One-dose Killing of Cancer Cells

Structure of the engineered lipid bilayer covering and cutaway of the nanoporous silica interior of a protocell, showing the diversity of cytotoxic cargo that it can potentially  deliver into the interior of a cancer cell.

Sound futuristic? Perhaps not. Capturing the cover of the May 2011 (April 17 online) issue of Nature Materials, a paper first-authored by Sandia Truman Fellow Carlee Ashley and describing (partly LDRD-funded) work from the lab of Sandia Laboratory Fellow and UNM Distinguished Professor, Jeff Brinker presents a genuinely evolved route to that possible outcome (one-dose cancer-cell killing). Dubbed “protocells,” this ingenious nanoparticulate engineering of organic and inorganic materials goes one-better on liposomes, an already FDA-approved method of drug delivery. While a liposome is simply a bag of aqueous solution encapsulated by a ligand-decorated lipid-bilayer membrane (the same type of membrane that encloses all higher [eukaryotic] cells and many of their internal structures [organelles]), a protocell is far more nanostructurally complex. The outer bag of lipid bilayer encloses a nanoporous silica nanoparticle that acts as a high-surface-area container-binder for a diversity of cytotoxic compounds—drugs, nucleic acids (such as small interfering RNAs [siRNA]), proteins, and peptides of varying water solubility, some of which do not dissolve well in the aqueous internal medium of liposomes.

Additionally, the membrane of the protocell is “decorated” with both specific and nonspecific binding agents (peptide ligands) that stick it to receptors on a given cancer cell’s surface (in this instance, hepatocarcinoma) and promote its internalization into the cancer cell (via a process known as receptor-mediated endocytosis). Once internalized, it is engineered to disrupt the internal cellular compartment (endosome) into which its cargo is initially sequestered, thereby fully releasing its huge cargo of cytotoxins into the cell’s interior cytosol and nucleus. This cargo can be composed of such a disparate array of compounds—in terms of mechanism of action—that the probability of a kill is maximized, while the probability of the cancer cell’s developing drug resistance is minimized; in diversity lies strength. Wrapping the lipid bilayer around the silica nanoparticle imparts highly desirable physical characteristics to the fluidity and stability of the lipid bilayer that allows it to do more with less. These characteristics favor its highly specific binding to the cancer cell’s surface, a prerequisite for the aforementioned internalization (endocytosis), while simultaneously lowering its side-effect profile in binding to and killing normal cell types—in this instance, normal liver cells (hepatocytes).

Additionally, that aforementioned “more-with-less” nanoengineering renders the surface of the protocell quite soluble in body fluids such as blood, and even more importantly, confers lowered immunogenicity; that is, unlike a virus particle, the protocell nanoparticle does not strongly stimulate the immune system to act against and remove it. The higher solubility and lowered immunogenicity are both key characteristics of an effective agent in vivo. Although in vivo testing yet lies in the future, the in vitro results are stunning, showing that a single nanoparticulate protocell can deliver such a potent dose of cytotoxic agents so as to be effective at killing a hepatocarcinoma cell with a single dose, while sparing greater than 90% of normal liver hepatocytes.

Click here to read the Ashley paper on the Nature website.

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