Fig. 4 ^[7] Age distribution of patients with breast cancer Figure shows age distribution in China and the USA in 2008, and estimated distributions in China in 2020 and 2030; based on data from the WHO China country profile.22

The fast-pace-lifestyle in China's mega city have also caused breast cancer to arise in younger ages. In big cities like Shenzhen, young people face a lot of pressure and work long hours; as a result, they not only have higher chances of getting breast cancer, but also miss out on regular check ups in hospitals.

The reason why we notice the issue of breast cancer is that a lot of friends and family members have suffered from it. For example, Jerry (one of our team memebrs)’s grandmother got breast cancer several years ago. We want to do something for them by participating in breast cancer treatment.

Current Issue——mainstream treatments

Traditional treatment approaches for breast cancer, and most other cancers, include surgery, chemotherapy, and radiotherapy[1]. Not only do people want to eradicate tumors via these methods, but they also aim to maintain the overall health condition of patients[1]. However, these conventional treatments are severely challenged by issues such as side effect, tumor recurrence and drug resistance[1].

Surgery

Stage l breast cancer can be cured with surgical operational surgeries involves the removal of breast and lymph nodes, in some cases, some chest muscles have to be removed as well. However, it is not effective in case of tumor recurrence and metastases to distant organs including bone, lung and liver[1]. Also many women might not want to remove their breast, for various reasons.

Radiotherapy

Radiotherapy involves delivering powerful waves of energy to disrupt the tumor cell division, which results in the shrinkage or eradication of tumors, during the early stages. However, although radiation therapy is a local treatment that only affects the area of the tumor location, side effects can occur due to the damages caused on the neighboring healthy tissues due to its weak specificity[1].

Chemotherapy

The goal of chemotherapy is to use cytotoxic chemotherapeutic drugs either after or without surgery to interfere with tumor cell division and growth[1]. An example is kinase inhibitors, a chemical drug that inhibits tyrosine kinase at the end of the signaling pathway to kill cells that over-expresses HER2. However, the long-term adverse effects of chemotherapy on the patients’ healthy organs, due to the lack of specificity, have been increasingly concerned[1]. In addition to cancer cells, other rapidly dividing cells (e.g., hair, gastrointestinal epithelium, bone marrow) are affected by these drugs[3]. Furthermore, multi-drug resistance is also a challenging issue caused by over-expression of certain proteins in the tumor cells. The effect of chemotherapy is often drastically reduced in this case[1].

Conclusion

It is obvious that there is a urgent demand for better types of cancer treatments, for their intolerable side effects. The goal of our team is to design a new drug deliver system——more specific, cheaper, practical.

Targeted therapy

Targeted therapy is one of the successful solutions that has developed so far. Briefly, targeted drugs are to release drugs to specific areas only by targeting a specific molecular target, thus preventing normal cells being killed via maintaining appropriate drug concentration in the other body areas[4]. In comparison with chemotherapeutic drugs, targeted drugs blocks the proliferation of cancer cells via binding to specific molecules required for tumor development and growth rather than molecules presenting in normal tissues. The specificity of targeted drug can significantly reduce the side effects of cancer treatments and thus improves the therapeutic efficacy of drugs[4]. In the past decade, a dramatic shift in cancer treating field, from conventional treatments to targeted drugs, has occurred[3]. In comparison with a number of three chemotherapeutic drugs being approved by FDA, fifteen targeted drugs have been approved[3]. Attracted by the trending popularity of targeted therapy, our goal is to utilize this technology and engineer a new type of targeting drug to play a part in curing cancer. But what type of targeted drug we are looking for? Two main types of targeted drugs are monoclonal antibody and small molecule inhibitor.

1. (这两个并列段字体不需要变小，我不知道为啥变小了）Monoclonal antibody: engineered antibody binds to a specific receptor and kill the cancer cell via diverse ways. For example, the first ever antibody drug 'Herceptin' (Trastuzumab) was invented in the 90s, it binds to HER2 receptors and prevent growth factors to bind, thus killing the cell. In addition, scientists modifies the Fc domain of the antibody to increase its effect. Moreover, antibody-drug conjugate(ADC) an upgrade for traditional antibody drugs, functions by carrying a lethal payload, such as toxin or radioisotope, to the targeted cells[3]. 2. Small molecule inhibitor: small molecule inhibitors function by ceasing the proliferation of cancer cells by interfering with intracellular signaling of tyrosine kinases, and finally stoping cell growth, proliferation, migration, or angiogenesis. EGFR, HER2, VEGF receptors are all tyrosine kinases. Small molecule inhibitor has several merits in comparison to monoclonal antibody, such as they are chemically manufactured, which is less expensive. However, they achieve less specific targeting than do monoclonal antibodies[3].

Issues with the two popular types of targeted drugs

By communicating with some drug producing firms (See more in IHP(超链接）) and doing more researches online, we have known that there may be some difficulties with the current targeted drugs. For monoclonal antibodies, the cost is way too high for most patients due to the sophisticated antibody production method[3]. For example, multi-drug colorectal cancer treatment regimens containing Bevacizumab or Cetuximab cost up to $30,790 for eight weeks of treatment, compared with $63 for an eight-week regimen of Fluorouracil (Adrucil) and Leucovorin, the standard treatment until the mid-1990s[3]. For small molecule inhibitors, the weaker specificity and stability—most small molecule inhibitors have half-lives of only hours and require daily dosing—limits their applications[3]. Therefore, it is obvious that the current therapy is not satisfied and there is a need for developing a new type of targeted drug, which can solve these problems.

Conclusion

We plan to develop a new kind of targeted drug which can combine the advantages of the monoclonal antibody and small molecule inhibitor, while avoiding their disadvantages. The drug should be more stable, more specific, more versatile, and cost less

Our project—Oncokiller(more in Design(超链接）)

Overview

After long researching, we encountered aptamer. Our project aims at utilizing aptamers to develop a new type of targeted drug. In this project, we use HER2 aptamer, which will only target the breast cancer, but we believe that the system can also be used to kill other cancers by applying different aptamers. Compared to the traditional antibody-based targeted drugs whose specificity were provided by the antibody, our project uses aptamers as guide molecules, combining providing us with advantages such as lower production costs and shorter production period. Compared to the traditional targeted therapy, which applies antibodies and small molecule inhibitors, we use aptamers as guide molecules. Also, nanoparticles are used to encapsulate our drug. This design provides our drug with improvement in stability and specificity, also lower price. （图） Our drug deliver system consists of three parts: aptamer, nanoparticle, and drug.

Aptamer: specificity & cost

Aptamers, nucleic acid ligands generated using SELEX(more in design), are one of only a few classes of molecules that, like antibodies, can be crafted to bind to multiple different targets. For example, Pegaptanib, the first aptamer-based drug approved by FDA in 2004 for curing the loss of visual acuity, applies VEGF-specific aptamers. Our aptamer can specifically bind to HER2 receptors(more in design), leading the drug to the right place and killing the breast cancer cells.

Nanoparticles: stability

Nanoparticles are used to cover our drug and thus increase the stability of the whole system, otherwise the drug might easy be eliminated form the blood before reaching tumors. The two nanoparticles we will use are PLGA and liposome; we will choose the better one based on the experiment results.

Drug: our killer

Doxorubicin, a chemotherapeutic agent with strong activity against a wide range of human malignant neoplasms including acute leukemia, non-Hodgkin lymphomas, breast cancer, Hodgkin's disease and sarcomas, is the drug we apply. Originally, Doxorubicin is isolated from the fungus Streptomyces peucetius. It has been in use as a key anticancer drug for forty years and is thus well-researched[3].

By combing the three structures, we have developed a drug deliver system applying aptamer rather than antibody; aptamers for navigating; nanoparticles for protecting; drug for killing. However, we are not satisfied. To further improve the specificity and stability of the system, allowing it to compete with current antibody-based drugs and small molecule inhibitors, we plan to do modifications throughout our system. 1. Specificity: we have introduced one of the newest technologies, pH-sensitive motif, for increasing aptamer specificity 2. Stability: both aptamers and the nanoparticles are attached by chemicals such as PEG and CS( more in Design )

A collection of advantages of our system(图—暂时没有还不用放）

Future plan

Although ONCOKILLER seems prosperous. We have countered several issues during our time in the lab, which you can read about in our Results page. However, there is more to it than this. If ONCOKiller can be refined and optimized it could become a universal model for many cancer drugs. Due to the accessibility of aptamers and its versatility, drugs for diverse cancers can be produced using the our system, but with different aptamers. For example, targeted drug for liver cancer can apply aptamers specifically binding to liver cancer cells instead of HER2 aptamers. We believe that more cancer curing drugs can be made cheaper, allowing more families to be able to afford them. In the past few months, we've read through literature performed experiments; we overcame many difficulties, tried out different solutions and eventually led to our preliminary design for our project. Fighting cancer is hard. We know our targeting drug have many issues yet to be solved, but we wish to do our bit in this long-stretched fight.

Reference

1. Liyanage PY, Hettiarachchi SD, Zhou Y, Ouhtit A, Seven ES, Oztan CY, Celik E, Leblanc RM. Nanoparticle-mediated targeted drug delivery for breast cancer treatment. Biochim Biophys Acta Rev Cancer. 2019 Apr;1871(2):419-433
2. M. Zeglinski, Ludke, A., Jassal, D. S., Singal, P. K., Trastuzumab-induced cardiac dysfunction: A 'dualhit'. Exp. Clin. Cardiol. 16 (2011) 70-74
3. Gerber DE. Targeted therapies: a new generation of cancer treatments. Am Fam Physician. 2008 Feb 1;77(3):311-9. PMID: 18297955
4. A Review on Targeted Drug Delivery: its Entire Focus on Advanced
5. https://www.healthline.com/health/transgender/top-surgery
6. https://www.healio.com/news/hematology-oncology/20170314/shorter-radiation-could-safely-lower-costs-of-breast-cancer-treatment
7. Fan, L., Strasser-Weippl, K., Li, J. J., St Louis, J., Finkelstein, D. M., Yu, K. D., Chen, W. Q., Shao, Z. M., & Goss, P. E. (2014). Breast cancer in China. The Lancet. Oncology, 15(7), e279–e289. https://doi.org/10.1016/S1470-2045(13)70567-9
8. Imai, K., Takaoka, A. Comparing antibody and small-molecule therapies for cancer. Nat Rev Cancer 6, 714–727 (2006). https://doi.org/10.1038/nrc1913
9. Eun Seong Lee, Zhonggao Gao, You Han Bae,Recent progress in tumor pH targeting nanotechnology,Journal of Controlled Release,Volume 132, Issue 3, 2008, Pages 164-170, ISSN 0168-3659, https://doi.org/10.1016/j.jconrel.2008.05.003
10. Shaheen Sultana, Mohd Rashid Khan, Mukesh Kumar, Sokindra Kumar & Mohammed Ali (2013)Nanoparticles-mediated drug delivery approaches for cancer targeting: a review, Journal of Drug Targeting,21:2, 107-125, DOI: 10.3109/1061186X.2012.712130
11. Targeted delivery of cisplatin to prostate cancer cells by aptamer functionalized Pt(IV) prodrug-PLGA–PEG nanoparticles
12. ]https://www.news-medical.net/health/Carboplatin-Pharmacology.aspx
13. https://www.nature.com/articles/d41573-021-00079-
14. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/breast-cancer-facts-and-figures/breast-cancer-facts-and-figures-2019-2020.pdf