A research team led by scientists at The University of Texas Health Science Center at San Antonio (UT Health San Antonio) has made a groundbreaking discovery that could fundamentally transform how medications are delivered to patients. Their innovative approach, called "chemical endocytic medicinal chemistry," has the potential to convert intravenous drugs into oral treatments for challenging conditions including brain cancer and Alzheimer's disease.
The findings, published April 17 in the journal Cell, represent a significant advancement in pharmaceutical science that could reshape drug development, delivery, and administration protocols across the industry.
Leveraging the Body's Natural Transport System
The research team, led by Hong-yu Li, PhD, professor of medicinal chemistry and chemical biology at UT Health San Antonio, identified that CD36—a protein receptor found on the surface of many cells—can be chemically optimized to help large and water-soluble "polar" drugs enter cells more efficiently.
"This innovative chemical approach can potentially make any intravenous drug able to be taken orally," said Robert A. Hromas, MD, FACP, dean of the Joe R. and Teresa Lozano Long School of Medicine at UT Health San Antonio. "It also can promote any drug crossing the blood-brain barrier. This will remarkably broaden the number of agents we have to treat brain cancer or dementia."
The study, titled "C36-mediated endocytosis of proteolysis-targeting chimeras," was conducted in collaboration with researchers from Duke University and the University of Arkansas for Medical Sciences.
Breaking the 500 Dalton Rule
For decades, pharmaceutical development has been constrained by the belief that molecules larger than 500 Daltons (Da) were practically unusable as drugs due to challenges with cell access and bioavailability. This limitation has particularly restricted the development of induced proximity drugs, where molecules bring proteins together to create desired interactions.
Li's team has effectively bypassed this limitation by chemically enhancing CD36-mediated uptake, amplifying the efficiency with which larger and polar molecules can enter target cells. In their study, they validated the CD36-mediated endocytic uptake of chemical compounds ranging from 543 to 2,145 Da—far exceeding the traditional size limitations.
"This was completely unexpected in the research field," Li explained. "For decades, it was thought that molecules this large couldn't cross membranes effectively, since the endocytic cellular uptake of chemicals was unknown. Through chemistry and biology, we identified CD36 as a protein for uptake and optimized chemicals better engaging with CD36 to internalize these drugs to more efficiently reach target proteins."
The team was particularly surprised by the speed, effective uptake, and potency of the compounds when using their chemical endocytic medicinal chemistry strategy through CD36 interaction. Given the provocative nature of their findings, the researchers verified key results multiple times, with experimental outcomes independently reproduced by each team involved in the study.
Paradigm Shift in Drug Development
Traditional drug development involves an extensive, expensive process focused on optimizing chemical compounds for passive diffusion into cells by balancing contradictory characteristics of permeability, solubility, and stability. The new endocytic approach represents a paradigm shift by utilizing membrane receptor-mediated cellular entry instead.
"This breakthrough discovery will force us to rethink how we approach efficacy and pharmacokinetics and toxicity," Li said. "We believe it will also eventually change how regulatory agencies like the FDA evaluate and approve new endocytic drugs."
The implications extend beyond just creating new drugs. This approach could potentially resurrect drugs previously thought unusable due to poor absorption and transform them into viable treatments.
Personalized Medicine Applications
The research has also revealed important implications for personalized medicine. By analyzing tissue from prostate cancer patients, the team found CD36 expression levels varied widely among individuals, which may explain why different patients respond differently to certain cancer medications.
"By optimizing CD36 engagement through chemical endocytic medicinal chemistry, we may be able to target cancer and other diseases precisely through precision treatment based on the differential expression of CD36 in various tissues and different individuals," Li noted.
Future Directions and Potential
The discovery opens numerous avenues for future research and development. Li's laboratory continues to explore additional cell receptors that could be targeted for chemical endocytosis. The high levels of CD36 receptors in intestinal, brain, and skin cells suggest promising applications for improved drug delivery with higher oral bioavailability, better blood-brain barrier penetration, or transdermal administration.
"In the next 10 to 20 years, this may become a foundational approach in drug discovery and a new research field within medicinal chemistry," Li predicted. "We feel incredibly lucky to have made this discovery and opened the door to hope for previously untreatable diseases."
For San Antonio, this discovery reinforces the city's emerging status as a leader in biomedical innovation, particularly through the work of UT Health San Antonio's Barshop Institute, Mays Cancer Center, and Center for Innovative Drug Discovery.
The breakthrough represents not just a technical achievement but potentially a transformative moment in pharmaceutical science that could dramatically expand treatment options for patients with complex conditions while reducing the burden of intravenous administration.
