivo experiments, therapeutically suitable temperatures were reached after 20 s of heating for a particle concentration in the tumor of 1% and field parameters of H=24 kA/m and f=410 kHz. This review on our recent investigations for particle optimization demonstrates that tuning magnetic properties of MNPs can be obtained by the alteration of their structure, size, and size distribution. This can be realized by means of control of particle size during synthesis or subsequent size-dependent fractionation. The here-developed particles show high potential for biomedical applications.

Multifunctional carbon nanomaterial hybrids for magnetic manipulation and targeting.

Nanosized materials and multifunctional nanoscale platforms have attracted in the last years considerable interest in a variety of different fields including biomedicine. Carbon nanotubes and graphene are some of the most widely used carbon nanomaterials (CNMs) due to their unique morphology and structure and their characteristic physicochemical properties. Their high surface area allows efficient drug loading and bioconjugation and makes them the ideal platforms for decoration with magnetic nanoparticles (MNPs). In the biomedical area, MNPs are of particular importance due to their broad range of potential applications in drug delivery, non-invasive tumor imaging and early detection based on their optical and magnetic properties. The remarkable characteristics of CNMs and MNPs can be combined leading to CNM/MNP hybrids which offer numerous promising, desirable and strikingly advantageous properties for improved performance in comparison to the use of either material alone. In this minireview, we attempt to comprehensively report the most recent advances made with CNMs conjugated to different types of MNPs for magnetic targeting, magnetic manipulation, capture and separation of cells towards development of magnetic carbon-based devices.