Cancer therapy has recently relied on the use of several drugs derived from biological sources, including various bacteria and viruses, among others. However, these biologically based drugs are easily degraded and therefore inactivated when administered to the body. Therefore, efficient delivery and release of these drugs to the target sites of the tumor are of the utmost importance from the point of view of cancer therapy.
Recently, scientists have discovered unique three-dimensional polymers that contain water, called hydrogels, as efficient drug delivery systems (DDS). Drugs loaded into these hydrogels remain relatively stable thanks to the network structure and consistency of the organic tissues of these DDSs. In addition, drug release from the hydrogel can be controlled by designing it to swell and decrease in response to certain stimuli or minor changes in conditions, such as temperature or pH (which determine the acidity of the environment). For example, when conditions are only at the appropriate level of acidity in the tumor microenvironment, these DDSs either shrink or swell and release the drug.
However, there was no method for the synthesis of hydrogels in a single pot that respond to multiple such stimuli and degrade to release drugs at target tumor sites. So far.
Now a team of scientists, led by Professor Akihiko Kikuchi of Tokyo University of Science, is reporting on the production of unique degradable hydrogels that respond to changes under multiple conditions in “shrinking” environments that mimic the microenvironment of tumors. As noted by prof. Kikuchi, “In order to prepare degradable drug-releasing hydrogels in response to changes in the tumor microenvironment, we prepared hydrogels that respond to temperature, pH, and reducing environment and analyzed their properties.”
In their study published in Journal of Controlled Release, Professor Kikuchi – together with his colleagues from the University of Tokyo, Dr. Syuuhei Komatsu, Ms. Moeno Tago and Ms. Yu Ando, and his research associate, prof. Taka-Aki Asoh from the University of Osaka – describes in detail the steps of designing these new hydrogels from a synthetic polymer of poly (ethylene glycol) diglycidyl ether and an organic cystamine compound that contains sulfur. In response to low temperatures, these hydrogels swell as they shrink at physiological temperatures. In addition, hydrogels respond to changes in pH due to the presence of tertiary amino groups. It should be noted here that the pH of the tumor microenvironment varies between 5.5 and 6.5 due to glycolysis in tumor cells. Under the reducing conditions of this environment, the hydrogels decompose due to the disruption of disulfide bonds and turn into oligomers soluble in water of low molecular weight that are easily excreted from the body.
To further test their drug release properties, the scientists filled these hydrogels with specific proteins by exploiting their temperature-dependent behavior, swelling, and tested the controlled release of drugs under acidic or reducing conditions. It has been found that the amount of drug loaded on these hydrogels can be controlled by changing the mesh size of the hydrogel polymer network by changing the temperature, indicating the possibility of adjusting these DDSs for a specific drug delivery. In addition, the structure of the hydrogel network and the electrostatic interactions in the network ensured that the proteins were kept intact until delivery, without the influence of swelling and shrinkage of the hydrogels with a change in pH in the surrounding environment. The scientists found that the loaded protein drugs were completely released only under reduced conditions.
Using these hydrogels and the possibility of their conductivity, doctors will soon be able to design “custom” hydrogels that are specific to patients, giving personalized medicine a big boost. In addition, this new DDS provides a way to kill cancer cells left after surgery. According to prof. Kikuchi, “Implantation of this material into the affected area after cancer resection can eliminate residual cancer cells, making it a more powerful therapeutic tool.”
As cancer around the world tightens its grip, treatment options need to be changed and upgraded to adapt and treat effectively. This unique and simple design technique for producing multi-stimulus-responsive hydrogels to efficiently deliver drugs to tumor target sites may be just one of several such promising techniques to address the challenge that cancer poses to humanity.
Reference: Komatsu S, Tago M, Ando Y, Asoh TA, Kikuchi A. Easy preparation of multigrade hydrogels that respond to stimuli for protein loading and release. J. Control. Let go. 2021; 331: 1-6. doi: 10.1016 / j.jconrel.2021.01.011
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