Capsule Containing a TRAIL Mimicking Apoptosis-Inducing Molecule to Eliminate Complicated Surgeries
By: Aditi Bang and Sonika Tatipalli
Abstract
Colon polyps are lumps of cells that can form in the colon or rectum lining and can become harmful as they can progress into cancerous cells. Typically, a physician conducts a colonoscopy on the patient to diagnose the polyps. Another surgery, such as polypectomy, is then performed to remove the harmful tissue. However, there are many injurious side effects to this procedure such as severe abdominal pain and heavy bleeding.
Our proposed solution is to use a much safer technique: an edible capsule with a hypromellose coating which contains a TNF-related apoptosis-inducing ligand (TRAIL) mimicking a molecule and a microcamera to monitor progress. The molecule inside the capsule should resemble TRAIL, a protein cytokine produced by healthy cells. In this way, it can bind to the death receptors, DR4 and DR5, to start the apoptosis pathway in the polyps. This capsule could be the new way of a safer polyp treatment.
Significance of the Targeted Problem
Colon polyps are present in 15-40% of individuals; they endanger more than 200,000 Americans each year (“Definition & Facts for Colon Polyps”). They are clumps of abnormal cells that can grow in the colon. As demonstrated in Figure 1, the polyps form near the lining of the rectum or the colon. There are two categories of polyps: neoplastic or non-neoplastic. Neoplastic polyps are more likely to become cancerous. Polyps in this category are either adenomas, the most common type of polyp, or serrated polyps. Non-neoplastic polyps are either hyperplastic or inflammatory which generally do not become cancerous (“Colon Polyps - Symptoms and Causes”).
Figure 1
Healthy Colon vs Colon with Polyps
Although colon polyps can easily develop in anyone, many risk factors put individuals to a higher chance: obesity, age 50 or higher, family history of polyps or cancer, and a rare inherited gene. As people age, the prevalence and chance of polyps increase; by age 60, more than one-third of people will have at least one polyp. This escalates the chance of additional polyps developing in the colon and forming again later. If there is a family history of polyps and colon cancer (a genetic condition such as familial adenomatous polyposis), a surgeon will most likely remove the colon and rectum, which can cause blood clots in the legs and leakages with many long-term effects (“Colon Polyps: Symptoms, Causes, Diagnosis, Treatment, and Prevention”).
Usually, individuals do not show symptoms, making it difficult to detect polyps before they become threatening. However, some individuals may experience blood in stools, abdominal pain, iron deficiency anemia, and a change in bowel patterns. Additionally, a large polyp may burst and lead to bowel obstruction, which may block food and fluids from going through the intestines properly. Some symptoms that may follow the bursting of the polyp include severe bleeding, colon perforation, and abdominal pain (“What You Should Know About Colon Polyps”). This obstruction may also cause a serious infection of the peritoneal cavity called peritonitis, an inflammation of the abdominal wall membrane lining (Pietrangelo).
Polyps can also subject the patient to risk because they sometimes lead to colon cancer. Although most polyps are benign, they can become cancerous with rapid mutations in genes. The cells begin to divide uncontrollably causing the polyp to expand. Even if a person has one polyp or a polyp greater than a centimeter, the likelihood of colon cancer increases (Marks). It is validated by many scientists and physicians that the larger the polyp, the more likely it is to cause cancer.
Insufficiencies of Current Solutions
Patients with polyps must first go through a colonoscopy procedure for being diagnosed. A colonoscopy, an endoscopic examination of the colon and other nearby parts, allows the physician to check if any polyps are present. A colonoscopy and a sigmoidoscopy are both similar: the doctor uses a thin flexible tube with a camera located near the end to examine the colon (“Scripps Health”). However, a sigmoidoscopy inspects the lower portion of the colon while a colonoscopy analyzes the whole colon. During a colonoscopy or possibly as a separate procedure, a polypectomy is assigned to the patient if the physician thinks it is necessary to remove the polyp. As demonstrated in Figure 2, a wire is placed around the polyp and is contracted to create an incision and detach the polyp. Cauterization can also be used to cut the polyp by utilizing a wire that contains a current to heat and close the blood vessels by relieving the bleeding (“Colon Polyps - Symptoms and Causes”). Another method used to treat more difficult polyps is laparoscopic colectomy in which short narrow tubes and instruments are placed in the abdomen through tiny incisions. The surgeon then uses these instruments to extract the polyps with the guidance of a camera (“Laparoscopic Surgery - Series—Incision”).
Figure 2
Steps of a Polypectomy
With any surgery, complications may occur; for a polypectomy, possible complications include severe pain, vomiting, bleeding, colon perforation, and infection (“Colon Polyps: Symptoms, Causes, Diagnosis, Treatment, and Prevention”). When a polyp is removed, there is a chance of heavy bleeding. This can happen during the surgery itself or after for up to a week. A colon perforation, a hole in the wall of the colon, could result in the contents of the colon to leak out creating inflammation or deadly infection (“Colon Perforation | Winchester Hospital”). This requires immediate attention or could lead to serious conditions such as sepsis or even death. An infection might start near the removal site due to the equipment. Rare but possible side effects of a cauterization include, but not are limited to, heart attacks, strokes, and deadly lung infections (“Colon Polyps - Symptoms and Causes”). A laparoscopic procedure may also cause visceral injuries. Although there is a low chance for these complications, when they do occur, the patient’s life is at serious risk.
Our Proposed Solution
Most polyps can be extracted during a simple half-hour colonoscopy. They are then sent for a pathological diagnosis to distinguish between cancerous or non-cancerous polyps (“Colonoscopy - Mayo Clinic”). If the test shows that the polyp was cancerous, further treatment, usually surgery, is needed. However, since surgery can be risky, our proposed drug acts as a replacement.
Unlike these exhausting, potentially deadly surgeries, this potential solution has almost no risks. Our solution is an edible capsule containing a molecule that imitates the TNF-related apoptosis-inducing ligand (TRAIL) which is a ligand that induces the apoptosis pathway. It also contains a micro-camera so the physician can monitor the patient’s progress. The coating of the capsule is made of hypromellose so that the pill is resistant to the stomach acid and is able to reach the colon. In the colon, it should dissolve and release the TRAIL mimicking molecule.
TNF-related apoptosis-inducing ligand is a cytokine (a molecule regulating cell immunity mechanism). This protein can regulate immunity throughout the body. There are two pathways that lead to apoptosis: the extrinsic pathway and the intrinsic pathway. The extrinsic pathway works by receiving incoming signals from cells while the intrinsic pathway senses cell stress such as a viral infection or DNA damage so the cell automatically dies. The TRAIL apoptosis pathway is extrinsic and is initiated by the binding of the death ligand, TRAIL, to the death receptors, DR4 and DR5, which are designed to only function in malignant cells. As displayed in Figure 3, after the ligand binds to the receptor, it will interact with the adaptors Fas-associated protein with death domain (FADD) and Tumor necrosis factor receptor type 1-associated DEATH domain protein (TRADD) to begin a caspase cascade inside the cell. This ultimately leads to apoptosis: the death of the cell (“Extrinsic Apoptosis Pathway - Creative Diagnostics”).
Figure 3
Apoptosis Pathway
TRAIL was used on breast cancer therapy in clinical phase I and II trials, but the breast cancer cells were resistant to TRAIL (Rahman). However, this has not been tried on colon polyps. If a new molecule could mimic TRAIL, this could potentially advance colon cancer research and beat other cancers too.
One of the foundations in biology is that structure defines function. TRAIL’s specific structure allows it to play a vital role in the apoptosis pathway by easily binding to the receptor. The molecule that we create should have an identical binding site to TRAIL’s so it can bind to DR4 and DR5 and launch the apoptosis pathway. Currently, some cancerous cells have resistance to the TRAIL, so a new molecule would trick these cells (“Targeting TNF-Related Apoptosis-Inducing Ligand (TRAIL) Receptor by Natural Products as a Potential Therapeutic Approach for Cancer Therapy”). This molecule can allow us to approach colon cancer from a different angle.
The molecule may not come in contact with all the polyps after consuming only one pill meaning that the patient may need to take multiple to eliminate all the colon polyps. Since it would be difficult for the doctor to do multiple colonoscopy procedures to check if the polyps were eliminated, a micro camera can also be placed in the pill to monitor the progress more conveniently. As it travels through the body, numerous pictures are taken so the doctor can analyze them and is then excreted as solid waste. This micro camera is already proven to work as it is used in other medications (“Capsule Endoscopy - Mayo Clinic”). During the initial colonoscopy for diagnosis, the physician can take note of the locations of the polyps. While the micro camera is traveling through the colon, the physician can check in those noted areas to see if the polyps are still present. With this, they can guide the patient about when to stop taking the medication.
This drug needs to be resistant to the stomach’s acidic environment for complete dissolution to happen in the colon. If it dissolves in the stomach, the molecule would enter the bloodstream making it a complete waste. Hypromellose coating will shrink as it passes through the gastrointestinal tract. Hypromellose is gastric acid-resistant making it a perfect choice as a coating for the capsule (“CapsCanada”). It causes almost no irritation and is also commonly used in oral medicinal products (Li). Hypromellose allows us to pass through the stomach acid because it breaks down at a pH of 5.5 or greater. After the highly acidic stomach (pH levels around 2-3), it dissolves as it reaches the intestines and colon which have a pH of around 6. The coating dissolves in the colon releasing the microcamera and the TRAIL mimicking molecule to target the malignant cells.
Obstacles
One important factor to ensure the capsule functions properly is to make sure that the binding site of the TRAIL mimicking molecule is an exact replica of the actual molecule’s site. Isolating the death receptors and creating a molecule to fit into the active site cells can be tedious. Many tests would have to be conducted which may use a vast amount of time, money, and resources. However, the number of lives this capsule can save outweighs these trivial issues.
Conclusion
We made an effort to propose a safer solution to commonly used surgical techniques for the management of polyps. While surgeries may have many life-threatening complications, our capsule has no risks in eliminating colon polyps. The edible pill, coated with hypromellose to resist gastric acid, contains a TRAIL mimicking molecule which starts the apoptosis pathway and a microcamera for the physician to guide the patient. This capsule could be a breakthrough for treating different colon cancers.
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