Hydrogels are widely used as drug delivery systems, but to be effective carriers for cancer drugs, they must respond to various stimuli in the tumor microenvironment. Now, scientists from Japan have developed novel hydrogels to effectively deliver drugs to tumor sites in response to temperature and pH changes in the tumor microenvironment. These multi-stimulus-responsive hydrogels can eliminate residual cancer cells after tumor removal through controlled drug release and offer hope for effective cancer treatment.
Recent cancer therapy has relied on the use of several drugs derived from biological sources, including various bacteria and viruses, among others. However, these bio-based drugs are easily broken down and therefore inactivated when administered into the body. Therefore, effective delivery to and release of these drugs to target tumor sites is of paramount importance from a cancer therapy perspective.
Recently, scientists have discovered unique three-dimensional, hydrous polymers called hydrogels as effective drug delivery systems (DDS). Drugs loaded into these hydrogels remain relatively stable due to the network-like structure and the organic tissue-like consistency of these DDS. In addition, drug release from hydrogels can be controlled by designing them to swell and shrink in response to specific stimuli or tiny changes in conditions such as temperature or pH (which determine the acidity of an environment). For example, if the conditions in the tumor microenvironment are just the right amount of acidity, these DDSs will shrink or swell and release the drug.
However, there is no method for the one-pot synthesis of hydrogels that respond to more than one such stimulus and degrade to deliver drugs to target tumor sites. Until now.
A team of scientists led by Professor Akihiko Kikuchi of Tokyo University of Science is now reporting on the production of unique degradable hydrogels that respond to changes under various conditions in “reducing” environments that mimic the microenvironment of tumors. As Prof. Kikuchi notes, "To create degradable hydrogels that can release drugs in response to changes in the tumor microenvironment, we created hydrogels that respond to temperature, pH and reducing environment and analyzed their properties."
In their study published in the Journal of Controlled Release, Prof. Kikuchi (together with his colleagues from Tokyo University of Science, Dr. Syuuhei Komatsu, Ms. Moeno Tago and Ms. Yu Ando and his collaborator on the study, Prof. Taka-Aki Asoh from Osaka University) explains the steps to design these new hydrogels made from the synthetic polymer poly (ethylene glycol) diglycidyl ether and the sulfur-containing organic compound cystamine. In response to low temperatures, these hydrogels swell, while at the physiological temperature they shrink. In addition, the hydrogels respond to changes in pH by having tertiary amino groups. It should be noted that the pH of the tumor microenvironment fluctuates between 5.5 and 6.5 due to glycolysis in the tumor cells. Under the reducing conditions of this environment, the hydrogels degrade due to the breaking of disulfide bonds and convert into water-soluble, low molecular weight oligomers that can be easily excreted from the body.
To further test their drug release properties, the scientists loaded these hydrogels with specific proteins by taking advantage of their temperature-dependent swelling / deswelling behavior, and tested the controlled release of drugs under acidic or reducing conditions. It was found that the amount of drug loaded on these hydrogels could be controlled by changing the mesh size of the hydrogel polymer network by changing the temperature, suggesting the possibility of tailoring these DDSs for specific drug delivery. In addition, the hydrogel network structure and the electrostatic interactions in the network ensured that the proteins remained intact until release without being affected by the swelling and shrinkage of the hydrogels with pH changes in the environment. The scientists found that the loaded protein drugs were only fully released under reducing conditions.
With these hydrogels and the tractability they offer, clinicians may soon be able to develop "bespoke" hydrogels that are patient-specific, giving a huge boost to personalized medicine. In addition, this new DDS offers a way to kill cancer cells that are left behind after surgery. As Prof. Kikuchi notes, "Implanting this material in the affected area after cancer resection can eliminate remaining cancer cells and make it a more powerful therapeutic tool."
As cancer tightens its vice grip around the world, treatment options need to be varied and improved for tailored and effective therapy. This unique and facile design technique for creating multi-stimulus responsive hydrogels for effective drug delivery to target tumor sites may be just one of several promising techniques to address the challenge cancer poses to humanity.
Source: Tokyo University of Science