Abstract
Hyperthermia is considered to be a promising tool for the treatment of tumours. Intensive research activities reveal a distinct impact not only on the cellular level but also on tumour ...physiology which favours the combination with the classical oncologic modalities radio- and chemotherapy. Different techniques have been established so far. Among them, magnetic hyperthermia exploits the intrinsic magnetic properties of iron oxide nanoparticles (magnetite and maghemite) which induce heating during the exposure to an alternating magnetic field. Beyond the advantage that heating is generated within the tumour and not from outside the body, the amounts of magnetic material and their intratumoral distribution patterns are key factors determining the therapeutic outcome. They can be influenced by the use of different application routes, which will be discussed in this paper.
Many different nanostructures have been developed for biomedical applications to date. Among them, iron oxide nanoparticles have been very prominent in MRI in diagnostic radiology. Nowadays, ...nanoparticle-based therapeutic applications have gained increased interest, leading to the development of a great variety of different and, in parts, sophisticated nanoparticle formulations. Whereas nanotherapy has been confined to the preclinical phase, magnetic hyperthermia has entered into the clinical phase via controlled studies in patients. Owing to the versatility of nanoparticles, researchers envision the combination of multiple modalities (e.g., targeting, diagnostics and therapy) to one carrier. Nevertheless, such approaches have been challenging due to the necessity of the adaptation of at least partially counteracting parameters between the different modalities, which will be analyzed in this review.
Magnetic nanoparticles (MNPs) are prone to exhibit physicochemical changes caused by their interaction with biological solutions. However, such interactions have been less considered in cancer ...therapy studies. The behavior of four iron oxide MNP formulations with different surface coatings, namely, chitosan (CS), polyvinyl alcohol (PVA), carboxymethyldextran (CMX), and polydimethylamine (PEA), was investigated, after their exposure to four different cell culture media (DMEM/F12 and MEM, among others) and six different cancer cell lines (HT29, HT1080, T24, MDA-MB-231, BxPC-3, and LS174T). The sedimentation (V
) and diffusion (V
) velocities of MNPs in different culture media were calculated. Atomic absorption spectroscopy (AAS) and dynamic light scattering (DLS) were used to quantify cell uptake efficiency and physicochemical properties, respectively. Apart from PVA-coated MNPs, CMX-, CS-, and PEA-coated MNPs clustered and increased notably in size when dispensed in culture media. The different MNP formulations led either to a low (PVA-coated MNPs), medium (CS- and CMX-coated MNPs), or high (PEA-coated MNPs) clustering in the different culture media. Clustering correlated with the V
and V
of the MNPs and their subsequent interaction with cells. In particular, the CMX-coated MNPs with higher V
and lower V
internalized more readily than the PVA-coated MNPs into the different cell lines. Hence, our results highlight key considerations to include when validating nanoparticles for future biomedical applications.
Magnetic nanoparticles (MNPs) have shown promising features to be utilized in combinatorial magnetic hyperthermia and chemotherapy. Here, we assessed if a thermo-chemotherapeutic approach consisting ...of the intratumoral application of functionalized chitosan-coated MNPs (CS-MNPs) with 5-fluorouracil (5FU) and magnetic hyperthermia prospectively improves the treatment of colorectal cancer. With utilization of a human colorectal cancer (HT29) heterotopic tumor model in mice, we showed that the thermo-chemotherapeutic treatment is more efficient in inactivating colon cancer than either tumor treatments alone (i.e., magnetic hyperthermia vs. the presence of 5FU attached to MNPs). In particular, the thermo-chemotherapeutic treatment significantly (p < 0.01) impacts tumor volume and tumor cell proliferation (Ki67 expression, p < 0.001) compared to the single therapy modalities. The thermo-chemotherapeutic treatment: (a) affects DNA replication and repair as measured by H2AX and phosphorylated H2AX expression (p < 0.05 to 0.001), (b) it does not distinctly induce apoptosis nor necroptosis in target cells, since expression of p53, PARP cleaved-PARP, caspases and phosphorylated-RIP3 was non-conspicuous, (c) it renders tumor cells surviving therapy more sensitive to further therapy sessions as indicated by an increased expression of p53, reduced expression of NF-κB and HSPs, albeit by tendency with p > 0.05), and (d) that it impacts tumor vascularity (reduced expression of CD31 and αvβ3 integrin (p < 0.01 to 0.001) and consequently nutrient supply to tumors. We further hypothesize that tumor cells die, at least in parts, via a ROS dependent mechanism called oxeiptosis. Taken together, a very effective elimination of colon cancers seems to be feasible by utilization of repeated thermo-chemotherapeutic therapy sessions in the long-term.
Pancreatic ductal adenocarcinoma (PDAC), characterized by hypovascularity, hypoxia, and desmoplastic stroma is one of the deadliest malignancies in humans, with a 5-year survival rate of only 7%. The ...anatomical location of the pancreas and lack of symptoms in patients with early onset of disease accounts for late diagnosis. Consequently, 85% of patients present with non-resectable, locally advanced, or advanced metastatic disease at diagnosis and rely on alternative therapies such as chemotherapy, immunotherapy, and others. The response to these therapies highly depends on the stage of disease at the start of therapy. It is, therefore, vital to consider the stages of PDAC models in preclinical studies when testing new therapeutics and treatment modalities. We report a standardized induction of cell-based orthotopic pancreatic cancer models in mice and the identification of vital features of their progression by ultrasound imaging and histological analysis of the level of pancreatic stellate cells, mature fibroblasts, and collagen. The results highlight that early-stage primary tumors are secluded in the pancreas and advance towards infiltrating the omentum at week 5–7 post implantation of the BxPC-3 and Panc-1 models investigated. Late stages show extensive growth, the infiltration of the omentum and/or stomach wall, metastases, augmented fibroblasts, and collagen levels. The findings can serve as suggestions for defining growth parameter-based stages of orthotopic pancreatic cancer models for the preclinical testing of drug efficacy in the future.
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Photodynamic therapy (PDT) of tumors causes skin photosensitivity as a result of unspecific accumulation behavior of the photosensitizers. PDT of tumors was improved by calcium ...phosphate nanoparticles conjugated with (i) Temoporfin as a photosensitizer, (ii) the RGDfK peptide for favored tumor targeting and (iii) the fluorescent dye molecule DY682-NHS for enabling near-infrared fluorescence (NIRF) optical imaging in vivo. The nanoparticles were characterized with regard to size, spectroscopic properties and uptake into CAL-27 cells. The nanoparticles had a hydrodynamic diameter of approximately 200nm and a zeta potential of around +22mV. Their biodistribution at 24h after injection was investigated via NIRF optical imaging. After treating tumor-bearing CAL-27 mice with nanoparticle-PDT, the therapeutic efficacy was assessed by a fluorescent DY-734-annexin V probe at 2days and 2weeks after treatment to detect apoptosis. Additionally, the contrast agent IRDye® 800CW RGD was used to assess tumor vascularization (up to 4weeks after PDT). After nanoparticle-PDT in mice, apoptosis in the tumor was detected after 2days. Decreases in tumor vascularization and tumor volume were detected in the next few days. Calcium phosphate nanoparticles can be used as multifunctional tools for NIRF optical imaging, PDT and tumor targeting as they exhibited a high therapeutic efficacy, being capable of inducing apoptosis and destroying tumor vascularization.
Magnetic nanoparticles have been investigated for microwave imaging over the last decade. The use of functionalized magnetic nanoparticles, which are able to accumulate selectively within tumorous ...tissue, can increase the diagnostic reliability. This paper deals with the detecting and imaging of magnetic nanoparticles by means of ultra-wideband microwave sensing via pseudo-noise technology. The investigations were based on phantom measurements. In the first experiment, we analyzed the detectability of magnetic nanoparticles depending on the magnetic field intensity of the polarizing magnetic field, as well as the viscosity of the target and the surrounding medium in which the particles were embedded, respectively. The results show a nonlinear behavior of the magnetic nanoparticle response depending on the magnetic field intensity for magnetic nanoparticles diluted in distilled water and for magnetic nanoparticles embedded in a solid medium. Furthermore, the maximum amplitude of the magnetic nanoparticles responses varies for the different surrounding materials of the magnetic nanoparticles. In the second experiment, we investigated the influence of the target position on the three-dimensional imaging of the magnetic nanoparticles in a realistic measurement setup for breast cancer imaging. The results show that the magnetic nanoparticles can be detected successfully. However, the intensity of the particles in the image depends on its position due to the path-dependent attenuation, the inhomogeneous microwave illumination of the breast, and the inhomogeneity of the magnetic field. Regarding the last point, we present an approach to compensate for the inhomogeneity of the magnetic field by computing a position-dependent correction factor based on the measured magnetic field intensity and the magnetic susceptibility of the magnetic particles. Moreover, the results indicate an influence of the polarizing magnetic field on the measured ultra-wideband signals even without magnetic nanoparticles. Such a disturbing influence of the polarizing magnetic field on the measurements should be reduced for a robust magnetic nanoparticles detection. Therefore, we analyzed the two-state (ON/OFF) and the sinusoidal modulation of the external magnetic field concerning the detectability of the magnetic nanoparticles with respect to these spurious effects, as well as their practical application.
Abstract
The outcome of tumor treatment via hyperthermia in the clinic has been reported to be heterogeneous. Here, we assessed how the presence of gastrin-releasing peptide receptor (GRPR) and α
v
β
...3
integrin together with the morphology of the vascularization reflects the growth behavior of tumors after hyperthermia treatment. MDA-MB-231 tumor bearing mice were treated either with high (46 °C) or low dose (42 °C) water hyperthermia for 60 min. Changes of GRPR and α
v
β
3
integrin expression were assessed via multiplexed optical imaging. Vascularization was reconstructed and quantified by µCT imaging after contrast agent injection. We found that high dose hyperthermia is capable of increasing the expression of GRPR, α
v
β
3
integrin, CD31, and Ki67 in tumors. Also the morphology of tumor vasculature changed (increased relative blood volume and small-diameter vessel density, decreased expression of α-SMA). Low dose hyperthermia induced comparatively moderate effects on the investigated protein expression pattern and vascular remodeling. We conclude that under defined circumstances, specific temperature doses affect the reorganization of tumor regrowth, which is triggered by residual “dormant” cells even though tumor volumes are transiently decreasing. Further on, GRPR, α
v
β
3
integrin expression are versatile tools to surveil potential tumor regrow during therapy, beyond the conventional determination of tumor volumes.
In the pursuit of controlling the heat exposure mediated by magnetic nanoparticles, we provide new guidelines for tailoring magnetic relaxation processes via dipolar interactions. For this purpose, ...highly crystalline and monodisperse magnetic iron oxide nanocrystals whose sizes range from 7 to 22 nm were synthesized by thermal decomposition of iron organic precursors in 1-octadecene. The as-synthesized nanoparticles are soft nanomagnets, showing superparamagnetic-like behavior and SAR values which progressively increase with particle size, field frequency, and amplitude up to 3.6 kW/gFe. Our data show the influence of media viscosity, particle size, and concentration on dipolar interactions and consequently on the magnetic relaxation processes related to the heat release. Understanding the role of dipolar interactions is of great importance toward the use of iron oxide nanoparticles as efficient hyperthermia mediators.
Ulcerative colitis is a disease that causes inflammation and ulcers in the colon and which is typically recurrent, and NF-κB proteins are important players during disease progression. Here, we assess ...the impact of silica-coated calcium phosphate nanoparticles carrying encapsulated siRNA against NF-κB p65 on a murine model of colitis. To this end, nanoparticles were injected intravenously (2.0 mg siRNA/kg body weight) into mice after colitis induction with dextran sulfate sodium or healthy ones. The disease activity index, the histopathological impact on the colon, the protein expression of several NF-κB-associated players, and the mediator secretion (colon tissue, blood) were analyzed. We found that the nanoparticles effectively alleviated the clinical and histopathological features of colitis. They further suppressed the expression of NF-κB proteins (e.g., p65, p50, p52, p100, etc.) in the colon. They finally attenuated the local (colon) or systemic (blood) pro-inflammatory mediator secretion (e.g., TNF-α, IFN-β, MCP-1, interleukins, etc.) as well as the leucocyte load of the spleen and mesenteric lymph nodes. The nanoparticle biodistribution in diseased animals was seen to pinpoint organs containing lymphoid entities (appendix, intestine, lung, etc.). Taken together, the nanoparticle-related silencing of p65 NF-κB protein expression could well be used for the treatment of ulcerative colitis in the future.
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