The ability of antibodies to recognize specific cancer cells is used in oncology to specifically target those cells with small active agents. Sankaran Thayumanavan, University of Massachusetts, Amherst, USA, and colleagues have built a transport system that delivers even large protein-based drugs into cancer cells. This study demonstrates how proteins can arrive at their target intact, protected from destructive proteases by polymer brushes.
Inserting Active Agents into Cancer Cells
Developing anticancer treatments involves two recurring problems for researchers. An active agent needs to be able to kill cells at the root of the cancer, and it should be active in target cancer cells rather than in healthy cells. Many medical researchers are, therefore, working on the concept of a “cargo” package. The active agent stays protected and packaged until it reaches the target location, while antibodies that only attach to cancer cells help with finding the right “address”.
These antibodies recognize specific receptor structures on the outer membrane of cancer cells. They attach to these structures and the cell absorbs the active agent. However, this strategy is generally unsuccessful when the active agents are large proteins. Proteins of this type are usually water-soluble and they cannot pass through the cell membrane. A further issue is caused by the body’s own protease enzymes, which break down the transported proteins before they can reach their target location.
Protein–Antibody Conjugates (PACs)
The researchers developed a particular protected nanosized cargo package, which meets both requirements of targeted delivery and keeping the cargo intact. They use minuscule beads made of silicon dioxide with a diameter of just 200 nanometers. The surface of these beads is covered with brush-like polymer strands made of polyethylene glycol (PEG) that can be doubly functionalized, giving tiny “brush beads” (pictured left).
The team attached the desired active-agent protein and antibodies to the polymer bristles using simple click chemistry. The finished bead-shaped packages (pictured right) have antibodies on the very outside, with the proteins tucked away safely within the forest of polymer strands.
As well as being able to transport water-soluble proteins, this type of protein–antibody conjugate (PAC) also afforded the researchers another potential advantage: the possibility of attaining a high protein–antibody ratio in this format. They say that, at least in theory, more than 10,000 proteins could be transported per (expensive) antibody using the researchers’ PACs, unlike the maximum of four active agents per antibody in previous antibody–drug combinations.
The team tested their system on various cell cultures with different antibodies and test proteins. As planned, the proteins reached their targets in the cell and fulfilled their deadly role.
The researcher’s next steps involve working out whether the cargo packages can be protected from the body’s macrophages. However, they are optimistic because the PEG functionalities and the surface antibodies are designed for a quick delivery while minimizing clearance by macrophages.
- Protein–Antibody Conjugates (PACs): A Plug‐and‐Play Strategy for Covalent Conjugation and Targeted Intracellular Delivery of Pristine Proteins,
Bin Liu, Khushboo Singh, Shuai Gong, Mine Canakci, Barbara A. Osborne, S. Thayumanavan,
Angew. Chem. Int. Ed. 2021.