'Click' chemistry produces hydrogel with less toxicity and greater tissue localization in mouse cancer model

June 4, 2014
‘Click’ chemistry produces a hydrogel with less toxicity and greater tissue localization in a mouse cancer model
The oxaliplatin-peptide conjugate, formed using click chemistry, self-assembles into a hydrogel (bottom left) that can be injected for localized drug delivery. Credit: Royal Society of Chemistry

Platinum-based chemotherapy drugs are commonly used to treat a wide variety of solid tumors, including cancers affecting the breast, colon and lung. However, only a small amount of these anticancer drugs typically reaches the target organ system. This inefficiency not only reduces the efficacy of the drug; it also leads to severe side effects, ranging from nausea to kidney toxicity or deafness.

Charlotte Hauser and her co-workers at the A*STAR Institute of Bioengineering and Nanotechnology in Singapore have now developed a platform for the localized and sustained release of platinum-based anticancer therapeutics that overcomes many of these limitations. The research team's novel gel formulation—a combination of specialized peptides and the oxaliplatin—led to dramatic growth inhibition when injected directly into the of mice. In addition, the gel treatment produced a better tolerance profile than standard oxaliplatin drug therapy.

"Compared to the free drug, our injectable drug-loaded conjugate is just as effective in inhibiting tumor growth, but with lower systemic toxicity and higher localization in the target tissue," says Charlotte Hauser.

Hauser's team started with a unique class of ultrashort peptides that have the ability to spontaneously self-assemble and form hydrogels. The researchers attached oxaliplatin to the peptides using a technique known as 'click' chemistry, which enables the synthesis of complex molecules through the joining of multiple attached parts (see image). The resulting oxaliplatin-peptide hydrogels proved highly lethal against two human cell lines derived from cervical cancer and tissues, respectively. Laboratory analyses showed that the hydrogels bound to the DNA of the cancer cells, arresting their replication cycle—just as free oxaliplatin does. Furthermore, the whole construct was biocompatible and generally non-immunogenic.

The researchers compared their hydrogel head-to-head with unmodified oxaliplatin in a mouse model by injecting the drugs locally into the mouse tumors. Where the drug was delivered as a hydrogel, they documented higher rates of drug accumulation in the tumor—but lower levels of drug toxicity in the kidneys and livers—compared to the free control. As a result, the mice given the hydrogel maintained more body weight, which can be used as a surrogate measure of their overall health.

"This combination product could serve as a tissue replacement device for the controlled release of important drugs that require localized and injectable treatments," says Hauser. "We are exploring if this general approach can be utilized to attach a variety of other bioactive molecules."

Explore further: Scientist proves potential of new nanoparticle design for cancer therapy

More information: Reithofer, M. R., Chan, K.-H., Lakshmanan, A., Lam, D. H., Mishra, A. et al. "Ligation of anti-cancer drugs to self-assembling ultrashort peptides by click chemistry for localized therapy." Chemical Science 5, 625–630 (2014). dx.doi.org/10.1039/c3sc51930a

Related Stories

Recommended for you

New polymer creates safer fuels

October 1, 2015

Before embarking on a transcontinental journey, jet airplanes fill up with tens of thousands of gallons of fuel. In the event of a crash, such large quantities of fuel increase the severity of an explosion upon impact. Researchers ...

Researchers print inside gels to create unique shapes

September 30, 2015

(Phys.org)—A team of researchers at the University of Florida has taken the technique of printing objects inside of a gel a step further by using a highly shear-rate sensitive gel. In their paper published in the journal ...

How a molecular motor untangles protein

October 1, 2015

A marvelous molecular motor that untangles protein in bacteria may sound interesting, yet perhaps not so important. Until you consider the hallmarks of several neurodegenerative diseases—Huntington's disease has tangled ...

Anti-aging treatment for smart windows

October 1, 2015

Electrochromic windows, so-called 'smart windows', share a well-known problem with rechargeable batteries – their limited lifespan. Researchers at Uppsala University have now worked out an entirely new way to rejuvenate ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.