By Dan Samorodnitsky, PhD
Nanomedicine options are expanding so quickly that staying up to date can be an overwhelming task. According to Nanowerk, a website devoted to nanotechnology education, 140 companies in the United States and 117 companies abroad are focused on nanomedicine, or the use of nanotechnology for medical applications. These numbers are bound to increase because the global nanomedicine industry is growing at an impressive rate. According to Grand View Research, the nanomedicine market is worth roughly $150 billion and will reach $350 billion by 2015.
Other indications that nanomedicine is burgeoning include the proliferation of “nano” terms in conference agendas, published articles, clinical trials, and regulatory guidance documents. Nonetheless, relatively few FDA-approved products that incorporate nanotechnology are on the market. That may seem incongruous or even, for the casual observer, an excuse for complacency. But consider that nanomedicine consists of many subdisciplines, many of which are relatively new. What’s more, various subdisciplines are maturing roughly simultaneously. Consequently, multiple products representing these subdisciplines may burst upon the scene in a brief span of time, catching many unawares—but not, hopefully, the readers of articles such as this one.
A good way to appreciate the speed with which nanomedicine is transitioning from a clutter of sample tables to a full-blown buffet is to do a little grazing. Start with this article. It presents a handful of nanomedicine companies of the sort that deserve close attention. They’re not yet giants of the industry. (These are generally acknowledged to include Abbott Laboratories, CombiMatrix, Johnson & Johnson, GE Healthcare, Merck & Co., and Pfizer.) And they’re not startups. They’re establishing themselves in key nanomedicine subdisciplines such as diagnostics, drug delivery vehicles, and therapeutic molecules or conjugates. Granted, there are additional subdisciplines, as well as numerous sub-subdisciplines. But by sampling just a few companies from a few key subdisciplines, one may get a taste for nanomedicine without the risk of demonstrating that one’s eyes are bigger than one’s stomach.
Nano-based analytical technology
Cardea Bio (formerly Nanomedical Diagnostics) got its start in the garage of chief technology officer Brett Goldsmith, PhD, and is now, after several evolutions, one of the first companies mass producing and selling nanotech that incorporates graphene, a material that consists of a single layer of carbons in a hexagonal lattice. (A technique for isolating graphene from graphite was developed by University of Manchester researchers Andre Geim, PhD, and Kostya Novoselov, PhD. In 2010, they were awarded a Nobel Prize for their efforts.)
Cardea Bio produces graphene-based field-effect biosensors (FEBs) that can be used to detect biomolecules without the need for labeling, amplification, or purification steps. In proof-of-principle experiments, the company has shown that antibodies affixed to a graphene matrix can still correctly bind to their antigens. (For example, the company uses antibodies directed against interleukin-6, an inflammatory cytokine expressed in autoimmune disorders and some cancers.) The company also has shown that its approach achieves similar or better sensitivity in real time than common assays like the ELISA. The FEBs, the company asserts, can produce results in around 15 minutes.
Cardea Bio is refining its FEB technology for amplification-free detection of nucleic acids instead of proteins with the use of graphene transistors. The company affixes CRISPR-Cas9 protein and client-specified guide RNA sequences to a graphene transistor matrix, and the transistor can then detect the charge from DNA upon Cas9 binding to a sample. The company’s goal is to get DNA detection out of the lab and into the field. Goldsmith and chief executive officer Michael Heltzen give the example of a farmer in a field examining a crop with something growing on it. “Oh, this looks sick. Wonder what fungi that is, and is my pesticide is going to work on it?”
T2 Biosystems is also in the business of analyzing samples to aid in diagnostics. Instead of avoiding amplification, T2’s technology utilizes a benchtop instrument to conduct a sort of multiplex polymerase chain reaction (PCR). The company’s innovation is a nuclear magnetic resonance (NMR) technology that binds and isolates nucleic acids of interest—T2’s name comes from a mathematical constant important for NMR—allowing users to skip the purification and cleanup steps that are frequently necessary for optically based techniques, which can’t tolerate high background signal. T2 says this purification step results in loss of sensitivity. The company’s technique can skip purification because NMR is “agnostic to background matrix.”
T2’s current lead product identifies bacteria commonly present in the blood of sepsis patients. This is a notoriously thorny problem, since bacterial cultures can take two to three days—time that sepsis patients cannot typically afford. Using a particularly sensitive variation on multiplex PCR, T2 is banking on its three- to five-hour detection time being attractive to hospital labs. Since T2 uses a nucleic acid–based approach, the company’s technology is also agnostic to the presence of antibiotics, which can limit detection of bacteria by blood culture.
With an eye on future innovations, T2 is also working to launch a resistance panel, similar in spirit to the company’s bacteria-sepsis panel but specifically tailored for detecting the presence of antibiotic resistance markers in patient blood. T2 is also working on a Lyme disease detection panel.
Although T2’s technology is tied to a desktop instrument, the company suggests that affordability is not a problem. For lower-income nations, T2’s chief scientific officer Tom Lowery, PhD, says, “Less wealthy countries could use it if they have a reliable power source. The benchtop instrument is like any other one. [There are] no special requirements for our magnetic resonance detector.”
Nano-based drug delivery systems
Sitka Biopharma is interested less in curing diseases with new technology than in improving the administration of existing treatments. Sitka produces a hyperbranched polyglycerol (HBP) drug delivery system. The HBP system functions like a lipid micelle, with a hydrophobic interior and a hydrophilic exterior, but it is monomolecular, leaving it far more stable than lipid vesicles over a range of conditions. A drug is attached to the HBP molecule, either covalently or noncovalently, with other functions optionally fitted to the exterior surface. Sitka says that this approach helps overcome problems with the amount of time a drug spends in contact with its target tissue.
At present, Sitka is focused on combining HPG technology and taxane-class chemotherapeutics to attack intermediate and high-risk non-muscle-invasive bladder cancer. For example, the company’s lead candidate, STK-1, incorporates docetaxel, a 30-year-old chemotherapeutic. Sitka’s HPG technology could also work with other established drugs. This approach could reduce the cost of Sitka’s therapeutics.
On the subject of affordability, Sitka’s president and chief scientific officer Michael Parr, PhD, says, “We have done some modeling for cost of goods at scale and believe that we can easily fit into standard therapy regimens for bladder cancer patients and compare favorably on a per treatment cost basis, all in from manufacturing to supply chain and ultimately patient administration.” Looking beyond bladder cancer, Parr says that Sitka is also thinking of using its technology to treat ovarian cancer but notes that HPG delivery can be used for a variety of noncancer diseases as well as assist in imaging and immune modulation.
Sitka is not the only nanomedicine company that combines the old and the new. Another example is Keystone Nano. Instead of inventing a new medicine out of whole cloth, Keystone has developed new, nanofocused ways of delivering existing treatment ideas. It has been known for years that concentrations of ceramide, a sphingolipid, increase in cancer cells killed by chemotherapeutics. And cancer biologists have attempted to increase endogenous ceramide synthesis, inhibit breakdown of already existing ceramide, or deliver exogenous ceramide to cancer cells. However, delivering ceramide as a therapeutic without it breaking down—whether due to its short half-life or its insolubility—has been a challenging technical issue.
Keystone’s NanoLiposome platform for delivering ceramide to liver cancer cells received orphan drug status from the FDA in October 2016. A Phase I trial of Ceramide NanoLiposome in patients with advanced solid tumors commenced in March 2017. Although the trial, which involved testing centers in Virginia, Maryland, and South Carolina, was originally scheduled for completion in August 2019, results have yet to be announced as of this article’s preparation. Instead of attempting to administer pure sphingolipid, NanoLiposome incorporates ceramide into the bilayer of a synthetic spherical lipid, which selectively fuses with cancer cells, delivering its payload there without interacting with healthy cells.
Keystone is also developing another nanodelivery technology. This technology, called NanoJacket technology, is similar in spirit to NanoLiposome, hence the variant-on-a-theme name. Instead of a lipid bilayer, however, NanoJacket utilizes small calcium and phosphate spheres. And rather than delivering lipids, NanoJacket will deliver other biologicals that may not be as stable in the blood, such as mRNA, siRNA, or miRNA. These jackets can be tuned to target different cell types, whereupon they can deliver their payloads.
Cour Pharmaceuticals was spun out of research coming out of Northwestern University. The company is approaching autoimmune disorders such as Celiac’s disease with a “teach the immune system tolerance” approach. Cour manufactures tolerizing immune modifying nanoparticles (TIMPs), which are composed of poly(lactide-co-glycolide) (PLG) polymers. PLG is a popular drug delivery polymer because it’s biodegradable, biocompatible, and best of all, already FDA approved.
Celiac’s disease is triggered by T cells that inappropriately attack the lining of the small intestine in response to the gluten in wheat, or more specifically, the peptide components of gluten, gliadins and glutenins. The TIMP approach attaches gliadin peptide fragments to PLG polymers, which are then intravenously injected. This essentially reprograms a patient’s immune system to recognize gliadin antigens as “self,” and not react to them. Although this approach is novel with respect to nanotechnology, other companies are using similar “tolerizing” approaches to create treatments for Celiac’s disease. (For example, ImmunsanT is developing a treatment called Nexvax2.) Cour’s TIMP-gliadin treatment has recently finished Phase I trials.
Cour’s other arm is in what the company calls immune modifying nanoparticle (IMP) technology. It is similar in some ways to the TIMP technology, hence the similar acronym. But, instead of promoting immune tolerance, IMP uses highly negatively charged PLG polymers to target macrophages through a specific receptor (the MARCO receptor), which causes those cells to undergo apoptosis and be taken up by the spleen. Cour is using this approach to treat inflammation in myocardial infarctions and malaria.
Dan Samorodnitsky, PhD, is a freelance writer for GEN.