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Cancer Treatment Breakpoint: A Discovery of 225Ac – H4py4pa Complex

Posted on April 8, 2022 | Leave a comment

Like the Earth itself, the world of science never stops turning.

More specifically, the world of cancer research never stops turning; there are always improvements to be made. With this mindset, scientists Lily et al. from the Orvig group wrote and published a paper about the characteristics of a molecule called H4py4pa in early 2021. They studied the molecule at multiple locations, such as the UBC Chemistry Labs, TRIUMF and BC Cancer Research Centre, in hopes of improving the effectiveness of a specific type of cancer treatment called targeted alpha therapy. The paper supports the effectiveness of this new molecule by comparing characteristics, such as stability, with the original molecule used in targeted alpha therapy.

With all that said… What is targeted alpha therapy and how exactly does it work?

What in the Jargon?… A Carefully Defined Mechanism of H4py4pa

Before we get into the meat and potatoes, we need to define some of the terms here.

H4py4pa is a ligand, which is essentially a big molecule, that is able to bind to metal atoms. Ligands binding to metal atoms is a chemical phenomenon known as chelation. The metal atom in this case is Actinium-225 (225Ac). Essentially, chelation of H4py4pa to 225Ac can deliver four net alpha particles, which are a particulate form of concentrated radiation. Radiation is known to destroy cancer cells. In other words, radiation is tumoricidal. This process is known as targeted alpha therapy.

Molecular Structure of H4py4pa and visual summary of the study. Source: Bioconjugate Chemistry

Starting from 2:50, you get a visualization of how the mechanism works. Source: STORYHIVE

The Body is ASTOUNDINGLY Large

We, as humans, are fairly large organisms. So the question becomes: How does the 225Ac-H4py4pa find the tumour site? 225Ac is normally bound to a specific antibody, called Trastuzumab, which is attached to the HER2+ protein. The HER2+ gene most notably contributes to breast cancer. This means that 225Ac already has a natural affinity for certain tumour sites in the body. However, 225Ac is still capable of unintentionally interacting with other areas of the complex body. This is where H4py4pa comes in. H4py4pa is a very big molecule that hugs around the 225Ac and prevents it from binding to anything other than the intended antibody.

A good way to visualize this mechanism is through a 4-component arrow mechanism. The 225Ac is the arrowhead that will do the damage to its target (in this case the tumour) while the shaft and the feathers of the arrow are the directional components that direct the 225Ac arrowhead to the right area of the body.

The issue with solely injecting 225Ac into the body, however, is that it’ll go straight to the bone instead of the cancerous area. As you may have heard, opposites attract, so because 225Ac is positively charged, it’ll be attracted to the bone, which has a lot of negatively-charged phosphate groups.

This is where the H4py4pa comes into play.

The fourth component of the arrow is H4py4pa, which acts as the linker for the arrowhead and shaft, binding to the 225Ac and holding it in place as the directional components of the arrow move the 225Ac arrowhead straight towards its target.

We’ve prepared a video in order to visualize this:

So what are the Discoveries of this Study?

Through many trials and tests, it was found that H4py4pa was very effective in conducting targeted alpha therapy with 225Ac. It was the most stable ligand that was bound to 225Ac relative to previously used ligands. There was much more control inside the body and it was less likely to spontaneously react with molecules other than the intended antibody. Furthermore, 225Ac maintained its radioactivity in the body. With some ligands, 225Ac did not release its alpha particles due to incompatible binding. However, with H4py4pa, 225Ac still had high radioactivity in tumour areas and low radioactivity in non-tumour areas such as the bones and the liver. This reduces the risk of untargeted toxicity in the body.

How Does it Differ from Chemotherapy?

Perhaps you’ve heard of chemotherapy before? It’s a fairly common and well-known treatment for cancer. While it is effective, there are drawbacks to chemotherapy as well; to quote Dr. Orvig:

“…the thing about cancer chemotherapy is just using conventional chemicals is that you basically poison the patient. And because the cancer is a little more susceptible, you’re poisoning the cancer a little bit more.”

Dr. Chris Orvig, March 2022

Essentially, chemotherapy reduces cancer by targeting fast-growing cells in the body. Unfortunately, this includes the entire body, so while the fast-growing cancer cells are affected by chemotherapy, fast-growing healthy cells can be affected too.

On the other hand, targeted alpha therapy is able to directly target the tumorous areas of the body by binding to the antibody of the tumourous cell. This means that the 225Ac is able to directly destroy the cancerous cells without doing as much damage to the surrounding healthy cells.

Who were the people behind this all?

Well, the initial propagator of the idea behind H4py4pa was Dr. Lily Li who, at the time of the study, was a Ph.D. student with Dr. Orvig. After hearing about that idea, Dr. Chris Orvig, a UBC Chemistry Professor and an associate member of the faculty of Pharmaceutical Sciences, initiated the study. He also gathered the funding and the people for the study and helped conduct it as well.

For a bit more detail behind the history of this study and Dr.Orvig, we have a podcast prepared:

Now, that was all about the past, but what does this mean for our future?

Why is this so important?

Significance of H4py4pa and Targeted Alpha Therapy

H4py4pa and targeted alpha therapy could lead to many advancements in cancer treatment research.

As mentioned before, targeted alpha therapy is able to directly target tumours with less damage to the patient’s healthy cells; this could potentially reduce the fatigue most chemotherapy patients experience throughout their entire body. However, it does has limitations.

Before H4py4pa, the molecule used for target alpha therapy tended to bind to Actinium slower than preferred in its surrounding temperatures, which can lead it to be less effective.

This is why H4py4pa is so important.

Not only is it able to bind quicker to Actinium, but it’s also more stable than the previous molecules, all while remaining just as effective against cancer

In the future, this means that different companies can use Actinium and H4py4pa against different types of cancers. In reference to the arrow metaphor, they could adjust the directional components of the arrow (the shaft and the feathers) and direct the Actinium to different areas of the body.

“… I think it’s quite possible that we will see in the future Actinium used in different chemical constructs to treat a number of different cancers. And the hope would be that you give a patient one or two or three shots of this over a two or three-month period, and that we could drive many different cancers into remission. “

Dr. Chris Orvig, March 2022

[Group 5: Bill Yang, Evelyn Zhong & Christine Sun]

How to Synthesize 40,000 Biochemical Weapons in Six Hours!

Posted on March 21, 2022 | 1 comment

In the media, we constantly hear about Artificial Intelligence (AI) advancing for the benefit of society. It is assumed that this advancement will aid us in fields such as healthcare and drug development by simplifying complex human tasks. However, what if it did not? What if this AI was abused to potentially harm society?

Collaborations Pharmaceuticals, Inc. had designed a molecule generator called MegaSyn, which discovers new potential drugs that can target and prevent human diseases through machine learning model predictions. This functions as the AI of the story. Essentially, the model depicts all of the predicted target drugs that are synthesizable, while deleting all of the molecules that are considered toxic to humans. The company proposed the idea that they could synthesize toxic molecules by simply inverting this program. Due to the universal abundance of possibilities, they used VX, which is one of the most toxic biochemical nerve agents developed, as a model to focus the results. In less than six hours, the program produced a model that generated 40,000 molecules that were within the same calibre of toxicity as VX.

A few grains of VX (6-10 mg) are enough to kill a person. Source: Periodic Videos

The Potential Misuse of AI Programs

Although the company did not synthesize any of the molecules in their model, this experiment raises serious concerns over the consequences of AI misuse. There are hundreds of commercial companies with technologies that are able to replicate MegaSyn. Furthermore, another AI program that can make this risk more severe is retrosynthesis software, which can computationally break down a molecule into the steps from which it is synthesizable. Although this model was based on VX-like compounds, it would be simple to look for other toxic molecules through minimal adjustments to the program. The abuse of AI should be alarming because all you need is the ability to code in order to greatly lower the technical skills required to synthesize potentially dangerous biochemical weapons.

Quantitative Structure-Activity Relationship is an example of a similar program that is used for Drug Discovery. You can substitute VX as the molecule to apply to this study. Source: Data Professor

Rapid Synthesis Using Combinatorial Chemistry

Complimenting the advancements on the technological side, there have also been significant advancements on the chemical side in the last century. The development of combinatorial chemistry allows for the synthesis of mass numbers (perhaps millions) of similar compounds within a single process. Essentially, there is a large array of structurally diverse compounds, also known as the chemical library, which interacts with biological targets of interest to simultaneously synthesize thousands of peptides. With the AI-generated model acting as the chemical library with its toxic-focused molecule (such as VX), the process of combinatorial chemistry becomes much more easily accessible.

Combining different structures together using biological target interactions to synthesize multiple compounds. Source: Wikimedia Commons

So, Is This Technology Beneficial Or Not?

The molecule-generating AI program is concerning due to its applications in biochemical warfare. If the program is misused, it can easily be employed in war and cause the loss of thousands of lives, not to mention the environmental impacts of such chemicals. However, this program could just as easily be used for the benefit of mankind. The key is transparency. Collaborations Pharmaceuticals decided to be transparent with their findings and inform the public about the power of their program. Therefore, there is peace of mind that they will use this program for the benefit of drug discovery.

~ Bill Yang

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Posted in Biological Sciences, Issues in Science, Public Engagement, Science Communication, Science in the News

Tagged Artificial Intelligence, Biochemical Weapons, Biotechnology, Chemical Synthesis, chemistry, Drug Development, Nerve Agents, Pharmaceuticals

Everyday, You Create Infinite Universes

Posted on January 24, 2022 | 1 comment

Someone approaches you and asks you on a date. You’re nervous, but you answer with a “yes”. Meanwhile, another you says “no”. Regardless, you just created two different universes. Wait, what do I mean by “another you”?

The Many-Worlds Interpretation (MWI) hypothesizes that for every observation of one state or outcome, there exists a separate world, or worlds, in which a different outcome becomes that separate world’s reality. Therefore, whenever an experiment with multiple different outcomes is conducted, we have achieved all possible outcomes. Each of those outcomes creates a new universe. This hypothesis was stated by theoretical physicist Sean Carroll in his 2019 book, Something Deeply Hidden. Note that this is an interpretation, not a comprehensive theory. Consequently, there are multiple interpretations from different individuals (which is both ironic and analogous to the topic). The interpretation I have defined above is what I will be discussing.

A decision/state branches into different quantum outcomes.
Source: Flickr

Why Are There “Infinite” Universes?

We accomplish several tasks during the day. Even the smallest outcomes matter. For example, when we style our hair in the morning, every single hair placement can create another universe. Every step you take or do not take creates universes. Now consider that there are also billions of other people in our world that are, themselves, creating universes with their outcomes. On a smaller scale, even the particles in our world interact differently from one another. The Second Law of Thermodynamics states that entropy, which is a measure of disorder, increases in an isolated system. A relevant example of an isolated system is one universe. Essentially, the natural order is disorder. An example may be two particles colliding together at various possible angles, with each angle forming a universe. Further abstraction can postulate that particles interacting with other particles differently can cause different behaviours that create different universes. An example of this would be matter acting like waves or particles. These outcomes lead to what can only be considered as an infinite number of universes.

Source: Science & Cocktails

So When Can I Meet These Other “Mes”?

Unfortunately, you currently cannot. The new universes that we constantly create cannot intersect with our own, meaning that we only observe the outcome that we see in our world. Assuming these universes physically exist, research conducted by theoretical physicist Alexander Vilenkin suggests that different universes are in their own bubbles. These bubbles never intersect because they continue to expand faster than the speed of light, which is faster than we can travel. This means that the MWI is currently neither observable nor falsifiable. In other words, it cannot be proven nor disproven. Hence, it is an interpretation rather than a concrete theory.

Bubbles That Contain Different Universes
Source: Pixabay

Do Our Decisions Really Matter?

For every decision that we make, no matter how minute it may seem, there exists another us that makes the exact opposite decision. If all outcomes are achieved in the MWI, is there any weight to the decisions that we make? While this is an interesting argument, the MWI is not currently falsifiable. Overall, we should continue making decisions that are unique to us while being open-minded about the possibility that we are creating many universes.