New Drug Self-Assembles and Delivers Itself to Its Target
First the peptide adopts a hairpin-shaped conformation (teal ribbons) and then self-assembles into spherical nanoparticles that fuse spontaneously with the plasma membrane and disassemble. Once within the lipid bilayer, the peptide changes its conformation into an alpha-helix shape that interferes with the CXCR4 receptor (green).
Viruses self-assemble with high precision and disassemble upon fusion with the cell membrane and deliver this way their cargo to the interior of the cells. Using this talent, viruses are able to inject whole proteins and large nucleic acid molecules into certain types of cells.
A group of scientists from CCR’s Structural Biophysics Laboratory, Laboratory of Cell Biology, and Laboratory of Molecular Immunoregulation lead by Nadya I.Tarasova, Ph.D., in NCI’s Cancer and Inflammation Program, have learned from these clever actions of virus particles. In designing their new drug delivery system, they noted and imitated the critical properties that enable viruses to be so effective in delivering very fragile molecules in such cell-selective way.
As described in a recent PNAS article, the Tarasova team developed possibly the first fully synthetic virus-like particles. They generated a peptide inhibitor of the CXCR4 receptor that can precisely self-assemble into biologically active fusion-prone particles. Self-assembly protects the inhibitor from degradation in the body and allows it to inhibit CXCR4 receptor activity in vivo. This is important because the CXCR4 receptor plays a critical role in tumor metastasis to the lung and bone.
The design involved making many fine-tuned alterations to peptide structure. The effort paid off because resulting nanoparticles are remarkably stable and are more than 99 percent homogeneous in size.
Tarasova and colleagues ended up with fusion-prone nanoparticles with built-in biological activity. They work this way: First the peptide, which is derived from the second transmembrane helix of the CXCR4 receptor, adopts a hairpin-shaped conformation (teal ribbons) and then self-assembles into spherical nanoparticles in aqueous solution. These nanoparticles fuse spontaneously with the plasma membrane and disassemble upon fusion. Once within the lipid bilayer, the peptide changes its conformation into an alpha-helix shape that has inhibitory properties and interferes with the proper functioning of the CXCR4 receptor (green).
The team also tested the ability of the nanoparticles to encapsulate and deliver cytotoxic agents. Confocal laser scanning microscopy allowed observation of rapid release and accumulation of encapsulated fluorescent toxin, bis- imidazoacridone WMC26 in the nucleus of treated cells within minutes after addition of nanoparticles to cells.
Additional experiments conducted by Zack O.M. Howard, Ph.D., and Joost Oppenheim Ph.D., also in CCR’s Cancer and Inflammation Program, demonstrated activity of the new nanoparticles in nude mice. Mice were injected intravenously with highly metastatic MDA-MB-231 breast cancer cells. After two months, control animals began to succumb to tumors or had to be sacrificed. Necropsy revealed numerous tumor metastases, mostly in the lung. The group of mice that received nanoparticles exhibited slower growth of tumors and life spans that were significantly prolonged.
So it is now possible to achieve precision and reproducibility in constructing self-assembling biological systems that are based upon molecules created by chemical synthesis. The Tarasova team’s newly developed nanoparticles demonstrate proof of principle that it is possible to generate highly homogeneous virus-like particles with desired size, biological activity, and surface and targeting properties, for a wide range of applications.
The Tarasova nanoparticles offer an unusual approach to drug delivery—a drug that self-assembles and, in doing so, delivers itself to its target.Summary Posted: 06/2011
http://www.pnas.org/content/early/2011/05/25/1014598108.full.pdf+html/ Reviewed by Donna Kerrigan