Gold Nanoparticles for Cancer Treatment

There are many ways to treat cancer, and some of them are nearly as frightening as the disease itself. But today, researchers are beginning to unravel some new approaches, including one that comes from seemingly miraculous recoveries in cancer patients who experienced severe fever.

And the interesting part is that gold might be just the ingredient needed to take advantage of a weakness some cancers have to a sudden increase in our body temperature.

That’s important, because cancer isn’t going away.

In the United States, cancer is the second leading cause of death. The American Cancer Society estimates that in 2022, there will be 1.9 million new cancer cases and more than 600,000 cancer deaths.

That’s the equivalent of 5,250 new cases of cancer each day. Cancer is an enormous health concern.

The leading treatment options for cancer aren’t always successful and carry with them a slew of possible side effects such as nausea, vomiting, hair loss, increased risk of infections, and the possibility of secondary tumors.

Hyperthermia, also known as overheating, is a therapy that uses heat to kill cancer cells. It’s best used alongside other therapies such as chemotherapy or radiation therapy.

One of the challenges to using hyperthermia to treat cancer is making sure the heat goes to the right place. That’s where the gold comes in. Ongoing research reveals gold nanoparticles can be used to heat and kill tumor cells with great precision and minimal side effects. This form of hyperthermia is called photothermal therapy, and it has shown very promising results for a number of cancer types.

Cancer Is a Problem

Cancer is a serious health concern worldwide.

According to recent data by the American Cancer Society, U.S. females have a 38.5 percent chance of developing invasive cancer over their lifetime, while males have a 40.2 percent chance.

Cancer becomes invasive when it spreads beyond the layer of tissue where it developed and into surrounding healthy tissues and lymph nodes.

If untreated, cancer cells may enter the blood or lymphatic fluid and emigrate to other tissues or organs. This process of metastasis often results in secondary tumors in the body.

Leading Treatment Options for Cancer Aren’t Ideal

Since cancer is so varied, there’s no single, fully comprehensive approach to treatment. Leading treatment options include surgery, radiotherapy, chemotherapy, and immunotherapy.

While surgery is generally considered an effective therapy for early-stage cancers, it isn’t ideal for metastatic cancers since the cancer cells have spread to other regions of the body. In some cases, even if surgery is done early on, the cancer can return.

Radiation therapy uses high-energy radiation to damage the DNA of cancer cells. This type of therapy often also damages surrounding healthy tissue. As with surgery, it is difficult to treat metastatic cancer with radiation therapy.

Chemotherapy can treat many different types of cancer, even if the cancer has metastasized. Unfortunately, chemotherapy drugs can be toxic to healthy, non-cancerous tissues of the body.

A significant problem with radiation therapy and chemotherapy is that both can cause cancer, making secondary cancer a serious possible side-effect.

Immunotherapy is a cancer therapy that helps the immune system fight cancer. As a biological therapy, this treatment uses substances produced by other living organisms.

There are several types of immunotherapy treatments including T-cell transfer therapy, monoclonal antibodies, immune system modulators, treatment vaccines, and immune checkpoint inhibitors.

While side effects from immunotherapy typically aren’t as troublesome as the side effects from chemotherapy, they can still occur.

Since the body’s immune system has been amped up to fight against cancer cells, there may be some collateral damage to healthy cells, such as flu-like symptoms, heart palpitations, and organ inflammation.

A significant portion of cancer therapy research is dedicated to discovering therapies that can complement or replace current therapy options with greater effectiveness and fewer side effects.

Hyperthermia as Approach to Cancer Treatment

In the 1800s, doctors began noticing a number of intriguing cases of cancer patients who, after suffering high fevers from contracting erysipelas, found their cancer symptoms decreased. Some patients experienced complete tumor regression.

Erysipelas is a skin infection caused by Streptococcus bacteria, typically S. aureus or S. pyogenes. A key feature of the infection is a fever, which may be very high.

One surgeon, Dr. William Coley, was fascinated by these case studies and in 1891 injected S. pyogenes into a patient’s inoperable tumor to see if the infection would help shrink it.

The patient’s body temperature rose to 105 degrees. Days after the fever began, his tumor started to shrink. Remarkably, within two weeks, the tumor was gone.

Coley spent years perfecting bacterial injections to treat tumors. These formulations became known as Coley’s toxins.

One pharmaceutical company created preparations of Coley’s toxins from 1899 to 1951, making the treatment available to physicians in the United States and Europe.

The results varied on different cancer types, but The Iowa Orthopaedic Journal notes the treatment was especially effective on bone cancers and soft-tissue sarcomas.

Soft-tissue sarcomas are cancers that form in muscles, fat, nerves, the lining of joints, blood vessels, and tendons.

In 1962, the FDA removed Coley’s toxins from the list of approved drugs, so it became illegal to use this toxin to treat cancer. At this time surgery, radiotherapy, and chemotherapy were becoming mainstays of cancer treatment.

Though these other therapies took the spotlight, scientists continued to research how hyperthermia reduces tumors.

Over the decades, they have generated a massive body of knowledge about treating cancer with hyperthermia. Let’s take a quick look at some of the basics of the biology behind this therapy.

What We Know Now About Heat and Cancer

Tumors are generally more acidic than regular tissues and they often have regions of hypoxia (inadequate oxygen supply). A study in the International Journal of Hyperthermia notes these two factors make tumors resistant to chemotherapy and radiation, but more susceptible to heat stress.

A study included in the journal Nanomedicine found hyperthermia causes cell apoptosis (programmed cell death) by causing irreparable mitochondrial damage.

Hyperthermia can also trigger cell necrosis (uncontrolled cell death) by damaging the cell membrane and denaturing proteins, according to research published in Cytometry Part A, the journal of the International Society for Advancement of Cytometry.

Hyperthermia can initiate both of these cell death pathways in a single tumor simultaneously. The amount of necrosis versus apoptosis occurring in the tumor depends on several factors, especially the degree of heat applied.

Apoptosis is a much “cleaner” and more organized process than necrosis. Necrosis is destructive to surrounding tissue, so it’s important for doctors to choose the intensity and duration of heat treatment carefully.

In their review article, “Gold Nanoparticles in Cancer Theranostics,” authors note that malignant cancer cells tend to have diminished heat shock protection responsiveness, making them more susceptible to thermal stress.

Thermal stress makes tumors more vulnerable to radiation therapy, making this therapy more effective. This sensitization occurs through several cellular pathways according to research published in the journal Cancers. Similarly, thermal stress makes tumors more susceptible to chemotherapeutics.

For instance, one in vitro study in the journal Scientific Reports found that when malignant melanoma was treated with hyperthermia and clinically relevant chemotherapy drugs, hyperthermia made more than one chemotherapy drug more effective. This is great news for treating tumor cells.

The question is, how do we directly target tumor cells with hyperthermia so as not to damage healthy tissue?

Some current methods are invasive, particularly if the tumor is deep. For many methods, the heating distribution often isn’t uniform. In addition, these methods tend to be directed at the tumor based on what can be seen with scans and the human eye, but they aren’t precise on a cellular level.

Nanoparticles

The trick to truly effective hyperthermia is to get the heat inside the tumor without heating all the tissue around it, and nanoparticles are key to that capability. Using nanoparticles and near-infrared light to generate heat in a tumor is minimally invasive, more uniform, and much more precise in targeting the tumor on a cellular level.

Nanoparticles are tiny, though they do vary in size from 1 to 100 nanometers (nm), though some scientists would argue nanoparticles can be up to 1000 nm in size.

If one of your hairs were blown up to be the size of a telephone pole, a nanoparticle would be a little dot with a diameter about as wide as the thickness of a piece of paper.

They are too small to be seen without an electron microscope, but they can exert a powerful effect depending on how they are used.

How Would Nanoparticles Get Into Tumor?

The blood vessels in tumors are different from the blood vessels in a typical organ. The tumor is not healthy, normal tissue, so the blood vessels that feed it aren’t normal or healthy either.

Healthy blood vessels that bring oxygenated blood into tissues have small gaps between the endothelial cells which line the blood vessels. Imagine a tiny straw with little slits in it. These endothelial cells are surrounded by smooth muscle cells. Imagine another straw, which is much stronger and slightly larger, with the smaller straw inside.

In tumors, the inner straw has much larger holes and no strong outer straw surrounding it. The result is that tumors are fed by very leaky blood vessels.

Your body relies partly on the lymphatic system to clear out the waste of dead cells and other body processes. Imagine a system very much like all your blood vessels but with a different role.

In a tumor, lymphatic vessels are compressed, causing poor lymphatic drainage out of the tumor.

The leaky blood vessels and poor lymphatic drainage cause an effect that allows the nanoparticles to move from the bloodstream into the tumor and accumulate there, according to a review article published in the journal Cancer in 2020.

Gold Nanoparticles Ideal for Photothermal Therapy

Gold nanoparticles are an ideal candidate for photothermal therapy, which typically uses infrared light to heat tissues. This form of light can penetrate deep into the body. That’s good, but even better if the heat is more intense in the area of the tumor. In that scenario, you don’t have to risk damaging other tissues as much.

That’s where gold becomes essential. Gold is fairly biocompatible as it is an inert metal. Gold nanoparticles can absorb light energy and heat up to above 113 degrees Fahrenheit.

Near-infrared (NIR) light in the range of 800 to 1200 nanometers can be directed into the body, where it hits the nanoparticles, which then heat up. Think of it like a microwave that heats your cold coffee but not your mug. Depending on size and shape, gold nanoparticles can absorb different frequencies of light and can be designed for maximum absorption of NIR light.

The size of the gold nanoparticles matter. In general, smaller metallic nanoparticles more efficiently convert light energy to heat energy than larger metallic nanoparticles do.

According to research published in the journal Application of Nanomaterials in Biomedical Imaging and Cancer Therapy in 2021, there are typically two methods for inducing hyperthermia in a tumor.

First, the gold nanoparticles can be heated to high temperatures (higher than 113 degrees Fahrenheit) for several minutes. This leads to cell death through thermal ablation. The downside is that this can trigger the blood to stop flowing through the tumor and the tumor may hemorrhage. This would inhibit further treatment with a secondary therapy.

A second method creates mild hyperthermia (107.6 to 109.4 degrees Fahrenheit) within the tumor. This triggers cellular damage and makes the tumor blood vessels more leaky. This method allows for a synergistic therapy such as chemotherapy to be used simultaneously.

Pair Photothermal Therapy With Another Therapy

Because the blood vessels that feed the tumor aren’t healthy, there may be areas of a tumor that don’t have good blood supply—this is why certain regions of a tumor may be hypoxic.

The nanoparticles may not accumulate in these regions since the blood supply is deficient, which means photothermal therapy alone may not destroy all the cancer cells in the tumor.

Importantly, research shows that surviving tumor cells exposed to heat can quickly become resistant to thermal stress, resulting in recurrence and spread of the cancer (metastasis), according to findings in the review “Multifunctional Gold Nanoparticles in Cancer Diagnosis and Treatment.”

The above two points reveal why it’s important that in cases where photothermal therapy can’t fully destroy the tumor, this therapy is paired with a secondary therapy such as chemotherapy, radiotherapy, or immunotherapy.

Conclusions

The National Cancer Institute notes that hyperthermia has been used to treat the following types of advanced cancers: appendix cancer, bladder cancer, brain cancer, breast cancer, cervical cancer, esophageal cancer, head and neck cancer, liver cancer, lung cancer, melanoma, mesothelioma, sarcoma, and rectal cancer.

As a type of hyperthermia, photothermal therapy used in combination with other cancer therapies has great potential in treating primary tumors or metastatic cancer for several different types of cancer.

A number of gold nanoparticle-based platforms have been assessed in clinical trials. While the results so far are mostly encouraging, the review “Multifunctional Gold Nanoparticles in Cancer Diagnosis and Treatment” notes many of these studies are still in early phase one or phase one clinical trials.

As researchers and clinicians perfect treatment with photothermal therapy, the hope is that one day it will become an available option for cancer patients everywhere.

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