Health Brazil , Brasil, Wednesday, March 07 of 2018, 11:44

Structure of an antitumor agent analyzed with synchrotron light

A study conducted in the US with a Brazilian first author aims to improve the formulation of drugs against metastatic breast cancer and reduce doses

FAPESP AGENCY/DICYT Highly complex drugs such as antitumor agents can have adverse side-effects and must often be used in high doses. To improve both such therapies and the resulting patient quality of life, it is necessary to undertake equally complex analyses not only of the molecules that constitute such drugs but also of the relations between their structure and physicochemical properties.


A group of researchers have succeeded for the first time in describing the structure and atomic interactions of the cancer drug lapatinib, especially its interactions with polymers that can be used to optimize the drug.


The study, published in Scientific Reports, used high-energy X-rays generated by synchrotron light sources at Argonne National Laboratory near Chicago in the United States. It was conducted at Purdue University, Indiana, and supported by FAPESP via a Research Scholarship Abroad.


“The study focused on seeking structural information regarding the interaction between polymers used to improve solubility and stability and the antitumor agent lapatinib. We obtained interesting results that will help accelerate the development of formulations, choose the most suitable polymer, and potentially, in the future, also reduce the dose required,” said Gabriel Lima Barros de Araujo, the first author of the article. Araujo is a professor in the Pharmacy Department of the University of São Paulo’s School of Pharmaceutical Sciences (FCF-USP).


Lapatinib is an oral antitumor agent used to treat metastatic or advanced breast cancer. It belongs to a group of drugs known as small-molecule tyrosine kinase inhibitors, which act by inhibiting the cell proliferation signaling cascade.


“This is one of the most specific oral therapies around. However, clinical response varies considerably. Patients typically need to take the drug in high doses, comprising some six tablets per day,” Araujo said. “Moreover, diet is known to interfere with its absorption in many cases, producing adverse side-effects. One of the options is to improve the formulation.”


In the study, in addition to analyzing intermolecular interactions by means of high-energy X-rays – which showed that lapatinib molecules do not cluster in the manner observed in previous research that used other techniques – the researchers also used a novel analytical method.


“We used a data treatment methodology called a ‘pair distribution function’, which measures the distance between pairs of atoms,” Araujo said. “This furnished a great deal of information on the antitumor agent’s intermolecular interactions with polymers.”


Amorphous systems


Understanding how interactions occur is essential to improving formulations. However, in this study, the analysis of lapatinib was made more complex by the use of an amorphous solid dispersion, which is unstable but nonetheless improves solubility and hence absorption when the drug is administered orally. An amorphous solid dispersion is formed by dissolving crystals of the drug and dispersing its molecules in polymers.


“Ion bonds between the drug and the polymer are used to make it stable. However, these systems are extremely hard to study because they’re disorderly. They lack a well-defined structure,” Araujo said.


The growing amount of research on amorphous and nanocrystalline systems aims to surmount the problem of low solubility and enhance the effectiveness of complex drugs, including antitumor agents such as lapatinib, he added.


The search for methods of characterizing atom-to-atom interactions in amorphous systems comprising drugs and polymers has intensified. In amorphous systems, atoms are arranged mainly at short or medium distances of between 2-5 Angstrom and 5-20 Angstrom (1 Angstrom is one ten-billionth of a meter or 0.1 nanometer). This scale makes determining their atomic structure a challenging task that cannot be performed by classical crystallography.


The high-energy X-rays produced by synchrotron radiation permit the use of short wavelengths, a prerequisite for the enhancement of real-space resolution and data accuracy.


The group plan to analyze other active principles using the same approach. “In 2017, we began new work based on this study in collaboration with Chris Benmore at Argonne National Laboratory and Stephen Byrn, a professor at Purdue,” Araujo said. “We mean to proceed with this partnership and analyze other drugs in the future.”




The article “Local structure of ion pair interaction in lapatinib amorphous dispersions characterized by synchrotron X-ray diffraction and pair distribution function analysis” (doi: 10.1038/srep46367) by Gabriel L. B. de Araujo, Chris J. Benmore and Stephen R. Byrn can be read in Scientific Reports at