Abstract
Cancer targeting nanoparticles have been extensively studied, but stable and applicable agents have yet to be developed. Here, we report stable nanoparticles based on hepatitis B core antigen (HBcAg) for cancer therapy. HBcAg monomers assemble into spherical capsids of 180 or 240 subunits. HBcAg was engineered to present an affibody for binding to human epidermal growth factor receptor 1 (EGFR) and to present histidine and tyrosine tags for binding to gold ions. The HBcAg engineered to present affibody and tags (HAF) bound specifically to EGFR and exterminated the EGFR-overexpressing adenocarcinomas under alternating magnetic field (AMF) after binding with gold ions. Using cryogenic electron microscopy (cryo-EM), we obtained the molecular structures of recombinant HAF and found that the overall structure of HAF was the same as that of HBcAg, except with the affibody on the spike. Therefore, HAF is viable for cancer therapy with the advantage of maintaining a stable capsid form. If the affibody in HAF is replaced with a specific sequence to bind to another targetable disease protein, the nanoparticles can be used for drug development over a wide spectrum.
Highlights
If a multifunctional agent that can perform delivery to the disease site and provide therapeutic function is developed, it will play a significant role in the treatment of cancer
hepatitis B core antigen (HBcAg) was expressed in Escherichia coli (E. coli) using the pET28a vector (Figure 1a) and purified using sucrose gradient centrifugation and size exclusion chromatography (SEC) (Supplementary Figure S1a,b)
HBcAg was visualized through transmission electron microscopy (TEM) and the diameter of the HBcAg was found to be 31–35 nm (Figure 1b)
Summary
If a multifunctional agent that can perform delivery to the disease site and provide therapeutic function is developed, it will play a significant role in the treatment of cancer. Researchers have attempted to develop such agents [1,2,3,4,5]. In many cases, such agents had the drawbacks of cytotoxicity and/or instability. To overcome these negative effects, we developed nanoparticles based on hepatitis B core antigen (HBcAg). The nanoparticles bound to a tumor cell receptor, performed magnetic hyperthermia-based ablation of tumor cells, and were spontaneously disassembled over time—exhibiting negligible cytotoxicity. The binding mechanism between the nanoparticles and tumor cell receptor could not be fully explained without 3D structures of the nanoparticles. We obtained the molecular structures of the nanoparticles using cryogenic electron microscopy (cryo-EM)
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