Minimal-invasive magnetic heating of tumors does not alter intra-tumoral nanoparticle accumulation, allowing for repeated therapy sessions: an<i>in vivo</i>study in mice

Kettering, Melanie; Richter, Heike; Wiekhorst, Frank; Bremer-Streck, Sibylle; Trahms, Lutz; Kaiser, Werner A.; Hilger, Ingrid

doi:10.1088/0957-4484/22/50/505102

Cited by 42 publications

(40 citation statements)

References 24 publications

(27 reference statements)

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“…The fact that magnetic thermoablation is very effective in terms of inducing apoptosis/necrosis and reducing tumor volumes has been shown previously. 19 Taken together, our results show for the first time the impact of magnetic thermoablative stimuli (2 minutes) to temperatures up to approximately 65°C on the molecular expression pattern of selected proteins in the tumor region 2 hours after heat shock. As previous results have shown, a threshold for thermoablative temperatures for the elimination of tumor cells was found to be 55°C-60°C as cell survival was strongly impaired when more than 50% of total DNA was irreversibly damaged.…”

Section: Discussionsupporting

confidence: 62%

“…Furthermore, no delocalization of MNP due to thermoablative treatment could be observed by comparing the X-ray images obtained before and after AMF, and is in accordance with the literature. 19 Although several publications reported that especially smaller MNP (approximately between 20 nm and 100 nm) were preferentially taken up by tumor cells (eg, by endocytosis), the possibility of the used MNP to be taken up by BT474 tumor cells or, at least, be bound to their membrane was verified in previous experiments. [20][21][22] Two hours after the application of thermoablative temperatures in the tumor region, a downregulation of BCL2 and FGF-R1 was found whereas HSP70 remained unchanged.…”

Section: Discussionmentioning

confidence: 95%

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Magnetic thermoablation stimuli alter BCL2 and FGF-R1 but not HSP70 expression profiles in BT474 breast tumors

Stapf¹,

Pömpner²,

Kettering³

et al. 2015

IJN

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Magnetically induced heating of magnetic nanoparticles (MNP) in an alternating magnetic field (AMF) is a promising minimal invasive tool for localized tumor treatment that eradicates tumor cells by applying thermal stress. While temperatures between 42°C and 45°C induce apoptosis and sensitize the cells for chemo- and radiation therapies when applied for at least 30 minutes, temperatures above 50°C, so-called thermoablative temperatures, rapidly induce irreversible cell damage resulting in necrosis. Since only little is known concerning the protein expression of anti-apoptotic B-cell lymphoma 2 (BCL2), fibroblast growth factor receptor 1 (FGF-R1), and heat shock protein (HSP70) after short-time magnetic thermoablative tumor treatment, these relevant tumor proteins were investigated by immunohistochemistry (IHC) in a human BT474 breast cancer mouse xenograft model. In the investigated sample groups, the application of thermoablative temperatures (<2 minutes) led to a downregulation of BCL2 and FGF-R1 on the protein level while the level of HSP70 remained unchanged. Coincidently, the tumor tissue was damaged by heat, resulting in large apoptotic and necrotic areas in regions with high MNP concentration. Taken together, thermoablative heating induced via magnetic methods can reduce the expression of tumor-related proteins and locally inactivate tumor tissue, leading to a prospectively reduced tumorigenicity of cancerous tissues. The presented data allow a deeper insight into the molecular mechanisms in relation to magnetic thermoablative tumor treatments with the aim of further improvements.

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Section: Discussionsupporting

confidence: 62%

Section: Discussionmentioning

confidence: 95%

Magnetic thermoablation stimuli alter BCL2 and FGF-R1 but not HSP70 expression profiles in BT474 breast tumors

Stapf¹,

Pömpner²,

Kettering³

et al. 2015

IJN

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“…[70][71][72][73][74] In later clinical applications, applied MNP will stay at the site of injection up to weeks, allowing the generation of drug depots for a prolonged and/or repeated tumor treatment. 75 By this, the utilization of MTX-MNP as a combinatory therapy is capable of achieving higher cytotoxic results in later clinical applications, with less systemic side effects than systemically applied free MTX.…”

mentioning

confidence: 99%

Heterogeneous response of different tumor cell lines to methotrexate-coupled nanoparticles in presence of hyperthermia

Stapf¹,

Pömpner²,

Teichgräber³

et al. 2016

IJN

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Today, the therapeutic efficacy of cancer is restricted by the heterogeneity of the response of tumor cells to chemotherapeutic drugs. Since those therapies are also associated with severe side effects in nontarget organs, the application of drugs in combination with nanocarriers for targeted therapy has been suggested. Here, we sought to assess whether the coupling of methotrexate (MTX) to magnetic nanoparticles (MNP) could serve as a valuable tool to circumvent the heterogeneity of tumor cell response to MTX by the combined treatment with hyperthermia. To this end, we investigated five breast cancer cell lines of different origin and with different mutational statuses, as well as a bladder cancer cell line in terms of their response to exposure to MTX as a free drug or after its coupling to MNP as well as in presence/absence of hyperthermia. We also assessed whether the effects could be connected to the cell line-specific expression of proteins related to the uptake and efflux of MTX and MNP. Our results revealed a very heterogeneous and cell line-dependent response to an exposure with MTX-coupled MNP (MTX–MNP), which was almost comparable to the efficacy of free MTX in the same cell line. Moreover, a cell line-specific and preferential uptake of MTX–MNP compared with MNP alone was found (probably by receptor-mediated endocytosis), agreeing with the observed cytotoxic effects. Opposed to this, the expression pattern of several cell membrane transport proteins noted for MTX uptake and efflux was only by tendency in agreement with the cellular toxicity of MTX–MNP in different cell lines. Higher cytotoxic effects were achieved by exposing cells to a combination of MTX–MNP and hyperthermal treatment, compared with MTX or thermo-therapy alone. However, the heterogeneity in the response of the tumor cell lines to MTX could not be completely abolished – even after its combination with MNP and/or hyperthermia – and the application of higher thermal dosages might be necessary.

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“…Additionally, the exposure to an alternating magnetic field and the induction of apoptosis did not affect MNP accumulation. Consequently, localized magnetic heating therapy of tumors might be applied periodically for better therapeutic outcome [19].…”

Section: Mnp Exposure To An Alternating Magnetic Field Does Not Releamentioning

confidence: 99%

Means to increase the therapeutic efficiency of magnetic heating of tumors

Kettering

Grau

Pömpner

et al. 2015

Biomedical Engineering / Biomedizinische Technik

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Abstract: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.

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Minimal-invasive magnetic heating of tumors does not alter intra-tumoral nanoparticle accumulation, allowing for repeated therapy sessions: anin vivostudy in mice

Cited by 42 publications

References 24 publications

Magnetic thermoablation stimuli alter BCL2 and FGF-R1 but not HSP70 expression profiles in BT474 breast tumors

Magnetic thermoablation stimuli alter BCL2 and FGF-R1 but not HSP70 expression profiles in BT474 breast tumors

Heterogeneous response of different tumor cell lines to methotrexate-coupled nanoparticles in presence of hyperthermia

Means to increase the therapeutic efficiency of magnetic heating of tumors

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