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Magnetic fluid-modeled microgravity: A novel way to treat tumor
Medical Hypotheses 77 (2011) 953–955
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Magnetic fluid-modeled microgravity: A novel way to treat tumor Jun Chen a, Zhiqiang Yan b, Rongrong Liu c, Nanding Wang a, Jing Li d, Zongren Wang a,⇑ a
Department of Traditional Chinese Medicine, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi Province 710032, People’s Republic of China Department of Neurosurgery, Tang-du Hospital, Fourth Military Medical University, Xi’an, Shaanxi Province 710032, People’s Republic of China c Department of Immunology, Fourth Military Medical University, Xi’an, Shaanxi Province 710032, People’s Republic of China d Department of Chinese Traditional Medicine, PLA NAVY General Hospital, Beijing 100000, People’s Republic of China b
a r t i c l e
i n f o
Article history: Received 28 February 2011 Accepted 18 July 2011
a b s t r a c t With the advances of nanotechnology in recent years, our understanding of the therapy of cancers has deepened and the development of new technologies for cancer diseases has emerged. Here, with the recent discoveries of nanomagnetic fluids as well as microgravity effects upon cancerous cells, we suggest an innovative method of treating tumor using magnetic fluid-modeled microgravity. Magnetic fluids are delivered by outside magnetic field to tumor issue either intravenously or through direct injection, and this is followed by application of an uniform external magnetic field that causes microgravity. The modeled microgravity is to inhibit cancerous cells growth and invasion. Ó 2011 Published by Elsevier Ltd.
Introduction Cancer is a main cause of human death [1,2]. Current strategies for cancer therapy are based primarily on surgical excision and medical approaches such as chemotherapy and radiation, often in combination. Surgery often fails to eradicate all cancerous cells and is associated with significant morbidity; moreover, a large number of tumors are regarded as inoperable due to their adjacency to critical tissue structures. Although it is impossible to solve this dilemma in general, two main strategies offer at least partial resolutions [3,4]. One is minimal invasiveness, which means that technologies should be used to treat the target area accurately while preserving the proximate tissues, especially the functionally important structures. The other is individual, patient-centered treatment strategies. With several pioneering studies, the MagForce Nano-Cancer therapy maybe fulfill the criterion of minimal invasiveness and is therefore a candidate for a way out of the dilemma. Properties of ferrofluids and application of magnetic fluid hyperthermia Ferrofluids (FF) are suspensions of small magnetic particles with a mean diameter of about 10 nm in appropriate carrier liquids. The special feature of FF is the combination of normal liquid behavior with superparamagnetic properties. Moreover, some properties like the viscosity, the phase behavior, or their optical ⇑ Corresponding author. Tel.: +86 02984775352. E-mail addresses: [email protected] (J. Chen), zongren@ fmmu.edu.cn (Z. Wang). 0306-9877/$ - see front matter Ó 2011 Published by Elsevier Ltd. doi:10.1016/j.mehy.2011.07.053
birefringence properties, can be changed by applying an external magnetic field. FF possess a wide range of potential technical and biomedical applications [5]. These fluids can be magnetically targeted to cancerous tissue after intravenous application [1]. The magnetic particles extravasate into the tumor due to the high microvascular permeability and interstitial diffusion in neoplastic tissue [6]. In the past few years, magnetic nanoparticles have been investigated so as to use in thermal treatment of cancer. In magnetic fluid hyperthermia (MFH), magnetic nanoparticles are delivered to a tumor issue either intravenously or via direct injection. This is followed by application of an alternating magnetic field that causes the particles to heat. As the temperature rises in nearby cancerous cells, they are eradicated due to rupture of the cellular membrane or denaturation of proteins. It has also been postulated that an immune response may be stimulated to destroy remaining tumor cells [7]. The heating phenomenon of magnetic materials was first investigated by Gilchrist et al. in 1957 [8]. Of the materials tested, iron oxide particles were the most promising, and they were demonstrated no adverse effects on healthy tissue when delivered into the lymph nodes of dogs [1]. In the light of these initial studies, the biocompatibility of iron oxide nanoparticles has become well established, and they have remained the most thoroughly investigated agent for MFH [1]. Recently, the first two clinical studies regarding magnetic fluid hyperthermia were published [9,10]. In the first, a 67 year-old patient with prostate cancer received injection of 12.5 ml aminosilane-coated iron oxide nanoparticles. Following the injection, the patient was exposed to an alternating magnetic field (100 kHz, 4–5 kA/m) once a week for 6 weeks. The results of this study projected that the nanoparticles were retained in the prostate for
954
J. Chen et al. / Medical Hypotheses 77 (2011) 953–955
the entire 6-week period. In addition, the feasibility of the technique and the ability to obtain temperatures satisfactory for ablation of tumor cells were proven [9]. The second clinical report was a feasibility and tolerability study on 14 patients with glioblastoma multiforme [10]. Patients were treated for 6 weeks with a combination of external beam radiotherapy and MFH using aminosilane-coated iron oxide nanoparticles injected directly into the tumor with help of navigational controls. The appearance of iron oxide particles in the tumor can be appreciated in the postinjection computed tomography image. In this study, the magnetic field applied had a frequency of 100 kHz, and the therapy was well tolerated at magnetic field strengths ranging from 3.8 to 13.5 kA/m [1]. Overall the findings indicate that MFH does not cause any adverse effects on patients, and future studies need to be performed to determine the efficacy of the treatment [1]. Effects of microgravity upon cancerous cells A couple of years ago, China launched its first manned space mission—ShenZhou4, with which thousands of cancerous cells were carried at the same time. Scientists from Beijing Sino-Japan Friendship Hospital studied the cells and confirmed that the returned cancerous cells underwent several striking changes. The cells grew slower and showed a decreased adherence to endothelium. From the news mentioned above, we can postulate that microgravity could inhibit tumor growth and migration in a sense. Our previous works have concluded that modeled microgravity causes changes in the cytoskeleton and focal adhesions, and decreases in migration in malignant human MCF-7 cells [11]. Takeda found that simulated microgravity could significantly inhibit the growth rate and mitochondrial activity of malignant glioma cells [12]. It was also demonstrated that an 18-day space flight induced a 3.6-fold accumulation of tumor suppressor p53 in rat skeletal muscle, thereby safeguarding genomic stability against the stressful space environments [13]. Whereas the mechanism of the effect of microgravity is still vague, most of current researches considered the changes of cytoskeleton might result in the inhibition of tumor cell growth. Magnetic fluid-modeled microgravity Given our current understanding of properties of ferrofluids and the significant impact of microgravity on cancerous cells, we hypothesized that magnetic fluid-modeled microgravity can treat tumor precisely and effectively. This hypothesis rests on the theory behind the application of ferrofluids, the inhibition of tumor cells growth, and the decreased migration with microgravity. This novel method not only causes an accurate local microgravity on tumor, but also exhibits very little or no interference with the surrounding tissues. The magnetic fluid also displays good tissue compatibility, produces non-toxic metabolites. Treatment of tumor by magnetic fluid-modeled microgravity serves the following main role: to impede tumor growth and invasion, and to promote the apoptosis of vascular endothelial cells in tumor. It has been evident that microgravity could increase the expression of caspase-3 and promote the apoptosis of endothelial cells [14]. Thus, if the blood circulation of tumor issue is destroyed, cancerous cells cannot survive. Discussion The key to implementing magnetic fluid-modeled microgravity is to develop outside magnetic field with uniform, and at the same time, gravity and magnetic forces counteracts in magnetic field with uniform gradient. Previous study has demonstrated that mag-
Fig. 1. Overweight and weightlessness experiment modeled by magnetic fluid. (a) A glass ball (5) tied by a rubber band (1) with a hand (2) is hanging in a measuring cylinder (6). Infusing the magnetic fluid (3) and recording the number. (b) Put a magnet (4) below the glass ball and find that the ball and the hand go up. (c) Put the magnet above the ball and find that the ball go down.
Fig. 2. The concept of magnetic fluid-modeled microgravity technology.
netic fluids will be in the overweight when magnetic force and gravity are in the same direction. In contrast, the nano-magnetic fluids will be in the weightlessness when magnetic force and gravity are in opposite direction (Fig. 1) [15]. Through the control of outside magnetic field, the magnetic fluid could be navigated to tumor issue with appropriate volume and then generates a microgravity environment Fig. 2. The concept of magnetic fluid-modeled microgravity to treat tumor is novel. Furthermore, the technology involved is simple, economical, and suitable for clinical applications. The method is attractive for cancer therapy as this physical approach avoids concern with drug resistance and biological variability between tumor types. Next step we will be to examine the conditions of how to achieve a steady microgravity environment by magnetic fluid and detect the effect of this approach in vivo. Conflict of interest The authors declare that they have no conflict of interest. There is no financial or other relationship that might be perceived as leading to a conflict of interest. Acknowledgments Jun Chen, Zhiqiang Yan and Rongrong Liu have the same contribution to this paper. No grants for the paper.
J. Chen et al. / Medical Hypotheses 77 (2011) 953–955
References [1] Day ES, Morton JG, West JL. Nanoparticles for Thermal Cancer Therapy. ASME J Biomech Eng 2009;131:074001. [2] Tartaj P, Morales MD, Veintemillas-Verdaguer S, Gonzalez-Carreno T, Serna CJ. The preparation of magnetic nanoparticles for applications in biomedicine. J Phys D Appl Phys 2003;36:R182. [3] Müller S. Minimal-invasive und nanoskalige Therapien von Gehirnerkrankungen—Eine medizinethische Diskussion. Nanotechnologien im Kontext. Akademische Verlagsgesellschaft 2006:345–70. [4] Müller S. Dilemmata bei operativen Eingriffen in das Gehirn. Sind die Gedanken frei? Medizinisch Wissenschaftliche Verlagsgesellschaft 2007:229–68. [5] Odenbach S, editor. Ferrofluids, Magnetically Controllable Fluids and Their Applications. Springer; 2002 [Lect Notes Phys]. [6] Gerlowski LE, Jain RK. Microvascular permeability of normal and neoplastic tissues. Microvasc Res 1986;31:288. [7] Ito A, Honda H, Kobayashi T. Cancer immunotherapy based on intracellular hyperthermia using magnetite nanoparticles: a novel concept of ‘‘heatcontrolled necrosis’’ with heat shock protein expression. Cancer Immunol Immunother 2006;55(3):320–8. [8] Gilchrist RK, Medal R, Shorey WD, Hanselman RC, Parrott JC, Taylor CB. Selective inductive heating of lymph nodes. Ann Surg 1957;146(4):596–606.
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[9] Johannsen M, Gneveckow U, Eckelt L, Feussner A, Waldofner N, Scholz R, et al. Clinical hyperthermia of prostate cancer using magnetic nanoparticles: presentation of a new interstitial technique. Int J Hyperthermia 2005;21(7):637–47. [10] Maier-Hauff K, Rothe R, Scholz R, Gneveckow U, Wust P, Thiesen B, et al. Intracranial thermotherapy using magnetic nanoparticles combined with external beam radiotherapy: results of a feasibility study on patients with glioblastoma multiforme. J Neuro-Oncol 2007;81(1):53–60. [11] Jing L, Shu Z, Jun C, Tingyuan D, Yongchun W, Zongren W, et al. Modeled microgravity causes changes in the cytoskeleton. Protoplasma 2009;238: 23–33. [12] Takeda M, Magaki T, Okazaki T, Kawahara Y, Manabe T, Yuge L, et al. Effects of simulated microgravity on proliferation and chemosensitivity in malignant glioma cells. Neurosci Lett 2009;463(1):54–9. [13] Ohnishi T, Wang X, Fukuda S, Takahashi A, Ohnishi K, Nagaoka S. Accumulation of tumor suppressor p53 in rat muscle after a space flight. Adv Space Res 2000;25(10):2119–22. [14] Grimm D, Bauer J, Ulbrich C, Westphal K, Wehland Markus, Infanger Manfred, et al. Different responsiveness of endothelial cells to vascular endothelial growth factor and basic fibroblast growth factor added to culture media under gravity and simulated microgravity. Tissue Eng Part A 2010;16:1560–72. [15] Zheng-liang Wang, Zun-yi Wang, Zhang-xian Lu. Create a weightlessness microgravity environment with nano-magnetic fluids. J Zhejiang Wanli University 2004;17.
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Magnetic fluid-modeled microgravity: A novel way to treat tumor Jun Chen a, Zhiqiang Yan b, Rongrong Liu c, Nanding Wang a, Jing Li d, Zongren Wang a,⇑ a
Department of Traditional Chinese Medicine, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi Province 710032, People’s Republic of China Department of Neurosurgery, Tang-du Hospital, Fourth Military Medical University, Xi’an, Shaanxi Province 710032, People’s Republic of China c Department of Immunology, Fourth Military Medical University, Xi’an, Shaanxi Province 710032, People’s Republic of China d Department of Chinese Traditional Medicine, PLA NAVY General Hospital, Beijing 100000, People’s Republic of China b
a r t i c l e
i n f o
Article history: Received 28 February 2011 Accepted 18 July 2011
a b s t r a c t With the advances of nanotechnology in recent years, our understanding of the therapy of cancers has deepened and the development of new technologies for cancer diseases has emerged. Here, with the recent discoveries of nanomagnetic fluids as well as microgravity effects upon cancerous cells, we suggest an innovative method of treating tumor using magnetic fluid-modeled microgravity. Magnetic fluids are delivered by outside magnetic field to tumor issue either intravenously or through direct injection, and this is followed by application of an uniform external magnetic field that causes microgravity. The modeled microgravity is to inhibit cancerous cells growth and invasion. Ó 2011 Published by Elsevier Ltd.
Introduction Cancer is a main cause of human death [1,2]. Current strategies for cancer therapy are based primarily on surgical excision and medical approaches such as chemotherapy and radiation, often in combination. Surgery often fails to eradicate all cancerous cells and is associated with significant morbidity; moreover, a large number of tumors are regarded as inoperable due to their adjacency to critical tissue structures. Although it is impossible to solve this dilemma in general, two main strategies offer at least partial resolutions [3,4]. One is minimal invasiveness, which means that technologies should be used to treat the target area accurately while preserving the proximate tissues, especially the functionally important structures. The other is individual, patient-centered treatment strategies. With several pioneering studies, the MagForce Nano-Cancer therapy maybe fulfill the criterion of minimal invasiveness and is therefore a candidate for a way out of the dilemma. Properties of ferrofluids and application of magnetic fluid hyperthermia Ferrofluids (FF) are suspensions of small magnetic particles with a mean diameter of about 10 nm in appropriate carrier liquids. The special feature of FF is the combination of normal liquid behavior with superparamagnetic properties. Moreover, some properties like the viscosity, the phase behavior, or their optical ⇑ Corresponding author. Tel.: +86 02984775352. E-mail addresses: [email protected] (J. Chen), zongren@ fmmu.edu.cn (Z. Wang). 0306-9877/$ - see front matter Ó 2011 Published by Elsevier Ltd. doi:10.1016/j.mehy.2011.07.053
birefringence properties, can be changed by applying an external magnetic field. FF possess a wide range of potential technical and biomedical applications [5]. These fluids can be magnetically targeted to cancerous tissue after intravenous application [1]. The magnetic particles extravasate into the tumor due to the high microvascular permeability and interstitial diffusion in neoplastic tissue [6]. In the past few years, magnetic nanoparticles have been investigated so as to use in thermal treatment of cancer. In magnetic fluid hyperthermia (MFH), magnetic nanoparticles are delivered to a tumor issue either intravenously or via direct injection. This is followed by application of an alternating magnetic field that causes the particles to heat. As the temperature rises in nearby cancerous cells, they are eradicated due to rupture of the cellular membrane or denaturation of proteins. It has also been postulated that an immune response may be stimulated to destroy remaining tumor cells [7]. The heating phenomenon of magnetic materials was first investigated by Gilchrist et al. in 1957 [8]. Of the materials tested, iron oxide particles were the most promising, and they were demonstrated no adverse effects on healthy tissue when delivered into the lymph nodes of dogs [1]. In the light of these initial studies, the biocompatibility of iron oxide nanoparticles has become well established, and they have remained the most thoroughly investigated agent for MFH [1]. Recently, the first two clinical studies regarding magnetic fluid hyperthermia were published [9,10]. In the first, a 67 year-old patient with prostate cancer received injection of 12.5 ml aminosilane-coated iron oxide nanoparticles. Following the injection, the patient was exposed to an alternating magnetic field (100 kHz, 4–5 kA/m) once a week for 6 weeks. The results of this study projected that the nanoparticles were retained in the prostate for
954
J. Chen et al. / Medical Hypotheses 77 (2011) 953–955
the entire 6-week period. In addition, the feasibility of the technique and the ability to obtain temperatures satisfactory for ablation of tumor cells were proven [9]. The second clinical report was a feasibility and tolerability study on 14 patients with glioblastoma multiforme [10]. Patients were treated for 6 weeks with a combination of external beam radiotherapy and MFH using aminosilane-coated iron oxide nanoparticles injected directly into the tumor with help of navigational controls. The appearance of iron oxide particles in the tumor can be appreciated in the postinjection computed tomography image. In this study, the magnetic field applied had a frequency of 100 kHz, and the therapy was well tolerated at magnetic field strengths ranging from 3.8 to 13.5 kA/m [1]. Overall the findings indicate that MFH does not cause any adverse effects on patients, and future studies need to be performed to determine the efficacy of the treatment [1]. Effects of microgravity upon cancerous cells A couple of years ago, China launched its first manned space mission—ShenZhou4, with which thousands of cancerous cells were carried at the same time. Scientists from Beijing Sino-Japan Friendship Hospital studied the cells and confirmed that the returned cancerous cells underwent several striking changes. The cells grew slower and showed a decreased adherence to endothelium. From the news mentioned above, we can postulate that microgravity could inhibit tumor growth and migration in a sense. Our previous works have concluded that modeled microgravity causes changes in the cytoskeleton and focal adhesions, and decreases in migration in malignant human MCF-7 cells [11]. Takeda found that simulated microgravity could significantly inhibit the growth rate and mitochondrial activity of malignant glioma cells [12]. It was also demonstrated that an 18-day space flight induced a 3.6-fold accumulation of tumor suppressor p53 in rat skeletal muscle, thereby safeguarding genomic stability against the stressful space environments [13]. Whereas the mechanism of the effect of microgravity is still vague, most of current researches considered the changes of cytoskeleton might result in the inhibition of tumor cell growth. Magnetic fluid-modeled microgravity Given our current understanding of properties of ferrofluids and the significant impact of microgravity on cancerous cells, we hypothesized that magnetic fluid-modeled microgravity can treat tumor precisely and effectively. This hypothesis rests on the theory behind the application of ferrofluids, the inhibition of tumor cells growth, and the decreased migration with microgravity. This novel method not only causes an accurate local microgravity on tumor, but also exhibits very little or no interference with the surrounding tissues. The magnetic fluid also displays good tissue compatibility, produces non-toxic metabolites. Treatment of tumor by magnetic fluid-modeled microgravity serves the following main role: to impede tumor growth and invasion, and to promote the apoptosis of vascular endothelial cells in tumor. It has been evident that microgravity could increase the expression of caspase-3 and promote the apoptosis of endothelial cells [14]. Thus, if the blood circulation of tumor issue is destroyed, cancerous cells cannot survive. Discussion The key to implementing magnetic fluid-modeled microgravity is to develop outside magnetic field with uniform, and at the same time, gravity and magnetic forces counteracts in magnetic field with uniform gradient. Previous study has demonstrated that mag-
Fig. 1. Overweight and weightlessness experiment modeled by magnetic fluid. (a) A glass ball (5) tied by a rubber band (1) with a hand (2) is hanging in a measuring cylinder (6). Infusing the magnetic fluid (3) and recording the number. (b) Put a magnet (4) below the glass ball and find that the ball and the hand go up. (c) Put the magnet above the ball and find that the ball go down.
Fig. 2. The concept of magnetic fluid-modeled microgravity technology.
netic fluids will be in the overweight when magnetic force and gravity are in the same direction. In contrast, the nano-magnetic fluids will be in the weightlessness when magnetic force and gravity are in opposite direction (Fig. 1) [15]. Through the control of outside magnetic field, the magnetic fluid could be navigated to tumor issue with appropriate volume and then generates a microgravity environment Fig. 2. The concept of magnetic fluid-modeled microgravity to treat tumor is novel. Furthermore, the technology involved is simple, economical, and suitable for clinical applications. The method is attractive for cancer therapy as this physical approach avoids concern with drug resistance and biological variability between tumor types. Next step we will be to examine the conditions of how to achieve a steady microgravity environment by magnetic fluid and detect the effect of this approach in vivo. Conflict of interest The authors declare that they have no conflict of interest. There is no financial or other relationship that might be perceived as leading to a conflict of interest. Acknowledgments Jun Chen, Zhiqiang Yan and Rongrong Liu have the same contribution to this paper. No grants for the paper.
J. Chen et al. / Medical Hypotheses 77 (2011) 953–955
References [1] Day ES, Morton JG, West JL. Nanoparticles for Thermal Cancer Therapy. ASME J Biomech Eng 2009;131:074001. [2] Tartaj P, Morales MD, Veintemillas-Verdaguer S, Gonzalez-Carreno T, Serna CJ. The preparation of magnetic nanoparticles for applications in biomedicine. J Phys D Appl Phys 2003;36:R182. [3] Müller S. Minimal-invasive und nanoskalige Therapien von Gehirnerkrankungen—Eine medizinethische Diskussion. Nanotechnologien im Kontext. Akademische Verlagsgesellschaft 2006:345–70. [4] Müller S. Dilemmata bei operativen Eingriffen in das Gehirn. Sind die Gedanken frei? Medizinisch Wissenschaftliche Verlagsgesellschaft 2007:229–68. [5] Odenbach S, editor. Ferrofluids, Magnetically Controllable Fluids and Their Applications. Springer; 2002 [Lect Notes Phys]. [6] Gerlowski LE, Jain RK. Microvascular permeability of normal and neoplastic tissues. Microvasc Res 1986;31:288. [7] Ito A, Honda H, Kobayashi T. Cancer immunotherapy based on intracellular hyperthermia using magnetite nanoparticles: a novel concept of ‘‘heatcontrolled necrosis’’ with heat shock protein expression. Cancer Immunol Immunother 2006;55(3):320–8. [8] Gilchrist RK, Medal R, Shorey WD, Hanselman RC, Parrott JC, Taylor CB. Selective inductive heating of lymph nodes. Ann Surg 1957;146(4):596–606.
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[9] Johannsen M, Gneveckow U, Eckelt L, Feussner A, Waldofner N, Scholz R, et al. Clinical hyperthermia of prostate cancer using magnetic nanoparticles: presentation of a new interstitial technique. Int J Hyperthermia 2005;21(7):637–47. [10] Maier-Hauff K, Rothe R, Scholz R, Gneveckow U, Wust P, Thiesen B, et al. Intracranial thermotherapy using magnetic nanoparticles combined with external beam radiotherapy: results of a feasibility study on patients with glioblastoma multiforme. J Neuro-Oncol 2007;81(1):53–60. [11] Jing L, Shu Z, Jun C, Tingyuan D, Yongchun W, Zongren W, et al. Modeled microgravity causes changes in the cytoskeleton. Protoplasma 2009;238: 23–33. [12] Takeda M, Magaki T, Okazaki T, Kawahara Y, Manabe T, Yuge L, et al. Effects of simulated microgravity on proliferation and chemosensitivity in malignant glioma cells. Neurosci Lett 2009;463(1):54–9. [13] Ohnishi T, Wang X, Fukuda S, Takahashi A, Ohnishi K, Nagaoka S. Accumulation of tumor suppressor p53 in rat muscle after a space flight. Adv Space Res 2000;25(10):2119–22. [14] Grimm D, Bauer J, Ulbrich C, Westphal K, Wehland Markus, Infanger Manfred, et al. Different responsiveness of endothelial cells to vascular endothelial growth factor and basic fibroblast growth factor added to culture media under gravity and simulated microgravity. Tissue Eng Part A 2010;16:1560–72. [15] Zheng-liang Wang, Zun-yi Wang, Zhang-xian Lu. Create a weightlessness microgravity environment with nano-magnetic fluids. J Zhejiang Wanli University 2004;17.