Nanoparticle Delivers Large Protein Complex to Cancer Cell Nucleus
Drug developers have been using nanoparticles to encapsulate a wide range of molecules for delivery to tumors. Now, they can add a large protein complex to that list thanks to research from the laboratory of Yi Tang of the University of California at Los Angeles (UCLA). In a study published in the journal Nano Today, Dr. Yi and his colleagues showed that not only could their degradable nanoscale shell carry proteins to cancer cells, but that they could transport a protein complex into the cell’s nucleus.
The UCLA team focused their work on the protein apoptin, a large complex derived from an anemia virus in birds. When delivered to the cell nucleus, this protein cargo signals the cell to undergo programmed self-destruction. Previous work by several groups had shown that healthy cells degrade this protein in the cytoplasm, but that cancer cells add a phosphate group to the protein, which causes it to accumulate in the cell nucleus and trigger cell death.
One of the challenges to deliver apoptin is that it is a large protein complex containing 30 to 40 copies of the protein. It is thought that this complex and not an individual copy of apoptin is important to effectively trigger cell death. The UCLA team overcame this challenge by choosing a water soluble polymer that self assembles around the protein complex and that can then be stabilized using a very mild chemical reaction. The chemical bonds formed during this stabilization reaction are stable enough to keep the particle intact as it circulates through the blood stream, but weak enough to fall apart in the reducing environment inside a cell.
Studies using cancer cell lines demonstrated that tumor cells readily took up the apoptin-containing nanoparticles and that the protein complex accumulated in the cell nucleus. Subsequent experiments with tumor-bearing mice showed that this construct, when administered intravenously every other day for 12 days, had a marked effect on slowing the growth of tumors. The researchers noted that they are now developing ways to more precisely target tumors, prolong the circulation time of the nanoparticles, and deliver other potentially therapeutic proteins to cancer cells.
This work is detailed in a paper titled, "Degradable polymeric nanocapsule for efficient intracellular delivery of a high molecular weight tumor-selective protein complex." Investigators from the University of Southern California also participated in this study." An abstract of this paper is available at the journal’s website.