It was reported in a new study in Nature communicationsthese molecular carriers can be chemically programmed to provide optimal drug concentration, making them more effective than current methods.

Optimal dosing at all times: a medical challenge

Alexis Vallee-Belisle Credit: Amélie Philibert | University of Montreal One of the key ways to successfully manage the disease is to provide and maintain a therapeutic dose of medication throughout the course of treatment. Suboptimal therapeutic exposure reduces efficacy and usually leads to drug resistance, while overexposure increases side effects. Maintaining the optimal concentration of drugs in the blood remains a major challenge in modern medicine. Since most drugs undergo rapid degradation, patients are forced (and often forget) to take multiple doses at regular intervals. And because each patient has an individual pharmacokinetic profile, the concentration of drugs in their blood varies significantly. Noticing that only around 50 percent of cancer patients receive the optimal drug dose during certain chemotherapy treatments, UdeM Associate Professor of Chemistry Alexis Vallée-Bélisle, an expert in bio-inspired nanotechnologies, began investigating how biological systems control and maintain the concentration of biomolecules. “We found that living organisms use protein transporters that are programmed to maintain a precise concentration of key molecules such as thyroid hormones, and that the strength of the interaction between these transporters and their molecules dictates the precise concentration of the free molecule,” he said. . This simple idea led Valléé-Belisle—who holds a Canada Research Chair in bioengineering and biotechnology—and his research team to begin developing artificial drug transporters that mimic the natural effect of maintaining a precise concentration of a drug during Treatment. UdeM PhD student Arnaud Desrosiers, first author of the study, first identified and developed two DNA transporters: one for quinine, an antimalarial, and the other for doxorubicin, a widely used drug for the treatment of breast cancer and of leukemia. He then showed that these artificial transporters could easily be programmed to deliver and maintain any specific drug concentration. “Most interestingly, we also discovered that these nanocarriers could also be used as a drug reservoir to prolong the drug’s action and minimize its dosage during treatment,” said Desrosiers. “Another impressive feature of these nanocarriers,” he added, “is that they can be directed to specific parts of the body where the drug is most needed—and this, in principle, should reduce most side effects.”

Nano-treated mice: reduced cardiotoxicity

To demonstrate the effectiveness of these nanocarriers, the researchers collaborated with Jeanne Leblond-Chain, a pharmacist at the University of Bordeaux in France. Luc DesGroseillers, biochemist at UdeM. Jérémie Berdugo, pathologist at UdeM. Céline Fiset, a pharmacist at the Montreal Heart Institute. and Vincent De Guire, clinical biochemist at the UdeM-affiliated Maisonneuve-Rosemont hospital. Using the new drug carrier developed for doxorubicin, the team showed that a specific drug carrier composition allows doxorubicin to be retained in the blood and drastically reduces its diffusion to key organs such as the heart, lungs and pancreas. In mice treated with this formulation, doxorubicin was retained 18 times longer in the blood and cardiotoxicity was also reduced, keeping the mice healthier as evidenced by their normal weight gain. “Another great property of our nanocarriers is their high flexibility,” said Vallée-Bélisle. “For now, we have proven the principle of operation of these nanocarriers for two different drugs. But thanks to the high programmability of DNA and protein chemistry, one can now design these transporters to precisely deliver a wide range of threat molecules.” And, he added, “in addition, these carriers could also be combined with human-engineered liposomal carriers that are now used to deliver drugs at various rates.”

Clinical study on blood cancers?

The researchers are now eager to validate the clinical efficacy of their discovery. From Their doxorubicin nanocarrier is programmed to optimally keep the drug in the bloodstream, they believe could be used to treat blood cancer. “We envision that similar nanocarriers can also be developed to deliver drugs to other specific locations in the body and maximize drug presence at tumor sites,” said Vallée-Bélisle. “This would drastically improve the effectiveness of drugs as well as reduce their side effects.”

About this study

“Programmable Self-Regulating Molecular Buffers for Accurate Sustained Drug Delivery,” by Arnaud Desrosiers et al., published on November 2, 2022 in Nature communications. doi:10.1038/s41467-022-33491-7 Alexis Vallée-Bélisle is associate professor of chemistry at UdeM and holds a Canada Research Chair in bioengineering and bionanotechnology. His laboratory develops bio-inspired nanotechnologies for health applications. Funding was provided by the National Science and Engineering Research Council of Canada, the Canada Research Chairs, Les Fonds de recherche du Québec – Nature et technology, and the Quebec Research Group on Protein Function, Engineering and Applications (PROTEO ).