IV medication could be taken orally for range of cancer, Alzheimer's treatments

The discovery could reshape how medicines are designed, delivered and administered. Currently, complex and large-molecule drugs for hard-to-treat cancers and other diseases cannot be administered as a pill and easily absorbed into cells, and therefore must by delivered intravenously or through infusion.

But these researchers unveiled a new strategy called chemical endocytic medicinal chemistry that could change all of that, and even influence how the FDA evaluates future drugs, while helping customize treatments based on a patient's unique biology -- ushering in a new era of precision and personalized medicine.

"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 findings were published April 17 in the journal Cell, titled, "C36-mediated endocytosis of proteolysis-targeting chimeras." It was led by Hong-yu Li, PhD, professor of medicinal chemistry and chemical biology with the Department of Pharmacology and the Sam and Ann Barshop Institute for Longevity and Aging Studies at UT Health San Antonio, in collaboration with partners at Duke University and the University of Arkansas for Medical Sciences.

Their strategy uses the body's own protein receptors found on the surface of many cells called CD36 to help large and water-soluble "polar" drugs enter cells more efficiently. They demonstrated how chemically optimizing interactions with CD36 allows drugs previously thought too large to be absorbed by cells.

Li said that chemical endocytic medicinal chemistry -- with "endocytic" describing the process of cells taking in substances from their surroundings -- has the potential to impact every aspect of endocytic drugs from drug discovery and development to clinical practice. "The implications of this for drug discovery and development are enormous," he said.

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.

Overcoming barriers for drug development

Small-molecule drugs have been limited due to the belief that the primary mechanism of cell entry was passive diffusion, or not actively driven. One of the most promising developments in recent years in drug discovery is induced proximity, in which molecules bring proteins together to create a desired interaction and/or chemical reaction.

Until now, molecules larger than 500 Daltons (Da), referring to units of mass used to measure molecule weight, were believed to be practically unusable due to the challenges of cell access and bioavailability. This greatly restricted the kinds of compounds that could be developed as induced proximity drugs.

The new mechanistic discovery by Li's team bypasses this limitation by chemically enhancing CD36-mediated uptake, amplifying the efficiency of larger and polar molecules to enter target cells. CD36 was known to play a role in lipid transport and metabolism, but the team found it also had unexpected potential for promoting cellular uptake of large and polar chemical drugs.

It also could resurrect drugs previously thought unusable due to poor absorption and turn them into useful treatments.

Provocative but well-validated results

In the study, the team first discovered and validated the CD36-mediated endocytic uptake of large and polar chemical compounds with sizes between 543 and 2,145 Da and then tested the efficacy of optimized CD36 action on the cellular uptake of "proteolysis targeting chimeras" (PROTACs). Those refer to a class of large molecular compounds that includes an E3 ligase protein-binding domain, or a binding domain for a target protein, and a linker.

The team was astonished at the speed, effective uptake and potency of the compounds when using the chemical endocytic medicinal chemistry strategy through CD36 interaction.

"This was completely unexpected in the research field," Li said. "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 key experimental results were independently reproduced by each of the teams involved in the study.

"As the research conclusion is so provocative, we verified the key results multiple times," Li said. "The implications of this for drug discovery and development are enormous."

Implications for drug development

Traditional drug development is an extensive, expensive process focused on optimizing chemical compounds for passive diffusion into a cell by considering its contradictory characteristics of permeability, solubility and stability. This new process for endocytic drugs represents a paradigm shift that removes these challenges by using the membrane receptor-mediated cellular entry.

"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."

By analyzing tissue from prostate cancer patients, the team found CD36 expression levels varied widely. Li said this may explain why different patients respond differently to some 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," he said.

What comes next

Li said that, along with CD36, it is likely that there are additional cell receptors that could be targeted for chemical endocytosis, which Li's laboratory continues to explore. He said the field of drug development may be significantly different in the next couple of decades due to this discovery and the potential it brings to induced proximity drugs.

There are high levels of CD36 receptors in intestine, brain and skin cells as well, he said, so the chemical endocytosis strategy brings promise for better drug delivery that provides higher oral bioavailability, effectively bridges the blood-brain barrier or enters through the skin.

"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 said. "We feel incredibly lucky to have made this discovery and opened the door to hope for previously untreatable diseases."