New research has developed a nanoparticle system that can deliver large, unwieldy protein-based chemotherapy drugs right to the doorsteps of cancer cells.
Some cancer treatments make use of antibodies’ ability to recognise specific cancer cells in order to target those cells with small active agents, but have not been able to deliver larger protein-based drugs.
Research published in the journal Angewandte Chemie shows how, using a new protein transport system, proteins can arrive at their target intact, protected from destructive proteases by polymer brushes.
Two problems keep coming up when scientists try to develop new anticancer drugs. Firstly, an active agent needs to be able to kill the body’s cells at the root of the cancer, and secondly it should be active in target cancer cells rather than in healthy cells. To this end, some medical researchers are trying to implement a cargo package as a method of delivery. 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 recognise specific receptor structures on the outer membrane of cancer cells, attaching to these structures with the cell absorbing the active agent. However, this strategy is unsuccessful when the active agents are large proteins.
These large proteins are usually water soluble, and unable to penetrate the cell membrane. The body’s own protease enzymes throw in another complication, because they break down the protein cargoes before they can reach their target location.
Sankaran Thayumanavan and colleagues at the University of Massachusetts in Amherst, USA, have now developed a protected nanosized cargo package, which meets both requirements of targeted delivery and keeping the cargo intact. For the container, they use miniscule beads made of silicon dioxide with a diameter of just 200 nanometres. The surface of these beads is coated with brush-like polymer strands made of polyethylene glycol (PEG) that can be doubly functionalised, giving tiny “brush beads”. This is termed a protein-antibody conjugate (PAC).
With simple click chemistry, the researchers attach the desired active-agent protein and antibodies to the polymer bristles. The finished bead-shaped packages have antibodies on the outermost layer, with the proteins safely concealed in the forest of polymer strands.
Besides the ability to transport water-soluble proteins, this PAC also possessed another advantage: a possible high protein-antibody ratio. The researchers said that, at least in theory, over 10 000 proteins could be transported per (expensive) antibody using the researchers’ PACs, compared to 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. The test was a success; the PACs delivered their deadly cargoes to their cellular targets as planned.
The team is now going to figure out if and how the packages can be shielded from macrophages. They are optimistic about this because the PEG functionalities and the surface antibodies are designed for a quick delivery while minimising clearance by macrophages.
Source: News-Medical.Net
Journal information: Liu, B., et al. (2021) Protein–Antibody Conjugates (PACs): A Plug‐and‐Play Strategy for Covalent Conjugation and Targeted Intracellular Delivery of Pristine Proteins. Angewandte Chemie International Edition. doi.org/10.1002/anie.202103106.
