A team of researchers at Université de Montréal (UdeM) has designed and validated a new class of drug transporters made of DNA. About 20,000 times smaller than a human hair, the molecular transporters, known as self-regulated nucleic acid molecular buffers, can be chemically programmed to deliver an optimal concentration of drugs, making them more efficient than current methods. The team suggests that their use could improve how cancers and other diseases are treated.
For a study described in Nature Communications, the researchers, led by UdeM chemistry associate professor Alexis Vallée-Bélisle, PhD, designed a drug transporter specifically to deliver the chemotherapeutic doxorubicin. Their results demonstrated that in mice treated using the new formulation to deliver the drug, doxorubicin was maintained for much longer in the blood, there was less diffusion to major organs, as well as reduced cardiotoxicity. The treated animals also remained healthier. Reporting on their technology in a paper titled, “Programmable self-regulated molecular buffers for precise sustained drug delivery,” the investigators concluded, “These programmable buffers can be built from any polymer and should improve patient therapeutic outcome by enhancing drug activity and minimizing adverse effects and dosage frequency.”
One of the key ways to successfully treat disease is to provide and maintain a therapeutic drug dosage throughout treatment, the authors explained. Suboptimal therapeutic exposure reduces efficiency and typically leads to drug resistance, while overexposure increases side effects. However, the team continued, “Maintaining an optimal therapeutic concentration at the target site, however, remains a major challenge in modern medicine for several reasons.”
Since most drugs undergo rapid degradation, patients are forced (and often forget) to take multiple doses at regular intervals. “This repeated dosage regimen typically leads to poor compliance and is responsible for 33–69% of medication-related hospital admissions in the USA.” And because each patient has a distinct pharmacokinetic profile, the drug’s concentration in their blood varies significantly.
Observing that only about 50% of cancer patients get an optimal drug dosage during certain chemotherapy, Vallée-Bélisle, an expert in bio-inspired nanotechnologies, started to explore how biological systems control and maintain the concentration of biomolecules. “Nature has evolved various mechanisms to achieve optimal self-regulated dosing of molecules regardless of an individual-specific pharmacokinetic profile,” the scientists continued. “Protein transporters, for example, act as molecular buffer agents to maintain a precise concentration of free active molecules using a mechanism analogous to pH buffers.”
Vallée-Bélisle further noted, “We have found that living organisms employ protein transporters that are programmed to maintain 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.”
This simple idea led Valléé-Belisle—who holds a Canada research chair in bioengineering and bionanotechnology—and his research team to start developing artificial drug transporters that mimic the natural effect of maintaining a precise concentration of a drug during treatment. UdeM PhD student Arnaud Desrosiers, the first author of the study, initially identified and developed two DNA transporters: one for the antimalarial quinine, and the other for doxorubicin, a commonly used drug for treating breast cancer and leukemia.
He then demonstrated that these artificial transporters could be readily programmed to deliver and maintain any specific concentration of drug. “More interestingly, we also found that these nanotransporters could also be employed as a drug reservoir to prolong the effect of the drug and minimize its dosage during treatment,” said Desrosiers. “Another impressive feature of these nanotransporters is that they can be directed to specific parts of the body where the drug is most needed—and that, in principle, should reduce most side effects.”
Further investigating the effectiveness of these nanotransporters, the researchers and their colleagues demonstrated in mice that a specific drug-transporter formulation allows doxorubicin to be maintained in the blood and drastically reduces its diffusion toward key organs such as the heart, lungs, and pancreas. In animals treated using this formulation, doxorubicin was maintained 18 times longer in the blood, and cardiotoxicity was reduced, keeping the mice more healthy as evidenced by their normal weight gain.
The combined results, the team noted, “… demonstrate that the precise/sustained pharmacokinetics of doxorubicin produced by our self-regulated buffers reduce some physiological effects of doxorubicin like weight loss and cardiomyocytes vacuolation, while enhancing some others like heart rate … With this in vivo proof of concept showcasing its potential, we believe that molecular buffers could improve the delivery of drugs that display a small therapeutic window and/or for which selection of an optimal therapeutic dosage remains a challenge.”
Further commenting on the new technology, Vallée-Bélisl said, “Another great property of our nanotransporters is their high versatility. For now, we have demonstrated the working principle of these nanotransporters for two different drugs. But thanks to the high programmability of DNA and protein chemistries, one can now design these transporters to precisely deliver a wide range of therapeutic molecules … additionally, these transporters could also be combined with human-designed liposomic transporters that are now being employed to deliver drugs at various rates.”
In conclusion, the team noted, “We have demonstrated how we can engineer bio-inspired self-regulated molecular buffers that are programmed to release and maintain a precise drug concentration in vivo … We showed that these buffers can be readily programmed to maintain a targeted drug concentration, that they can be employed as a drug reservoir to prolong the circulation time of a drug and that their stability can be tuned to match the desired pharmacokinetics profile.”
The researchers are keen to validate the clinical efficiency of the new system. Given that the doxorubicin nanotransporter is programmed to optimally maintain the drug in blood circulation, it could be ideal to treat blood cancers, they believe. “We envision that similar nanotransporters may also be developed to deliver drugs to other specific locations in the body and maximize the presence of the drug at tumor sites,” said Vallée-Bélisle. “This would drastically improve the efficiency of drugs as well as decrease their side effects.” The authors further stated, “As we enter the era of smart DDS [drug delivery systems], we envisage that molecular buffers will provide another generation of smart therapeutic tools that take into account the individual pharmacokinetic profiles of patients and help prevent medical overdosing and medication errors.”