Sonano: Curing Cancer with Just a Shot

When my mom was in college, my grandmother developed Uterine cancer. At the time, Cancer treatments were not what they were today and my grandmother eventually passed away from Cancer years before I was even born. Later, this same Cancer appeared in my mom’s sister when I was young. I remember her hair loss from her treatments and how she only had short hair the first few years that I knew her, she was luckily able to survive, but the fact remains that cancer runs in our family. My experience with cancer is not unique, almost 1/3 of Americans have been affected by Cancer leaving the rest of us knowing at least one if not more people who have suffered from the disease. Still, every year 1.8 million new Americans are diagnosed with Cancer, and among those more than 600,000 will eventually die.

Status Quo

Current treatments for cancer include Chemotherapy, Radiotherapy, and Surgery all of which have flaws. These treatments are the top 3 used, with 45% of cancer patients using Surgery, 28% getting chemotherapy, and 27% getting radiation therapy.

Chemotherapy can do plenty of harm even with the good, leading to hair loss and attacking the body’s cells painfully. Those going through chemo are even at the risk of developing lethal cancer later in life. Chemo’s survival rate is also low, with only 47% of patients still being alive after five years. Chemotherapy costs also add up fast, with prices like $12,000 a session and almost $20,000 out of pocket each year. These costs are so high largely because there are limited treatments for Cancer currently, so pharmaceutical companies can rack up costs on their product which is one of few methods available.

Radiotherapy is another painful procedure where radiation waves are concentrated on patients in order to kill cancerous cells. Radiation is inherently harmful to the body, killing healthy cells as well, and therefore can lead to many painful off-target effects. Costs of radiation can be as high as $25,144. Radiation therapy’s five-year survival rates are similar to Chemotherapy, hovering around 40%.

Surgery to remove cancerous areas also has its disadvantages. Surgery by definition is invasive and painful. There is no guarantee that cancer-removing operations will remove all cancer cells. Side effects such as pain, bleeding, damage to organs, and infection are also possible, damaging quality of life. Surgery is also costly, a 2014 study examining the costs of surgery involving various types of cancer found average costs range from $14,161 to $56,587. Overall, current treatments for cancer are time-consuming, expensive, mediocre, and painful.

Every year, national cancer costs are estimated to be about $150.8 billion. Americans are spending valuable dollars each year on treatments that could be drastically improved. So what’s the solution?

Enter Sonano.

With Sonano we are going to make Cancer treatments 10X more targeted to cancer sites and minimize harmful off-target effects. We believe in a future where you can get a shot one day and the next day go in for a half-hour to have an ultrasound. Then boom your tumor disappears. At Sonano, we’re going to make this a reality in the next five years. Treating one of the leading causes of death will be easier than getting a flu shot. We plan to use sonosensitizers inserted into polymeric micelles that trigger drug release when activated by ultrasound.

Sonodynamic Therapy

Sonodynamic therapy (SDT) is an emerging approach to cancer treatments that uses ultrasounds to non-invasively target and destroy tumors. It makes use of two different major components: ultrasounds and sonosensitizers. Ultrasounds are medical imaging machines that use high-frequency sound waves to produce images of structures inside the body. Until now, ultrasounds have been used mostly for diagnostic purposes. Sonosensitizers are molecules that react with sound waves and transfer the energy onto a nearby molecular structure. So, naturally, sonosensitizers enter and travel through the body at a ground state until a reaction is activated due to the high-frequency sound waves sent into the body. Ultimately, sonosensitizers release energy that powers a reaction that produces destructive, unstable molecules that drive the cell to self-destruct.

More specifically, the SDT mechanism works like this:

1. Acoustic cavitation: the high-frequency sound waves from the ultrasound inducing cavitation (oxygen bubbles) on the surface of cancer cells
2. Sonoluminescence: Cavitating bubbles release energy in the form of visible light, which activates sonosensitizers. As the excited sonosensitizer returns to the ground state, the energy released from that reaction can be transferred to nearby oxygen atoms, creating a large number of reactive oxygen species (ROS)
3. Apoptosis: ROS damages the mitochondrial membrane and triggers the release of the protein cytochrome c, which activates the cascade of caspases (enzymes involved in cell death) and ultimately leads to apoptosis.

Nanoparticle Drug Delivery

Nanoparticles are small particles of matter that are at a nanolevel. Nanoparticles have multiple uses and are an emerging field of medical treatment. One function of nanoparticles is targeted drug delivery. Nanoparticles can be injected like a vaccine into a tumor site and the drugs they contain can be released to target that area. Nanoparticles come in many shapes and forms but common nanoparticles are either liposomes or polymeric-based.

If you think back to high school bio, the cell consists of a phospholipid membrane with two layers of lipids facing opposite directions. The cell membrane has a hydrophobic inside and hydrophilic outside, which is why membranes are so effective at protecting the cargo inside. Membranes don’t just consist of phospholipids — if they did, only very small, non-polar particles (we’re talking like the size of a couple of atoms) could get through membranes by passive diffusion. In reality, they’re a patchwork of various lipids, carbohydrates, and proteins.

Proteins are especially vital to our discussion — there are many types of membrane proteins that do loads of important jobs, namely transport proteins that are chemically triggered to create a “channel” through the membrane into the cell. Each of these proteins can only be triggered by a very specific reaction and only facilitate the passage of very few molecules. These unique properties allow cell membranes to have a property called selective permeability; in simple terms, the membrane can “choose” what enters and exits the cell.

All these factors make membranes vital for life; so much so that we eukaryotic organisms (literally defined as organisms with membrane-bound nuclei) have membranes surrounding many of the organelles within the cell. Liposomes themselves are manmade — they were invented in the early 1960s, modeled after vesicles, which naturally occur in cells. Liposomes (and vesicles) consist of a phospholipid bilayer surrounding aqueous volume; liposomes are specifically designed to carry drugs within that aqueous center. The original nanoparticle drug delivery, if you will!

Diagram of a liposome with drugs in the center

Liposomes are meant to reduce the toxic side effects of anti-cancer drugs without inhibiting their efficiency. Because of the lipid bilayer protecting the drug “cargo” inside the liposome, liposome carriers can stay in the bloodstream a lot longer than the cancer drugs by themselves. Liposomes also enhance the solubility of the cancer drugs — many are relatively insoluble in water, which makes it very hard for cells to uptake the molecules necessary for the drug to work. Liposomes are the most widely used nanoparticle drug delivery systems in cancer treatment currently. Even so, very few nanoparticles by themselves are FDA approved to carry cancer chemotherapy drugs like Doxorubicin and Paclitaxel to target specific tumors. The liposomes that carry these drugs passively target tumor cells; that is, they just serve the function of transportation and protection and are not externally activated, so once injected into the bloodstream, we have no control over where the liposomes actually go and which tissues actually get targeted by the anticancer drugs.

The whole system of passive targeting is based on probability, just like conventional chemo. There is always an element of probability in medicine, but a treatment system shouldn’t be solely based on that. For a disease that is so deadly, there needs to be a better way to target cancer, a way that we can externally make sure that the drugs are where they need to be and do what they need to do.

Polymeric Micelles

Another type of nanoparticles that work well for drug delivery is polymeric-based. In particular, for cancer drug delivery, a type of nanoparticles called polymeric micelles (PMs) are effective. PMs also have an outer membrane with a hydrophobic coating and hydrophilic core like liposomes, and also work like vesicles.

However, the membrane of a micelle is not composed of a phospholipid bilayer, but a single layer of amphipathic (both hydrophobic and hydrophilic) lipids, some of which are artificial components, allowing for them to be easily engineered for specific purposes.

Their size can range from 5 to 100 nm diameter whereas liposomes can range from 30nm to multiple μm in diameter. The smaller size of micelles allows them to be able to penetrate the vasculature of tumor cells easier than liposomes.

Compared to liposomes, PMs have better cargo retention and stability. PMs self-assemble to form a sphere that holds therapeutic drugs and protects them as it transports the drugs through the body to their target. Micelles can have their membranes engineered to contain sonosensitizers which are activated by ultrasound to release the drug contents of the nanoparticle.

Polymeric micelles have also been used in clinical trials, furthering proof-of-concept. in addition, polymeric micelles can deliver proteins and genetic material in addition to drugs, which can lead to further research for even more effective treatment.

Solution

If sonosensitizers are combined with nanoparticles, ultrasounds can generate reactions to better target tumors in a non-invasive way. This reaction causes the sonosensitizing nano molecule — which doubles as a vessel for anti-cancer agents — to release or generate said agents, which “attack” the tumor. Ultrasounds can be concentrated in tumor areas, making drug release only occur at the tumor.

Treating cancer right now is like trying to get rid of weeds. You have weeds growing with a rosebush and you can either use a lawnmower which will get rid of the weeds but also hurt the rose bush (healthy cells) or you can use hedge clippers which can finely take out the weeds (cancer cells).

Sonano is the difference between current treatments. The standard for cancer treatment today is like using a lawnmower to get rid of weeds near a rosebush. There’s no way to select what gets trimmed and what doesn’t, just as there is no way for chemo drugs to target solely cancer cells. Sonano is the hedge clipper in this situation: we have control over what gets trimmed and what doesn’t, so we end up with only the rose bush surviving, and not damaged.

The benefits of ultrasound-dependent therapy are that it is non-invasive, low-cost, quick, and safe. Ultrasound waves also increase cell permeability or its cell membrane’s willingness to take in particles from outside, which is favorable for drug delivery to get nanoparticles to enter cancerous cells.

Why hasn’t this been done yet?

Sonodynamic therapy as a method of cancer treatment is still within its infancy. Only 63,000 people worldwide have had tumors treated with SDT, as part of different clinical studies. The results have proven optimistic: only one treatment on a dog with terminal-stage chondrosarcoma led to a 15% decrease in tumor size in 2015, although the researchers at Tokyo Women’s Medical University used different mechanisms to the common ones proposed above.

However, many more trials are required for this treatment to be even considered anything more than experimental. Even if the treatment were commercially available now, scalability proves a massive issue, as nanoparticle creation is quite complicated. Currently, nanoparticles tend to be made solely in highly equipped labs, so they can’t be mass-produced to fulfill the demand for cancer treatment.

In addition, the material composition of a nanoparticle is vital and quite complicated to perfect (one barrier to an increase in human trials, approval, and scaling). Nanoparticles must be able to survive within the harsh microenvironments of the body, evade T-cells and other immune responses, have the ability to release their contents in a controllable and predictable way, not be toxic, and, ideally, be biodegradable. To add to the list, in vivo studies with nanoparticles have generally been in animals, so it is challenging for scientists to understand the different reactions that animals and humans have, as well as adapting to heterogeneity, which, once again, affects scaling.

Scalability

Polymeric micelles are generally prepared by either of the two general methods:

• Top-down lithography - essentially like chipping a block of marble down to the desired shape, but with chemicals. This is usually high cost and wastes a lot of materials for a small amount of return — this wastes a lot of money but gets excellent results. The “top-down” approach involves the breaking down of large pieces of material to generate the required nanostructures from them. This method is particularly suitable for making interconnected and integrated structures such as in electronic circuitry.
• Bottom-up lithography - basically trying to build a house with a child’s drawing. This is cost-effective because you’re only using as much material as needed. In the “bottom-up” approach, single atoms and molecules are assembled into larger nanostructures. This is a very powerful method of creating identical structures with atomic precision, although, to date, the man-made materials generated in this way are still much simpler than nature’s complex structures.

Specifically, polymeric micelles are prepared either through the direct dissolution of the polymer in an appropriate solvent (direct dissolution is usually followed by stepwise dialysis) or the addition of a precipitating solvent for one block. The most common method for producing polymeric micelles is emulsion where oil is suspended in water with emulsifiers that help keep the two liquids together. While this works for relatively stable environments trying to keep the two together, it becomes difficult as soon as this is deployed in the body. This is why polymeric micelles are usually associated with the potential to leak the drugs prematurely.

Sonano takes the approach of using inverse flash nanoprecipitation: a new take on previously discovered flash nanoprecipitation. This works by essentially shooting streams of liquids at each other at high pressures (which can be done at high volumes) — with mixing chambers that prevent the liquids from separating, thus allowing drugs to be held together securely with sonosensitizers acting as the release switch. All that’s needed for this to scale is the materials and machines shooting liquid as well as the mixing chambers.

Economic Incentive

A new process in liposome production called SuperLip (Supercritical assisted Liposome formation) has proven extremely effective and is being scaled up for industrial production. Assuming that micelles can be created through a similar process (at lab-scale, micelles and liposomes are made in very, very similar processes).

Current scaling analyses estimate plant CAPEX at $82,891.25 in USD (€68,970), which is very affordable.

The CAPEX breakdown according to the analysis:

At the end of the day, insurance providers, especially in the United States, are going to choose the cheapest option for treatment. Based on these estimates, the cost of the equipment for an ENTIRE FACTORY is equivalent to the out-of-pocket costs for 3.5 years of chemo. Cancer is always going to need to be treated, so there is always a market for it, and by jumping on this opportunity now, Sonano will be able to establish a strong place for itself in the growing nanotechnology market. Health tech is also a very lucrative market — it will be expanding as long as human innovation is around, so it is important that Sonano established itself as the next generation in health tech in order to get a sizeable share. in an industry that’s always innovating, Sonano will be able to grow along with the demand thanks to growing market opportunities and the backing of insurance companies.

Thank you for taking the time to read this article, if you want more from Sonano check out our website!