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Wednesday, September 22, 2021

Smart therapy

Much of disease treatment relies on a simple principle: find out what agents in the body are causing a problem and eliminate them. People can employ very broad-sweeping measures to eliminate these problems. A good example of this is the use of antibiotics. For diseases like salmonella and tetanus, the use of the proper antibiotics can quickly and efficiently solve the problem.

However, many diseases are much more problematic and can’t be dealt with in broad strokes. The treatments for these diseases are much more complex and require pinpoint accuracy in targeting afflicted areas. One such disease is cancer.

Cancer, the unregulated growth of the body’s cells, is difficult to treat. The difficulty stems from the fact that the diseased cells are entirely native to the body; the treatments are targeting one’s own cells. The body’s immune system is great at detecting and eliminating foreign substances, but when the troubles are more domestic, it has trouble telling healthy cells from cancerous ones. As a result, the treatment options that kill the cancerous cells have the unfortunate side effect of killing the healthy cells as well. When chemotherapeutic treatments are administered in too high of a concentration, these potentially helpful drugs could end up being lethal.

In a recent publication, professor of hematology and oncology at the UC Davis School of Medicine Chong-Xian Pan developed a way to dramatically improve the efficacy and safety of some cancer treatments.

The improvement comes from changes to the delivery of the chemotherapeutic treatments through usage of nanoparticles called micelles. Micelles are aggregates of soap-like molecules that naturally form droplets when placed into an aqueous environment. The hydrophobic (water-avoiding) side of the micelle is repelled by water and forms the center of the drop. The hydrophobic side is used to form a protective coating around the chemotherapeutic agents meant to be delivered to a specific part of the body.
The way micelles are directed to specific parts of the body is through ligands, signal-triggering molecules that bind to sites on corresponding proteins. These ligands can be artificially constructed to bind to any conceivable protein with complementary sequences of amino acids. Proteins are made up of sequences of amino acids, otherwise known as peptides.

The peptide PLZ4 has been shown to preferentially bind to a structure on the surface of bladder cancer cells. The binding triggers the absorption of the micelle into the target cell. The binding process facilitates the emptying of the contents of the micelle directly into the cancer cell, allowing for much more efficient delivery of chemotherapeutic drugs.

“The micelles … are stable during blood circulation and release the [medication] quickly when triggered by the microenvironment of a tumor,” said Yaunpei Li, a collaborator in the investigation. “Our micelle could prevent premature drug release [into the body].”

According to Kit Lam, professor and chair of the UC Davis Department of Biochemistry and Molecular Medicine and a co-author of the article, the problem with freely administered cancer drugs in the bloodstream comes from developed resistance.

“The free drugs enter the cell through pumps, and then … kill the cell, eventually,” Lam said. “With resistance, the membrane pumps get blocked and the drug has no way of getting in to act.”
In the case of Dr. Pan’s work, the drug delivered is paclitaxel, a chemotherapeutic agent used in the treatment of breast, lung and bladder cancers. Unfortunately, paclitaxel has many adverse side effects when administered to the entire body, such as nausea, hair-loss and toxicity to bone marrow.
With the use of targeted micelles, the paclitaxel can be delivered directly to the cancerous regions of patients in higher concentrations and with fewer negative side-effects caused by nonspecific administration.
The implementation of the treatment has shown promising results in research trials with animal subjects. Micelles with the targeted PLZ4 ligand were augmented with green fluorescent protein and showed that the nanoparticles preferentially bound to cancer cells in the bladder.
Additionally in the experiment, the micelles were outfitted with different doses of paclitaxel to measure the efficacy of the treatments. For the control group, subjects were given micelles containing no paclitaxel and merely a saline solution. The first experimental group was administered targeted micelles containing the standard dosage of paclitaxel. Finally, the second experimental group was given micelles containing triple the normal dosage of paclitaxel. Subjects given the standard dosage showed significantly higher survival figures and lower tumor growths than the control group.

Subjects given the high dosage took the longest time for tumors to develop and showed the longest period of tumor control. Moreover, the high-dosage treatment subjects experienced significantly longer life spans than subjects given the same dosage of paclitaxel with the absence of targeted micelles.

The high-dosage treatment with the new delivery method promoted a far greater life expectancy with fewer negative side effects.

“The prognosis for advanced bladder cancer has not changed for three decades. Our findings have the potential to significantly improve outcomes,” Pan said,

ALAN LIN can be reached at science@theaggie.org.

1 COMMENT

  1. […] Smart therapy Much of disease treatment relies on a simple principle: find out what agents in the body are causing a problem and eliminate them. People can employ very broad-sweeping measures to eliminate these problems. A good example of this is the use of … Read more on The Aggie […]

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