Automation & Control

Fabricating Tomorrow’s Pharma at the Nano Scale

An expert practitioner discusses the potential of dip pen nanolithography

By Paul Thomas, Senior Editor

In 2010, we’ll look at cutting-edge technologies that, while little understood now, have the potential to transform future pharmaceutical manufacturing. Nanolithography is one such technology, in that researchers can fabricate nanoscale structures to serve a variety of purposes, from creating new drug delivery carriers, to constructing more orderly and predictable biomolecules, to encrypting data into solid dosage forms as a means of anticounterfeiting. (Click here for more on this latter application.)

We spoke with one of the country’s leading nanolithography researchers, Steven Lenhert, PhD, of Florida State University, who specializes in the art of dip pen nanolithography.

PhM: There’s a whole world of nanofabrication going on in the biosciences. Can you comment on where some of the real breakthroughs are taking place in regards to drug discovery and development?

S.L.: From a research perspective, generally two areas stand out in my mind—high-throughput screening, and novel materials.  For instance, micro- and nanoarrays for expression analysis can provide a variety of molecular information about which genes and pathways are affected by drugs, and how, as well as unprecedented diagnostic information.  Miniaturizing spot sizes allows higher throughput and lower sample volume and can even open entirely new readout capabilities.
Nanomaterials offer another avenue. Creating a specific micro- or nanostructure out of a potential drug or carrier can affect its function. A typical example of a size effect is in the case of delivery—for instance, where a smaller particle may be able to enter a capillary or a cell, while a larger particle may not.

PhM: Nanolithography has been used in the semiconductor industry to pattern silicon wafers, but how is it being applied in the pharmaceutical world?

S.L.: A major difference between computer chip manufacturing and bioscience applications of nanolithography is that, although very complex computer chips can be made out of relatively few materials, pharmaceutical applications like those described above require rapid prototyping and screening of as many different materials as possible. As a result, many of the top-down approaches (like carving or etching from a single material) that work great for computer-chip manufacturing are not quite as useful as bottom-up nanofabrication like chemical synthesis, self-assembly, and printing technologies.

PhM: What distinguishes dip-pen nanolithography, and what are some of the more promising areas of your research with it?

S.L.: Traditional lithography methods are either high resolution (like electron beam lithography), high throughput (like photolithography), or able to integrate multiple materials (like inkjet printing). Dip-pen nanolithography is unique in having all three of these properties. In my research, the ability to integrate multiple materials on subcellular scales, with high enough throughput for systematic screening, opens possibilities that so far as I know are not accessible by any other method. We can therefore determine entirely new size- and shape-dependent properties of nanostructured materials in the context of biological systems.

PhM: Your “ink” of choice is phospholipids. What makes them suited to DPN, and what kind of impact do they have on proteins and other molecules they are coupled with?

S.L.: The main physical property of phospholipids that makes them suitable for DPN is their lyotropic liquid crystalline nature—that is, they go through phase transitions that depend on a second material, which in the case of phospholipids is water. I found (somewhat surprisingly) that by controlling humidity, one can finely tune the fluidity (or viscosity) of phospholipid-based inks and therefore reliably control their transport and pattern sizes. In addition to this property, phospholipids are innately biofunctional and open the possibility of reconstituting a variety of biological functions. In particular, many proteins are perfectly at home in the presence of phospholipids, and a variety of functional lipids have been developed and characterized, for example from liposome industry, specifically for coupling to other biofunctional molecules such as proteins.

PhM: Your work involves patterning or templating biomolecules—how exactly would this lead to simplified molecules and interactions, and what might the implications be for gaining better control and predictability of biomolecules?

S.L.: Yes, I’m exploring a couple of approaches to that. One is to create model membrane systems and to investigate how small molecules interact with them. Because the model membranes are synthetic mixtures, we can then test hypotheses about mechanisms simply by varying the lipid composition.  Another approach is to grow cells on these surfaces and to investigate how the cells interact with the model systems and vice versa. This system can allow a kind of in vitro assay for the biological activity of nanomaterials. The high resolution and material-integration capabilities of DPN allow screening at subcellular scales.
Sensor functionalization and development of new biosensor elements is another approach.  Generally, we can investigate how nanostructures affect biomolecular function and how cells behave in their presence.

PhM: What are the implications for drug development? Could we make bioprocess development more cut and dry by increasing the consistency of the molecules?

S.L.: One approach is to develop novel assays that can provide insights into the mechanisms by which a drug functions. Although I’m focused on basic research, I see potential to use nano- and microstructured model membrane arrays to provide a variety of platforms for in vitro screening assays. Also, the ability to functionalize and fabricate new biosensor elements with multifunctional nanomaterials makes "lab-on-a-chip" type devices feasible and could therefore lower costs and open new possibilities for drug development.
And, yes, I think you make a good point about the consistency of new biomaterials. Something I haven’t mentioned yet is the importance of quality control in a lithographic process. I think the application of nanoanalytical methods to ensuring reproducible nanostructure fabrication could provide more reliable molecules, supramolecules, and materials.

PhM: Are there also implications for generic biologics (aka, biosimilars)? Could biologic drugs be made more repeatable via the work you’re doing, and thus generic equivalents more possible?

S.L.: Yes, there are, because even the same molecules, when produced in different ways, can have a variety of different nanostructures and functions. Of course, everything has some nanostructure; we just don’t know what it is most of the time. Reproducibility of biologic drugs may therefore be just a matter of getting them reliably nanostructured. Nanofabrication and related techniques provide a method for testing such hypotheses and moving beyond a purely heuristic approach to determining what might make a complex biologic work or not work.

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