Team:Korea HS/Implementation



Proposed End Users

The primary proposed end users of our cancer-specific cell-penetrating peptide include but are not limited to: cancer patients, medical oncologists, and cancer researchers. We envision cancer patients as one of the main beneficiaries of our cancer-specific cell-penetrating peptide. If our project proves to be effective and safe in not only in vitro conditions, but also in vivo conditions, hence passing all phases (I, II, III) of clinical trials, cancer patients would be able to be administered the commercial chemotherapeutic as their oncologists see apt and experience the extent of our peptide’s therapeutic efficiency.

Medical oncologists, who would administer the treatment to the cancer patients, are another group of primary proposed end users of the cancer-specific cell-penetrating peptide. In general, given our peptide’s potential to not only induce cancer cell death, but also to slow (if not halt) the proliferation of drug-resistant cancer cells, we envision our peptide to be administered by medical oncologists largely after or before surgery or other therapies (such as radiation therapy) as a form of adjuvant chemotherapy: the former mainly to prevent metastatic cancer, and the latter mainly to decrease the size and expansion of the tumor to facilitate operation. Furthermore, since systemic drug treatments and other forms of targeted therapy are already common treatments for those newly diagnosed with Stage 4 cancer, we also intend for our peptide to help those in urgent need of critical care by aiding control of the size of the cancer and improving general quality of life by alleviating symptoms entailing metastatic tumor growth; however, this should be executed with caution and only if the oncologists deem it appropriate, as there exists a component of risk administering cytotoxic drugs to Stage 4 cancer patients.

Regardless of whether the product can become commercially available to the previous two stakeholders, cancer researchers can use our peptide for experimentation and/or development. Even in the event that the peptide does not pass the required clinical trials, cancer researchers can still retain the CPP principle while manipulating one or more elements to address the issue that made the CPP clinically inapplicable; for instance, researchers can continue experimentation with chemotherapeutic agents other than Doxorubicin, an anthracycline (interfere with enzymes involved in copying DNA), and instead opt for topoisomerase or mitotic inhibitor drugs. Other forms of modification for experimentation include but are not limited to: change in type of CPP, change in method of CPP internalization, etc. Regardless of the marketability of our model CPP, we intend for cancer specialists and researchers to develop our cell-penetrating-peptide so that it exhibits improved uptake in tumor cells, reduction in cytotoxicity, increase in specificity, and thus overall enhancement of drug bioavailability and therapeutic efficiency.

Fusion CPPs as a New Cancer Treatment

In South Korea, cancer has been the leading cause of death since 1983, and it also has been named as one of the primary causes of death in the world. In 2019 alone, there were over 1.8 million deaths caused by trachea, bronchus, and lung cancers. Cancer can be developed in any cell in the human body. Unlike normal cells where cells go through the process of growing and dying(apoptosis), cancer cells undergo uncontrolled growth and often develop into cancerous tumors. In response to the formation of these tumors, cancer patients receive different types of treatment which includes radiation therapy, surgery, and chemotherapy. About 45% of all cancer patients undergo surgery to remove their tumor, around 28% of all cancer patients receive chemotherapy, and about 27% of patients receive radiation therapy during their course of illnesses. However, patients who received either chemotherapy or radiation therapy often suffer from long-term side effects such as hair loss, anemia, or bruising and bleeding. And these side effects are what prevent cancer patients from enjoying their normal lives.

To confirm the need for a new cancer treatment and the specifics of it, we conducted multiple interviews with researchers and doctors specialized in such areas and confirmed our area of focus: to reduce the cytotoxicity, while maintaining high efficiency of delivery into the cell and high specificity. CPP (cell-penetrating peptide) are the short peptides that penetrate the cell membranes and translocate the different cargoes, including the proteins, plasmid, siRNA into the cell through both active and passive transporting methods. Its ability to translocate CPP/cargo complexes allows different applications of CPPs in therapies that require noninvasive delivery of molecules. Previous studies show antimicrobial peptide Buforin IIB (RAGLQFPVGRLLRRLLRRLLR, +7) displays a high cell-penetrating ability and anticancer activity while affecting normal cell lines at high concentrations. Once developed into a treatment that can be injected directly to patients, similar to the injection method of chemotherapy, drugs will be put into bodies through a thin tube called a catheter placed in a vein, artery, body cavity, or body part.

Further Implementation of CPPs

CPP can travel across cell membranes, entering all types of cells without damaging them. This trait, which makes them the effective mode of drug delivery, also makes CPP less effective on transferring proteins. To fix this problem, CPPs can be modified by conjugation of specific molecules with CPP to target cells that they would like to treat. If we can gather information on the molecules attached to targeting peptides that specific cells produce, we can alter our CPP to target those specific cells.

In our research, we targeted lung cancer cells using CPP. However, our fusion CPP can be modified to target other types of cancer cells such as breast cancer and many more of them. And studies are currently being conducted to develop CPP mediated biological drugs. With further studies, researchers will be able to find many ways to target numerous diseases using CPP, eventually curing many diseases without damaging other parts of the human body.

According to current study, CPP is very effective in epidermal cells in mucous tissue, endothelial cells in blood vessels, macrophages, liver tissue, spleen, small intestine, colon, ophthalmic disease, respiratory disease, and skin disease. Researchers can aim for these diseases and could make new biologics, meaning better medicine can be developed.

Consideration of Safety Aspects

Some safety aspects of our cell-penetrating-peptide that we would need to consider include cytotoxicity to healthy cells, potential immunogenicity, side effects of intravenous delivery of Doxorubicin, and hypersensitivity to the treatment (allergic reaction).

Although the cytotoxicity of the CPP is lower than that of other chemotherapeutics, there is still some risk of damage to healthy cells, especially if the treatment is administered as multiple doses over prolonged periods; this can result in conventional side effects of chemotherapy, of which the severity varies by patient: fatigue, hair loss, bleeding, etc. all caused by damage to normal cells. Therefore, it is important that we consider the concentration and quantity of the cell-penetrating-peptide being administered so that it does induce cancer cell death, while causing minimal damage to normal cells.

Immunogenicity is another consideration we must take into account before the treatment can become clinically applicable. For instance, there is a potential the CPP can cause drug-induced immune hemolytic anemia, which occurs when a medicine triggers the immune system to attack red blood cells. Thus, conducting the necessary immunogenicity assays during Phase I (public safety) is critical for the implementation of our CPP.

There have been several reported side effects, both common and uncommon, of Doxorubicin when administered to patients over an extended period of time. Several common side effects include but are not limited to: cardiomyopathy, congestive heart failure, leucopenia, alopecia, nausea and vomiting, etc. Several uncommon side effects include but are not limited to: pericarditis, myocarditis, bone marrow, ulceration, etc. Therefore, patients and doctors should be cautious about drug interactions with previously-prescribed drugs that the patients may be taking to avoid increasing the risk of certain aforementioned side effects.

An important potential side effect, or response, to the treatment is hypersensitivity. Hypersensitivity reaction is an immune response in response to a foreign substance. Sometimes triggered by existing chemo treatments, hypersensitivity to the treatment should be tested performing allergy tests to ensure that patients do not experience sudden and deathly anaphylactic reactions.

Possible Challenges

There are a lot of possible challenges in the use of our fusion CPP in the world. The in vitro experiments are only the first step to its development as a cancer treatment and further steps such as animal trials, clinical trials, and a great amount of funds and government involvement are necessary for commercialization. Cost-effectiveness is another factor that should be taken into consideration in order to commercialize the product. Furthermore, results from in vitro experiments are extremely limited, with numerous unpredictable factors such as the cytotoxicity and hypersensitivity of the patient that cannot be considered in such an environment. Although CPP will reach the cancer cells, it can at the same time negatively affect the activity of the nearby normal cells.


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