In order to effectively treat cancer without additional side effects, we need a way to deliver drugs specifically to tumor cells. Protein assemblies have been widely used for drug delivery in the field of cancer treatment, but to use them for drug delivery they must first be functionalized, meaning they must be bound to the protein that recognizes the target tumor cell and deliver a drug that kills it. However, the functionalization process of protein assemblies is very complex, inefficient, and limited to small-sized chemical drugs, which limits their real-life applicability.
On March 14, a KAIST research team led by Professor Hak-Sung Kim from the KAIST Department of Biological Sciences reported the development of a clathrin assembly that can specifically deliver drugs to cancer cells.
Clathrin assemblies transport materials efficiently through endocytosis in living organisms. They are formed by the self-assembly of triskelion units, which are composed of three heavy chains bonded with three light chains. Inspired by this mechanism, the research team designed a clathrin chain to facilitate the functionalization of tumor cell recognition proteins and toxin proteins in order to deliver drugs specifically to tumor cells. From this, the team created a new type of clathrin assembly.
Figure 1. (Upper) Schematic diagram of the development of a new clathrin assembly that simultaneously functionalizes two types of proteins (cancer cell recognition protein and toxin protein) on heavy and light chains of clathrin in a one-pot reaction (bottom, left) Electron microscopy image of clathrin assembly: formation of an assembly with a diameter of about 28 nanometers (bottom, right) Cancer cell killing effect of CLA: CLA functionalized with epidermal growth factor receptor (EGFR) recognition protein and toxin protein kills only the cancer cells that overexpress EGFR.
The newly developed clathrin assembly requires a one-pot reaction, meaning both the toxin and tumor-recognition proteins can be functionalized simultaneously and show high efficiency. As a result, this technique is expected to be used in a wide variety of applications in the fields of biology and medicine including drug delivery, vaccine development, and diagnosing illnesses.
In this research, an epidermal growth factor receptor (EGFR), a common tumor marker, was used as the recognition protein, allowing drug delivery only to tumor cells. The clathrin assemblies that were functionalized to recognize EGFR showed a bonding strength 900-times stronger than it normally would due to the avidity effect. Based on this finding, the research team confirmed that treatment with toxin-functionalized clathrin assembly led to effective cell death for tumor cells, while it showed no such effect on healthy cells.
This research by Dr. Hong-Sik Kim and his colleagues was published in Small volume 19, issue 8 on February 22 under the title, “Construction and Functionalization of a Clathrin Assembly for a Targeted Protein Delivery”, and it was selected as the cover paper.
Figure 2. Cover Paper: This study was published in the international journal ‘Small’ on February 22nd, Volume 19, No. 8, and was selected as the cover paper.
First author Dr. Hong-Sik Kim said, “Clathrin is difficult to functionalize, and since it is extracted from mammals, realistic applications have been limited.” He added, “But the new clathrin assembly we designed for this research can be functionalized with two different types of proteins through a single-step reaction, and can be produced from E. coli, meaning it can become an applicable protein assembly technology for a wide range of biomedical fields.”
This research was funded by the Global Ph.D. Fellowship and the Mid-career Researcher Grant of the National Research Foundation.