Team:iBowu-China/Description
Description
Inspiration
According to the China Hospital Chinese Academy of Medical Sciences, China had more than 4.3 million new cancer cases in 2015 and more than 2.81 million cancer deaths, accounting for 28.82 percent of annual deaths in China. In this country, the fatal illness strides with a death rate of 35 percent, taking away 7,500 lives every day. Families are left in agony and desperation, their worlds like puzzles lifted at its corners. There is no cure for cancer. Yet.
This year, iBowu-China intends to address this global issue by taking a first step. After some research and a thorough brainstorm, we identified the magnetic protein crystal as a potential cancer treatment agent. This crystal's ability to respond to magnetic fields grants its use in biology, albeit being seen more commonly in the realm of physics. We have designed an active targeting liposome[11] delivery system encapsulating magnetic protein crystals to prompt cell death using magneto-hyperthermia induced by an external alternating magnetic field. The liposome's surface will be modified to have epidermal growth factors (EGF) GE11[11] to target the epidermal growth factor receptor (EGFR), which is highly expressed on lung cancer cells.
Shall a year of hard work yield fruitful results. May we surely locate - Sureloc - cancer and let the disease no longer be a nightmare tickling the minds of humanity.
This year, iBowu-China intends to address this global issue by taking a first step. After some research and a thorough brainstorm, we identified the magnetic protein crystal as a potential cancer treatment agent. This crystal's ability to respond to magnetic fields grants its use in biology, albeit being seen more commonly in the realm of physics. We have designed an active targeting liposome[11] delivery system encapsulating magnetic protein crystals to prompt cell death using magneto-hyperthermia induced by an external alternating magnetic field. The liposome's surface will be modified to have epidermal growth factors (EGF) GE11[11] to target the epidermal growth factor receptor (EGFR), which is highly expressed on lung cancer cells.
Shall a year of hard work yield fruitful results. May we surely locate - Sureloc - cancer and let the disease no longer be a nightmare tickling the minds of humanity.
Background
What is Non-Small Cell Lung Carcinoma
Figure 1: Non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) are the two main types of lung cancer. Among these, 85-90% are the non-small cell lung cancer.
Lung cancer is difficult to detect in its early stages and is also difficult to treat. Patients with early lung cancer normally have no apparent symptoms. Only when the cancer has already metastasized, will the patients suffer from bone pain, nervous system changes, and swelling of the lymph nodes. Also, this cancer relapses easily, with the five-year mortality rate staying very high.
Smoking is the leading and most significant risk factor of lung cancer – about 80% of lung cancer deaths are thought to result from smoking or exposure to secondhand smoke [3]. Other risk factors include exposure to asbestos, arsenic, chromium, various chemicals, as well as living in air pollution environments and being exposed to radiation from a range of sources such as radon.
Current Treatments of NSCLC
Figure 2: Current treatments of non-small cell lung cancer.
Firstly, the identification and targetability of mutant genes make individualized treatment possible based on tumor genotyping. Compared with patients who have not received targeted therapy, genotype targeted therapy improves the survival rate [5]. The research into targeted molecular therapy guided by targetable oncogenic drivers is progressing rapidly. Common NSCLC driver genes such as epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), c-ros oncogene 1-receptor tyrosine kinase (ROS1), and so on, have been developed, which can increase disease control time and overall survival time [3]. Secondly, because of the remarkable curative effect of immune checkpoint inhibitor, the treatment mode of advanced NSCLC has changed greatly, and its importance has become more prominent [6].
The use of targeted therapy and immunotherapy has led to survival benefits. However, the overall cure and survival rate for NSCLC remains low. Based on this, targeted magnetic hyperthermia may be considered a promising novel treatment.
Solution
Magnetic Hyperthermia Therapy and Our Solution
The advantage of magnetic hyperthermia is that the heating source can be placed directly at the target region. Local hyperthermia only addresses small areas, such as the tumor per se. Therefore, the utilization of magnetic materials right at the tumor areas is expected to improve the therapeutic efficiency [7]. Ferrite magnetic nanoparticles are considered to be ideal candidates for magnetic hyperthermia therapy because of their good biocompatibility and stability [8]. However, the current heat generation efficiency of magnetic nanoparticles in the radio frequency range is still relatively low. In addition, the targeting efficiency of drugs through a delivery system still needs to be improved. The above issues hinder the application of magnetic hyperthermia therapy in the clinical environment.
Triple targeting security 1. Active targeting ligand[13]: GE11 polypeptide shows affinity for Epidermal Growth Factor Receptor (EGFR) which is overexpressed in lung cancer cells. Thus, GE11 chosen to modify the surface of liposome to provide the primary assurance of active targeting. 2. Lung tissue-specific promoter[9][10]: SFTBP is a gene codes for surfactant protein B which serves an important function in respiratory movement and is only expressed in lung tissues. The SFTBP promoter[10] is incorporated into the vector to ensure the engineered DNA express only in lung tissues, providing a secondary insurance of accurate implementation. 3. Localized magnetic field: A magnetic protein crystal (MPC) contains more than 10 million ferritin subunits which are capable of mineralizing substantial amount of iron. With the implementation of a localized alternating magnetic field, the MPCs respond to the magnetic force and are guided toward the lung tissues. The accumulation of MPCs in lung cancer tissues ensures the tertiary security of targeting. Currently, we completed the in vitro isolation and purification of the MPCs with successful confirmation of their magnetism. The successive steps are to control the MPCs' size, add the internal targeting ligand[14], and experiment the targeting capabilities in vivo.
Figure 3: Our solution for the NSCLC. The magnetic protein is employed in magnetic hyperthermia therapy for cancer treatment. The protein sequence or expressed crystal is delivered by the targeting modified liposome.
Triple targeting security 1. Active targeting ligand[13]: GE11 polypeptide shows affinity for Epidermal Growth Factor Receptor (EGFR) which is overexpressed in lung cancer cells. Thus, GE11 chosen to modify the surface of liposome to provide the primary assurance of active targeting. 2. Lung tissue-specific promoter[9][10]: SFTBP is a gene codes for surfactant protein B which serves an important function in respiratory movement and is only expressed in lung tissues. The SFTBP promoter[10] is incorporated into the vector to ensure the engineered DNA express only in lung tissues, providing a secondary insurance of accurate implementation. 3. Localized magnetic field: A magnetic protein crystal (MPC) contains more than 10 million ferritin subunits which are capable of mineralizing substantial amount of iron. With the implementation of a localized alternating magnetic field, the MPCs respond to the magnetic force and are guided toward the lung tissues. The accumulation of MPCs in lung cancer tissues ensures the tertiary security of targeting. Currently, we completed the in vitro isolation and purification of the MPCs with successful confirmation of their magnetism. The successive steps are to control the MPCs' size, add the internal targeting ligand[14], and experiment the targeting capabilities in vivo.
References
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[4] Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature 511, 543–550 (2014)
[5] Kris, M. G. et al. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. J. Am. Med. Assoc. 311, 1998–2006 (2014)
[6] Gettinger, S. et al. Impaired HLA class I antigen processing and presentation as a mechanism of acquired resistance to immune checkpoint inhibitors in lung cancer. Cancer Discov. 7, 1420–1435 (2017)
[7] Melanie, Kettering, Ina et al. Means to increase the therapeutic efficiency of magnetic heating of tumors[J]. Biomedical Engineering, 2015.
[8] Kumar C S S R, Mohammad F . Magnetic nanomaterials for hyperthermia-based therapy and controlled drug delivery[J]. Adv Drug Deliv Rev, 2011, 63(9):789-808.
[9]Tabor, S. . (1990). Expression using the t7 rna polymerase/promoter system. Current Protocols in Molecular Biology, 11.
[10]Margana, R. K. , & Boggaram, V. . (1997). Functional analysis of surfactant protein b (sp-b) promoter. sp1, sp3, ttf-1, and hnf-3alpha transcription factors are necessary for lung cell-specific activation of sp-b gene transcription. Journal of Biological Chemistry, 272(5), 3083-3090.
[11]Song, S., Liu, D., Peng, J., Sun, Y. , Li, Z., & Gu, J. R., et al. (2008). Peptide ligand-mediated liposome distribution and targeting to egfr expressing tumor in vivo. International Journal of Pharmaceutics, 363(1-2), 155-161.
[12]Rinnerthaler, G., Gampenrieder, S., & Greil, R. . (2019). Her2 directed antibody-drug-conjugates beyond t-dm1 in breast cancer. International Journal of Molecular Sciences, 20(5).
[13]Min, L. , Weiyue, Z. , Birong, W. , Yang, G. , Zifang, S. , & Chang, Z. Q. . (2016). Ligand-based targeted therapy: a novel strategy for hepatocellular carcinoma. International Journal of Nanomedicine, 11, 5645-5669.
[14]Trapani, G. , Denora, N. , Trapani, A. , & Laquintana, V. . (2012). Recent advances in ligand targeted therapy. Journal of Drug Targeting, 20(1), 1-22..