Revision as of 03:16, 27 October 2020

Future

Magnetic Hyperthermia Therapy

In view of the development trend and concept of the integration of diagnosis and treatment, we hope that the engineering magnetosome as a contrast agent can provide further potential treatment. And then we came up with magnetic hyperthermia.

What is Magnetic Hyperthermia Therapy?

Magnetic hyperthermia therapy was first attempted in 1957 to treat cancers that had metastasised to the lymph nodes. The experimential animal was put in the copper spiral(Fig.1) and it built upon the principles of localised hyperthermia therapy by using magnetic nanoparticles and incorporating an alternating magnetic field to generate heat^[1].
In fact, many studies have shown that magnetic nanoparticles as a potential mediator have been proven to be useful in magnetic hyperthermia therapy for a variety of tumors^[2]-[5], including breast cancer^[6].
But some obstacles remain for optimal magnetic hyperthermia therapy application, especially inaccuracy intratumoural heating at the tumour site. Fortunately, MagHER2somes targeting HER2-positive breast cancer can fully meet the requirements of the magnetic hyperthermia medium and reduce the damage to healthy cells caused by unspecificity.
In addition, due to their thermally stable magnetic moment, the magnetosomes produce a larger amount of heat than the smaller super-paramagnetic chemically synthesised nanoparticles^[7].
Therefore, the application of an alternating magnetic field to magnetic nanoparticles could be applied to induce magnetic hyperthermia and partially or completely destroy small occult lesions limiting the extent of or completely avoiding the need for surgical intervention^[8].
Experiments conducted on mice showed that the temperature of magnetic hyperthermia therapy could reach as high as 46℃ when using the magnetosomes as the medium for magnetic hyperthermia. And after 30 days of treatment, tumors in some mice disappeared^[7].

Fig 1. The set-up used to carry out the treatment of the mice by positioning the mice inside the copper coil and by applying an alternating magnetic field.

How to Apply Magnetic Hyperthermia Therapy?

In order to minimize the potential side effects arising during the clinical treatments, the quantity of nanoparticles administered needs to be as small as possible but still retaining the desired effect.
We will refer to the experience of existing studies to determine the amount of contrast agent.
Studies applied to breast cancer showed that the core diameter of magnetosomes was 10nm, and the temperature could be raised to 71℃ in 242 seconds at a certain concentration (21 mg ± 9 magnetite per 299 mm³ target tissue) under an appropriate alternating magnetic field size (field amplitude: 6.5 kA/m, frequency: 400 kHz)^[9].

Fig2. When applying magnetic hyperthermia therapy with breast cancer, the temperature could be raised to 71℃ in 242 seconds at a certain concentration under an appropriate alternating magnetic field size

This gives us great encouragement, indicating that the effect of high temperature by using trace magnetosomes in magnetic hyperthermia therapy can be expected.
And last but not least is what stage of patients we apply magnetic hyperthermia therapy to and what kind of criteria we follow.
In fact, magnetic hyperthermia therapy is often is applied as an adjunctive therapy with various established cancer treatments such as radiotherapy and chemotherapy. Several phase III trials comparing radiotherapy alone or with hyperthermia have shown a beneficial effect of hyperthermia (with existing standard equipment) in terms of local control (e.g. recurrent breast cancer)[10]. In addition, we will strictly follow quality assurance guidelines for superficial hyperthermia clinical trials^[11].

Overproduction

All applications using magnetosome particles so far have been hampered by their poor availability due to the fastidious growth requirements of magnetotactic bacteria and the low magnetosome content of biomass. Therefore, an attractive possibility to increase magnetosome bioproduction would be genetic engineering or overexpression of biosynthesis pathway genes in native or foreign hosts^[12].
In a study, researchers present a strategy for the overexpression of magnetosome biosynthesis genes in the alphaproteobacterium Magnetospirillum gryphiswaldense MSR-1 by chromosomal multiplication of individual and multiple magnetosome gene clusters via transposition.
While stepwise amplification of the mms6 operon resulted in the formation of increasingly larger crystals (increase of ∼35%), the duplication of all major magnetosome operons (mamGFDC, mamAB, mms6, and mamXY, comprising 29 genes in total) yielded an overproducing strain in which magnetosome numbers were 2.2-fold increased^[12].
Therefore, in the future, we will use this method to control the production of magnetosome to achieve the overproduction of magnetosome, which will help us to use MagHER2some as a real product for the benefit of doctors and patients.

Fig3. Overproduction of magnetosome.

Size Control

It is well established that various physical characteristics of magnetic nanoparticles, such as sedimentation stability and magnetic remanence, are functions of their size^[13]. In order to obtain a uniform and stable contrast agent product, we hope to produce the magnetosome with narrow size distribution and control the particle size of the magnetosome to our desired size — 20nm.
Although sorting the obtained magnetosomes is a convenient way, it is not economical. We hope to further control the particle size of the magnetosomes by using biology method in the future.
Existing studies have shown that the size of magnetosomes is affected by many factors.
In a study, the size of magnetosomes cultured in the presence of Zn and Ni (23 ± 3 nm and 25 ± 5 nm, respectively) is considerably higher than that of magnetosomes in the control set (15 ± 3 nm)^[14].
Interestingly, the size of the magnetosome is not constant, and both the size and the heating power of the magnetosome will be reduced during the magnetic hyperthermia that we wish to apply. But it turns out that this change doesn't block antitumor activity[15]. In the future, we'll be able to control the conditions that affect the size of magnetosomes to make sure that the final MagHER2somes are superparamagnetic with sizes smaller than 20 nm and the overall particle size distribution is narrow so that the particles have uniform physical and chemical properties^[16].

Fig4. Control the size of magnetosome.

Targeted Platform

In the past work, we have successfully developed an engineered contrast agent MagHER2some which specifically targets HER2-positive breast cancer cells. The core technology we adopted is to display anti-HER2 antibodies on the surface of magnetosome taking advantage of the efficient combination of ZZ domain and Fc region. In the same way, we can design diverse scFv modified magnetosomes according to different tumor targets. Looking forward to the future, we aim to develop a versatile targeted imaging platform apply to the clinical diagnosis of more types of tumors.(Fig 2.)

Cancer	Target
Hepatocellular Carcinoma	AFP^[17],Arginase-1^[18],GPC3^[19]
Gastric Cancer	CD133^[20],E-cadherin^[21]
Lung Cancer	CEA^[22][23],CYFRA21-1^[22][23]
Non Hodgkin's lymphoma	CD20^[24]
Pancreatic Cancer	5mg
Vitamin B₁₂	uPAR^[25],SSTR^[26]

Table1.Specific targets that we can use for different types of tumors.

References

[1] Chang, D., Lim, M., Goos, J., Qiao, R., Ng, Y. Y., Mansfeld, F. M., Jackson, M., Davis, T. P., & Kavallaris, M. (2018). Biologically Targeted Magnetic Hyperthermia: Potential and Limitations. Frontiers in pharmacology, 9, 831. https://doi.org/10.3389/fphar.2018.00831

[2] Hu, R., Ma, S., Li, H., Ke, X., Wang, G., Wei, D., & Wang, W. (2011). Effect of magnetic fluid hyperthermia on lung cancer nodules in a murine model. Oncology letters, 2(6), 1161–1164. https://doi.org/10.3892/ol.2011.379

[3] Zadnik, P. L., Molina, C. A., Sarabia-Estrada, R., Groves, M. L., Wabler, M., Mihalic, J., McCarthy, E. F., Gokaslan, Z. L., Ivkov, R., & Sciubba, D. (2014). Characterization of intratumor magnetic nanoparticle distribution and heating in a rat model of metastatic spine disease. Journal of neurosurgery. Spine, 20(6), 740–750. https://doi.org/10.3171/2014.2.SPINE13142

[4] Jordan, A., Scholz, R., Maier-Hauff, K., van Landeghem, F. K., Waldoefner, N., Teichgraeber, U., Pinkernelle, J., Bruhn, H., Neumann, F., Thiesen, B., von Deimling, A., & Felix, R. (2006). The effect of thermotherapy using magnetic nanoparticles on rat malignant glioma. Journal of neuro-oncology, 78(1), 7–14. https://doi.org/10.1007/s11060-005-9059-z

[5] Zhao, Q., Wang, L., Cheng, R., Mao, L., Arnold, R. D., Howerth, E. W., Chen, Z. G., & Platt, S. (2012). Magnetic nanoparticle-based hyperthermia for head & neck cancer in mouse models. Theranostics, 2(1), 113–121. https://doi.org/10.7150/thno.3854

[6] Kossatz, S., Grandke, J., Couleaud, P., Latorre, A., Aires, A., Crosbie-Staunton, K., Ludwig, R., Dähring, H., Ettelt, V., Lazaro-Carrillo, A., Calero, M., Sader, M., Courty, J., Volkov, Y., Prina-Mello, A., Villanueva, A., Somoza, Á., Cortajarena, A. L., Miranda, R., & Hilger, I. (2015). Efficient treatment of breast cancer xenografts with multifunctionalized iron oxide nanoparticles combining magnetic hyperthermia and anti-cancer drug delivery. Breast cancer research : BCR, 17(1), 66. https://doi.org/10.1186/s13058-015-0576-1

[7] Alphandéry, E., Chebbi, I., Guyot, F., & Durand-Dubief, M. (2013). Use of bacterial magnetosomes in the magnetic hyperthermia treatment of tumours: a review. International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group, 29(8), 801–809. https://doi.org/10.3109/02656736.2013.821527

[8] Ahmed, M., & Douek, M. (2013). The role of magnetic nanoparticles in the localization and treatment of breast cancer. BioMed research international, 2013, 281230. https://doi.org/10.1155/2013/281230

[9] Hilger, I., Andrä, W., Hergt, R., Hiergeist, R., Schubert, H., & Kaiser, W. A. (2001). Electromagnetic heating of breast tumors in interventional radiology: in vitro and in vivo studies in human cadavers and mice. Radiology, 218(2), 570–575. https://doi.org/10.1148/radiology.218.2.r01fe19570

[10] Wust, P., Hildebrandt, B., Sreenivasa, G., Rau, B., Gellermann, J., Riess, H., Felix, R., & Schlag, P. M. (2002). Hyperthermia in combined treatment of cancer. The Lancet. Oncology, 3(8), 487–497. https://doi.org/10.1016/s1470-2045(02)00818-5

[11] Trefná, H. D., Crezee, H., Schmidt, M., Marder, D., Lamprecht, U., Ehmann, M., Hartmann, J., Nadobny, J., Gellermann, J., van Holthe, N., Ghadjar, P., Lomax, N., Abdel-Rahman, S., Bert, C., Bakker, A., Hurwitz, M. D., Diederich, C. J., Stauffer, P. R., & van Rhoon, G. C. (2017). Quality assurance guidelines for superficial hyperthermia clinical trials: I. Clinical requirements. International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group, 33(4), 471–482. https://doi.org/10.1080/02656736.2016.1277791

[12] Lohße, A., Kolinko, I., Raschdorf, O., Uebe, R., Borg, S., Brachmann, A., Plitzko, J. M., Müller, R., Zhang, Y., & Schüler, D. (2016). Overproduction of Magnetosomes by Genomic Amplification of Biosynthesis-Related Gene Clusters in a Magnetotactic Bacterium. Applied and environmental microbiology, 82(10), 3032–3041. https://doi.org/10.1128/AEM.03860-15

[13] Hergt, R., Hiergeist, R., Zeisberger, M., Schüler, D., Heyen, U., Hilger, I., & Kaiser, W. A. (2005). Magnetic properties of bacterial magnetosomes as potential diagnostic and therapeutic tools. Journal of Magnetism and Magnetic Materials, 293(1), 80-86. doi:10.1016/j.jmmm.2005.01.047

[14] Kundu, S., Kale, A. A., Banpurkar, A. G., Kulkarni, G. R., & Ogale, S. B. (2009). On the change in bacterial size and magnetosome features for Magnetospirillum magnetotacticum (MS-1) under high concentrations of zinc and nickel. Biomaterials, 30(25), 4211–4218. https://doi.org/10.1016/j.biomaterials.2009.04.039

[15] Alphandéry, E., Idbaih, A., Adam, C., Delattre, J. Y., Schmitt, C., Gazeau, F., Guyot, F., & Chebbi, I. (2019). Biodegraded magnetosomes with reduced size and heating power maintain a persistent activity against intracranial U87-Luc mouse GBM tumors. Journal of nanobiotechnology, 17(1), 126. https://doi.org/10.1186/s12951-019-0555-2

[16] Sun, Shouheng, and Hao Zeng. “Size-controlled synthesis of magnetite nanoparticles.” Journal of the American Chemical Society vol. 124,28 (2002): 8204-5. doi:10.1021/ja026501x

[17] Department of Medical Administration, National Health and Health Commission of the People's Republic of China (2020). Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology, 28(2), 112–128. https://doi.org/10.3760/cma.j.issn.1007-3418.2020.02.004

[18] Ordóñez N. G. (2014). Arginase-1 is a novel immunohistochemical marker of hepatocellular differentiation. Advances in anatomic pathology, 21(4), 285–290. https://doi.org/10.1097/PAP.0000000000000022

[19] Nakatsura, T., & Nishimura, Y. (2005). Usefulness of the novel oncofetal antigen glypican-3 for diagnosis of hepatocellular carcinoma and melanoma. BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy, 19(2), 71–77. https://doi.org/10.2165/00063030-200519020-00001

[20] Hashimoto, K., Aoyagi, K., Isobe, T., Kouhuji, K., & Shirouzu, K. (2014). Expression of CD133 in the cytoplasm is associated with cancer progression and poor prognosis in gastric cancer. Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association, 17(1), 97–106. https://doi.org/10.1007/s10120-013-0255-9

[21] Zhou, Y. N., Xu, C. P., Han, B., Li, M., Qiao, L., Fang, D. C., & Yang, J. M. (2002). Expression of E-cadherin and beta-catenin in gastric carcinoma and its correlation with the clinicopathological features and patient survival. World journal of gastroenterology, 8(6), 987–993. https://doi.org/10.3748/wjg.v8.i6.987

[22] Fiala, O., Pesek, M., Finek, J., Benesova, L., Minarik, M., Bortlicek, Z., & Topolcan, O. (2014). Predictive role of CEA and CYFRA 21-1 in patients with advanced-stage NSCLC treated with erlotinib. Anticancer research, 34(6), 3205–3210.

[23] Dansheng Lei, Pei Feng, Yu Jing, Kun Wang, & Yi Zhu. (2015). Tissue polypeptide antigen joint progrp, cea, nse, SCC, cyfra21-1 value in the diagnosis and treatment of lung cancer. Cancer Prevention Research(05), 488-492.

[24] Coiffier B, Haioun C, Ketterer N, et al.(1998). Rituximab (anti-CD20 monoclonal antibody) for the treatment of patientswith relapsing or refractory aggressive lymphoma:a mul-ticenter phaseⅡstudy[J]. Blood, 92(6) :1927-1932.

[25] Gorantla, B., Asuthkar, S., Rao, J. S., Patel, J., & Gondi, C. S. (2011). Suppression of the uPAR-uPA system retards angiogenesis, invasion, and in vivo tumor development in pancreatic cancer cells. Molecular cancer research : MCR, 9(4), 377–389. https://doi.org/10.1158/1541-7786.MCR-10-0452

[26] Ragozin, E., Hesin, A., Bazylevich, A., Tuchinsky, H., Bovina, A., Shekhter Zahavi, T., Oron-Herman, M., Kostenich, G., Firer, M. A., Rubinek, T., Wolf, I., Luboshits, G., Sherman, M. Y., & Gellerman, G. (2018). New somatostatin-drug conjugates for effective targeting pancreatic cancer. Bioorganic & medicinal chemistry, 26(13), 3825–3836. https://doi.org/10.1016/j.bmc.2018.06.032

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          <ul>
              <li>
-                 <a href="#magnetic_hyperthermia_therapy" style="background-color: #f6b37f;" class="nav-active rounded"><span>Magnetic Hyperthermia Therapy</span></a>
+                 <a href="#magnetic_hyperthermia_therapy" style="background-color: #f6b37f;"
+                    class="nav-active rounded"><span>Magnetic Hyperthermia Therapy</span></a>
              </li>
              <li>
-                 <a href="#overproduction" style="background-color: #7ecef4;" class="rounded"><span>Overproduction</span></a>
+                 <a href="#overproduction" style="background-color: #7ecef4;"
+                    class="rounded"><span>Overproduction</span></a>
              </li>
              <li>
-                 <a href="#targeted_platform" style="background-color:#d197f7;" class="rounded"><span>Targeted platform</span></a>
+                 <a href="#size_control" style="background-color:#eb6877;" class="rounded"><span>Size Control</span></a>
              </li>
              <li>
-                 <a href="#size_control" style="background-color:#eb6877;" class="rounded"><span>Size control</span></a>
+                 <a href="#targeted_platform" style="background-color:#d197f7;" class="rounded"><span>Targeted
+                        Platform</span></a>
              </li>
              <li>
-                 <a href="#reference" style="background-color: #cce198" class="rounded"><span>Reference</span></a>
+                 <a href="#reference" style="background-color: #cce198" class="rounded"><span>References</span></a>
              </li>
          </ul>
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                      <p>
-                         In view of the development trend and concept of the integration of diagnosis and treatment, we hope that the engineering magnetosome as a contrast agent can provide further
+                         In view of the development trend and concept of the integration of diagnosis and treatment, we
+                        hope that the engineering magnetosome as a contrast agent can provide further
                          potential treatment. And then we came up with magnetic hyperthermia.
                      </p>
-                     <h2>What is magnetic hyperthermia therapy?</h2>
+                     <h2>What is Magnetic Hyperthermia Therapy?</h2>
                      <p>
-                         Magnetic hyperthermia therapy was first attempted in 1957 to treat cancers that had metastasised to the lymph nodes. The experimential animal was put in the copper
+                         Magnetic hyperthermia therapy was first attempted in 1957 to treat cancers that had metastasised
-                         spiral(Fig.1) and it built upon the principles of localised hyperthermia therapy by using magnetic nanoparticles and incorporating an alternating magnetic field to generate
+                        to the lymph nodes. The experimential animal was put in the copper
+                         spiral(Fig.1) and it built upon the principles of localised hyperthermia therapy by using
+                        magnetic nanoparticles and incorporating an alternating magnetic field to generate
                          heat<a href="#reference"><sup>[1]</sup></a>.
                          <br>
-                         In fact, many studies have shown that magnetic nanoparticles as a potential mediator have been proven to be useful in magnetic hyperthermia therapy for a variety of
+                         In fact, many studies have shown that magnetic nanoparticles as a potential mediator have been
-                         tumors<a href="#reference"><sup>[2]-[5]</sup></a>, including breast cancer<a href="#reference"><sup>[6]</sup></a>.
+                        proven to be useful in magnetic hyperthermia therapy for a variety of
+                         tumors<a href="#reference"><sup>[2]-[5]</sup></a>, including breast cancer<a
+                            href="#reference"><sup>[6]</sup></a>.
                          <br>
-                         But some obstacles remain for optimal magnetic hyperthermia therapy application, especially inaccuracy intratumoural heating at the tumour site.
+                         But some obstacles remain for optimal magnetic hyperthermia therapy application, especially
-                         Fortunately, MagHER2some targeting HER2-positive breast cancer can fully meet the requirements of the magnetic hyperthermia medium and reduce the damage to healthy cells caused
+                        inaccuracy intratumoural heating at the tumour site.
+                         Fortunately, <b>MagHER2somes</b> targeting HER2-positive breast cancer can fully meet the
+                        requirements
+                        of the magnetic hyperthermia medium and reduce the damage to healthy cells caused
                          by unspecificity.
                          <br>
-                         In addition, due to their thermally stable magnetic moment, the magnetosomes produce a larger amount of heat than the smaller super-paramagnetic chemically synthesised
+                         In addition, due to their thermally stable magnetic moment, the magnetosomes produce a larger
+                        amount of heat than the smaller super-paramagnetic chemically synthesised
                          nanoparticles<a href="#reference"><sup>[7]</sup></a>.
                          <br>
-                         Therefore, the application of an alternating magnetic field to magnetic nanoparticles could be applied to induce magnetic hyperthermia and partially or completely destroy small
+                         Therefore, the application of an alternating magnetic field to magnetic nanoparticles could be
-                         occult lesions limiting the extent of or completely avoiding the need for surgical intervention<a href="#reference"><sup>[8]</sup></a>.
+                        applied to induce magnetic hyperthermia and partially or completely destroy small
+                         occult lesions limiting the extent of or completely avoiding the need for surgical
+                        intervention<a href="#reference"><sup>[8]</sup></a>.
                          <br>
-                         Experiments conducted on mice showed that the temperature of magnetic hyperthermia therapy could reach as high as 46℃ when using the magnetosomes as the medium for magnetic
+                         Experiments conducted on mice showed that the temperature of magnetic hyperthermia therapy could
-                         hyperthermia. And after 30 days of treatment, tumors in some mice disappeared<a href="#reference"><sup>[7]</sup></a>.
+                        reach as high as 46℃ when using the magnetosomes as the medium for magnetic
+                         hyperthermia. And after 30 days of treatment, tumors in some mice disappeared<a
+                            href="#reference"><sup>[7]</sup></a>.
                      </p>
                      <br>
                      <br>
                      <div class="imgbox">
-                         <img src="https://static.igem.org/mediawiki/2020/thumb/3/31/T--ZJU-China--Future_fig1.jpg/800px-T--ZJU-China--Future_fig1.jpg" alt="">
+                         <img src="https://static.igem.org/mediawiki/2020/thumb/3/31/T--ZJU-China--Future_fig1.jpg/800px-T--ZJU-China--Future_fig1.jpg"
-                         <h6>Fig 1. The set-up used to carry out the treatment of the mice by positioning the mice inside the copper coil and by applying an alternating magnetic field.</h6>
+                            alt="">
+                         <h6>Fig 1. The set-up used to carry out the treatment of the mice by positioning the mice inside
+                            the copper coil and by applying an alternating magnetic field.</h6>
                      </div>
                      <br>
                      <br>
-                     <h2>How to apply magnetic hyperthermia therapy?</h2>
+                     <h2>How to Apply Magnetic Hyperthermia Therapy?</h2>
                      <p>
-                         In order to minimize the potential side effects arising during the clinical treatments, the quantity of nanoparticles administered needs to be as small as possible but still
+                         In order to minimize the potential side effects arising during the clinical treatments, the
+                        quantity of nanoparticles administered needs to be as small as possible but still
                          retaining the desired effect.
                          <br>
                          We will refer to the experience of existing studies to determine the amount of contrast agent.
                          <br>
-                         Studies applied to breast cancer showed that the core diameter of magnetosomes was 10nm, and the temperature could be raised to 71℃ in 242 seconds at a certain concentration
+                         Studies applied to breast cancer showed that the core diameter of magnetosomes was 10nm, and the
-                         (21 mg±9 magnetite per 299 mm3 target tissue) under an appropriate alternating magnetic field size (field amplitude: 6.5 kA/m, frequency: 400 kHz)<a
+                        temperature could be raised to 71℃ in 242 seconds at a certain concentration
-                            href="#reference"><sup>[9]</sup></a>.
+                         (21 mg ± 9 magnetite per 299 mm<sup>3</sup> target tissue) under an appropriate alternating
+                        magnetic field
+                        size (field amplitude: 6.5 kA/m, frequency: 400 kHz)<a href="#reference"><sup>[9]</sup></a>.
                      </p>
                      <br>
                      <br>
                      <div class="imgbox">
-                         <img src="https://static.igem.org/mediawiki/2020/thumb/9/97/T--ZJU-China--Future_fig2.jpg/800px-T--ZJU-China--Future_fig2.jpg" alt="">
+                         <img src="https://static.igem.org/mediawiki/2020/thumb/9/97/T--ZJU-China--Future_fig2.jpg/800px-T--ZJU-China--Future_fig2.jpg"
-                         <h6>Fig2. When applying magnetic hyperthermia therapy with breast cancer, the temperature could be raised to 71℃ in 242 seconds at a certain concentration under an appropriate
+                            alt="">
+                         <h6>Fig2. When applying magnetic hyperthermia therapy with breast cancer, the temperature could
+                            be raised to 71℃ in 242 seconds at a certain concentration under an appropriate
                              alternating magnetic field size</h6>
                      </div>
@@ Line 350: / Line 386: @@
                      <br>
                      <p>
-                         This gives us great encouragement, indicating that the effect of high temperature by using trace magnetosomes in magnetic hyperthermia therapy can be expected.
+                         This gives us great encouragement, indicating that the effect of high temperature by using trace
+                        magnetosomes in magnetic hyperthermia therapy can be expected.
                          <br>
-                         And last but not least is what stage of patients we apply magnetic hyperthermia therapy to and what kind of criteria we follow.
+                         And last but not least is what stage of patients we apply magnetic hyperthermia therapy to and
+                        what kind of criteria we follow.
                          <br>
-                         In fact, magnetic hyperthermia therapy is often is applied as an adjunctive therapy with various established cancer treatments such as radiotherapy and chemotherapy. Several
+                         In fact, magnetic hyperthermia therapy is often is applied as an adjunctive therapy with various
-                         phase III trials comparing radiotherapy alone or with hyperthermia have shown a beneficial effect of hyperthermia (with existing standard equipment) in terms of local control
+                        established cancer treatments such as radiotherapy and chemotherapy. Several
-                         (eg, recurrent breast cancer)[10]. In addition, we will strictly follow quality assurance guidelines for superficial hyperthermia clinical trials<a
+                         phase III trials comparing radiotherapy alone or with hyperthermia have shown a beneficial
-                            href="#reference"><sup>[11]</sup></a>.
+                        effect of hyperthermia (with existing standard equipment) in terms of local control
+                         (e.g. recurrent breast cancer)[10]. In addition, we will strictly follow quality assurance
+                        guidelines for superficial hyperthermia clinical trials<a href="#reference"><sup>[11]</sup></a>.
                      </p>
                  </div>
@@ Line 367: / Line 407: @@
                      <h2>Overproduction</h2>
                      <p>
-                         All applications using magnetosome particles so far have been hampered by their poor availability due to the fastidious growth requirements of magnetotactic bacteria and the
+                         All applications using magnetosome particles so far have been hampered by their poor
-                         low magnetosome content of biomass. Therefore, an attractive possibility to increase magnetosome bioproduction would be genetic engineering or overexpression of biosynthesis
+                        availability due to the fastidious growth requirements of magnetotactic bacteria and the
+                         low magnetosome content of biomass. Therefore, an attractive possibility to increase magnetosome
+                        bioproduction would be genetic engineering or overexpression of biosynthesis
                          pathway genes in native or foreign hosts<a href="#reference"><sup>[12]</sup></a>.
                          <br>
-                         In a study, researchers present a strategy for the overexpression of magnetosome biosynthesis genes in the alphaproteobacterium <i>Magnetospirillum gryphiswaldense</i> MSR-1 by
+                         In a study, researchers present a strategy for the overexpression of magnetosome biosynthesis
-                         chromosomal multiplication of individual and multiple magnetosome gene clusters via transposition.
+                        genes in the alphaproteobacterium <i>Magnetospirillum gryphiswaldense</i> MSR-1 by
+                         chromosomal multiplication of individual and multiple magnetosome gene clusters <i>via</i>
+                        transposition.
                          <br>
-                         While stepwise amplification of the mms6 operon resulted in the formation of increasingly larger crystals (increase of <b>∼35%</b>), the duplication of all major magnetosome
+                         While stepwise amplification of the <i>mms6</i> operon resulted in the formation of increasingly
+                        larger
+                        crystals (increase of <b>∼35%</b>), the duplication of all major magnetosome
                          operons
-                         (mamGFDC, mamAB, mms6, and mamXY, comprising 29 genes in total) yielded an overproducing strain in which magnetosome numbers were <b>2.2</b>-fold increased<a
+                         (<i>mamGFDC</i>, <i>mamAB</i>, <i>mms6</i>, and <i>mamXY</i>, comprising 29 genes in total)
+                        yielded an overproducing strain
+                        in which magnetosome numbers were <b>2.2</b>-fold increased<a
                              href="#reference"><sup>[12]</sup></a>.
                          <br>
-                         Therefore, in the future, we will use this method to control the production of magnetosome to achieve the overproduction of magnetosome, which will help us to use MagHER2some
+                         Therefore, in the future, we will use this method to control the production of magnetosome to
+                        achieve the overproduction of magnetosome, which will help us to use <b>MagHER2some</b>
                          as a real product for the benefit of doctors and patients.
                      </p>
@@ Line 391: / Line 440: @@
              <div class="section services" id="size_control">
                  <div class="container1">
-                     <h2>Size control</h2>
+                     <h2>Size Control</h2>
                      <p>
-                         It is well established that various physical characteristics of magnetic nanoparticles, such as sedimentation stability and magnetic remanence, are functions of their size<a
+                         It is well established that various physical characteristics of magnetic nanoparticles, such as
+                        sedimentation stability and magnetic remanence, are functions of their size<a
                              href="#reference"><sup>[13]</sup></a>.
-                         In order to obtain a uniform and stable contrast agent product, we hope to produce the magnetosome with narrow size distribution and control the particle size of the
+                         In order to obtain a uniform and stable contrast agent product, we hope to produce the
-                         magnetosome to our desired size -- 20nm.
+                        magnetosome with narrow size distribution and control the particle size of the
+                         magnetosome to our desired size — <b>20nm</b>.
                          <br>
-                         Although sorting the obtained magnetosomes is a convenient way, it is not economical. We hope to further control the particle size of the magnetosomes by using biology method
+                         Although sorting the obtained magnetosomes is a convenient way, it is not economical. We hope to
+                        further control the particle size of the magnetosomes by using biology method
                          in the future.
                          <br>
-                         Existing studies have shown that the size of magnetic corpuscles is affected by many factors.
+                         Existing studies have shown that the size of magnetosomes is affected by many factors.
                          <br>
-                         In a study, the size of magnetosomes cultured in the presence of Zn and Ni (23 ± 3 nm and 25 ± 5 nm, respectively) is considerably higher than that of magnetosomes in the
+                         In a study, the size of magnetosomes cultured in the presence of Zn and Ni (23 ± 3 nm and 25 ± 5
+                        nm, respectively) is considerably higher than that of magnetosomes in the
                          control set (15 ± 3 nm)<a href="#reference"><sup>[14]</sup></a>.
                          <br>
-                         Interestingly, the size of the magnetosome is not constant, and both the size and the heating power of the magnetosome will be reduced during the magnetic hyperthermia that we
+                         Interestingly, the size of the magnetosome is not constant, and both the size and the heating
+                        power of the magnetosome will be reduced during the magnetic hyperthermia that we
                          wish to apply. But it turns out that this change doesn't block antitumor activity[15].
-                         In the future, we'll be able to control the conditions that affect the size of magnetosomes to make sure that the final MagHER2somes are superparamagnetic with sizes smaller
+                         In the future, we'll be able to control the conditions that affect the size of magnetosomes to
-                         than 20 nm and the overall particle size distribution is narrow so that the particles have uniform physical and chemical properties<a href="#reference"><sup>[16]</sup></a>.
+                        make sure that the final <b>MagHER2somes</b> are superparamagnetic with sizes smaller
+                         than 20 nm and the overall particle size distribution is narrow so that the particles have
+                        uniform physical and chemical properties<a href="#reference"><sup>[16]</sup></a>.
                      </p>
@@ Line 424: / Line 480: @@
              <div class="section appd" id="targeted_platform">
                  <div class="container1">
-                     <h2>Targeted platform</h2>
+                     <h2>Targeted Platform</h2>
                      <p>
-                         In the past work, we have successfully developed an engineered contrast agent MagHER2some which specifically targets HER2 positive breast cancer cells. The core technology we
+                         In the past work, we have successfully developed an engineered contrast agent <b>MagHER2some</b>
-                         adopted is to display anti-HER2 antibodies on the surface of magnetosome taking advantage of the efficient combination of ZZ domain and Fc region. In the same way, we can
+                        which
-                         design diverse scFv modified magnetosomes according to different tumor targets. Looking forward to the future, we aim to develop a versatile targeted imaging platform apply to
+                        specifically targets HER2-positive breast cancer cells. The core technology we
+                         adopted is to display anti-HER2 antibodies on the surface of magnetosome taking advantage of the
+                        efficient combination of ZZ domain and Fc region. In the same way, we can
+                         design diverse scFv modified magnetosomes according to different tumor targets. Looking forward
+                        to the future, we aim to develop a versatile targeted imaging platform apply to
                          the clinical diagnosis of more types of tumors.(Fig 2.)
                      </p>
@@ Line 444: / Line 504: @@
                                  <tr>
                                      <td>Hepatocellular Carcinoma</td>
-                                     <td>AFP<a href="#reference"><sup>[17]</sup></a>,Arginase-1<a href="#reference"><sup>[18]</sup></a>,GPC3<a href="#reference"><sup>[19]</sup></a></td>
+                                     <td>AFP<a href="#reference"><sup>[17]</sup></a>,Arginase-1<a
+                                            href="#reference"><sup>[18]</sup></a>,GPC3<a
+                                            href="#reference"><sup>[19]</sup></a></td>
                                  </tr>
                                  <tr>
                                      <td>Gastric Cancer</td>
-                                     <td>CD133<a href="#reference"><sup>[20]</sup></a>,E-cadherin<a href="#reference"><sup>[21]</sup></a></td>
+                                     <td>CD133<a href="#reference"><sup>[20]</sup></a>,E-cadherin<a
+                                            href="#reference"><sup>[21]</sup></a></td>
                                  </tr>
                                  <tr>
                                      <td>Lung Cancer</td>
-                                     <td>CEA<a href="#reference"><sup>[22][23]</sup></a>,CYFRA21-1<a href="#reference"><sup>[22][23]</sup></a></td>
+                                     <td>CEA<a href="#reference"><sup>[22][23]</sup></a>,CYFRA21-1<a
+                                            href="#reference"><sup>[22][23]</sup></a></td>
                                  </tr>
                                  <tr>
@@ Line 467: / Line 531: @@
                                  <tr>
                                      <td>Vitamin B<sub>12</sub></td>
-                                     <td>uPAR<a href="#reference"><sup>[25]</sup></a>,SSTR<a href="#reference"><sup>[26]</sup></a></td>
+                                     <td>uPAR<a href="#reference"><sup>[25]</sup></a>,SSTR<a
+                                            href="#reference"><sup>[26]</sup></a></td>
                                  </tr>
                              </tbody>
@@ Line 479: / Line 544: @@
              <div class="section our-team" id="our-team">
                  <div class="container1">
-                     <h2>Reference</h2>
+                     <h2>References</h2>
                      <p>
-                         [1] Chang D, Lim M, Goos JACM, et al. Biologically Targeted Magnetic Hyperthermia: Potential and Limitations. <i>Front Pharmacol</i>. 2018;9:831. Published 2018 Aug 2.
+                         [1] Chang, D., Lim, M., Goos, J., Qiao, R., Ng, Y. Y., Mansfeld, F. M., Jackson, M., Davis, T.
-                        doi:10.3389/fphar.2018.00831
+                        P., & Kavallaris, M. (2018). Biologically Targeted Magnetic Hyperthermia: Potential and
+                        Limitations. <i>Frontiers in pharmacology, 9,</i> 831. https://doi.org/10.3389/fphar.2018.00831
                      </p>
                      <br>
                      <p>
-                         [2] Hu R, Ma S, Li H, et al. Effect of magnetic fluid hyperthermia on lung cancer nodules in a murine model. <i>Oncol Lett</i>. 2011;2(6):1161-1164. doi:10.3892/ol.2011.379
+                         [2] Hu, R., Ma, S., Li, H., Ke, X., Wang, G., Wei, D., & Wang, W. (2011). Effect of magnetic
+                        fluid hyperthermia on lung cancer nodules in a murine model. <i>Oncology letters, 2</i>(6),
+–1164.
+                        https://doi.org/10.3892/ol.2011.379
                      </p>
                      <br>
                      <p>
-                         [3] Zadnik PL, Molina CA, Sarabia-Estrada R, et al. Characterization of intratumor magnetic nanoparticle distribution and heating in a rat model of metastatic spine disease.
+                         [3] Zadnik, P. L., Molina, C. A., Sarabia-Estrada, R., Groves, M. L., Wabler, M., Mihalic, J.,
-                         <i>J Neurosurg Spine</i>. 2014;20(6):740-750. doi:10.3171/2014.2.SPINE13142
+                        McCarthy, E. F., Gokaslan, Z. L., Ivkov, R., & Sciubba, D. (2014). Characterization of
+                        intratumor magnetic nanoparticle distribution and heating in a rat model of metastatic spine
+                         disease. <i>Journal of neurosurgery. Spine, 20</i>(6), 740–750.
+                        https://doi.org/10.3171/2014.2.SPINE13142
                      </p>
                      <br>
                      <br>
                      <p>
-                         [4] Jordan A, Scholz R, Maier-Hauff K, et al. The effect of thermotherapy using magnetic nanoparticles on rat malignant glioma. <i>J Neurooncol</i>. 2006;78(1):7-14.
+                         [4] Jordan, A., Scholz, R., Maier-Hauff, K., van Landeghem, F. K., Waldoefner, N., Teichgraeber,
-                        doi:10.1007/s11060-005-9059-z
+                        U., Pinkernelle, J., Bruhn, H., Neumann, F., Thiesen, B., von Deimling, A., & Felix, R. (2006).
+                        The effect of thermotherapy using magnetic nanoparticles on rat malignant glioma. <i>Journal of
+                            neuro-oncology, 78</i>(1), 7–14. https://doi.org/10.1007/s11060-005-9059-z
                      </p>
                      <br>
                      <p>
-                         [5] Zhao Q, Wang L, Cheng R, et al. Magnetic nanoparticle-based hyperthermia for head & neck cancer in mouse models. <i>Theranostics</i>. 2012;2(1):113-121.
+                         [5] Zhao, Q., Wang, L., Cheng, R., Mao, L., Arnold, R. D., Howerth, E. W., Chen, Z. G., & Platt,
-                        doi:10.7150/thno.3854
+                        S. (2012). Magnetic nanoparticle-based hyperthermia for head & neck cancer in mouse models.
+                        <i>Theranostics, 2</i>(1), 113–121. https://doi.org/10.7150/thno.3854
                      </p>
                      <br>
                      <p>
-                         [6] Kossatz S, Grandke J, Couleaud P, et al. Efficient treatment of breast cancer xenografts with multifunctionalized iron oxide nanoparticles combining magnetic hyperthermia
+                         [6] Kossatz, S., Grandke, J., Couleaud, P., Latorre, A., Aires, A., Crosbie-Staunton, K.,
-                        and anti-cancer drug delivery. <i>Breast Cancer Res</i>. 2015;17(1):66. Published 2015 May 13. doi:10.1186/s13058-015-0576-1
+                        Ludwig, R., Dähring, H., Ettelt, V., Lazaro-Carrillo, A., Calero, M., Sader, M., Courty, J.,
+                        Volkov, Y., Prina-Mello, A., Villanueva, A., Somoza, Á., Cortajarena, A. L., Miranda, R., &
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Difference between revisions of "Team:ZJU-China/Future"