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In This Issue
The Convergence of Engineering and the Life Sciences
Nanotechnology An Enduring Bridge Between Engineering and Medicine
Understanding and Harnessing the Immune System for the Rational Design of Therapies and Vaccines
Systems Biology and Systems Pharmacology
Regenerative Engineering Materials, Mimicry, and Manipulations to Promote Cell and Tissue Growth
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Fall Issue of The Bridge on the Convergence of Engineering and the Life Sciences
October 1, 2013 Volume 43 Issue 3

Nanotechnology An Enduring Bridge Between Engineering and Medicine

Tuesday, October 1, 2013

Author: Sarah Hurst Petrosko, Catherine A. Fromen, Evelyn Auyeung, Joseph M. DeSimone, and Chad A. Mirkin

Nanotechnology has matured over the past 20 years from a field focused on understanding miniaturization and its consequences to one defined by the rational design, synthesis, and manipulation of nanoscale objects. Many advances in nanotechnology have had an extraordinary impact specifically on the medical field, enabling some of the most meaningful developments in diagnostics, imaging, and therapeutics.

Nanotechnology represents a “third wave” of advancement in medical science. The first wave was initiated 60 years ago by Watson and Crick’s seminal discovery of the DNA structure (Watson and Crick 1953), which led to a paradigm shift in understanding of cell biology. The second originated with the birth of the field of genomics, which led to unparalleled insight into disease origins and drug response. The third wave of nanotechnology-based advances in medical understanding has been spurred by the rapid development of sophisticated new nanomaterials and processes that provide significant capabilities as compared to conventional approaches. In addition, the field has created a renaissance in analytical tool development that has enhanced the way researchers and physicians can study, track, and treat disease.

Medical breakthroughs using nanotechnology are made possible by the length scales of many biological systems. Nanomaterials, structures having at least one dimension less than 100 nm, are the ideal size to efficiently interact with biological structures, and they can act as scaffolds for the attachment and organization of a variety of biomolecules into useful architectures. Using robust synthetic methods, researchers can engineer nanoconstruct platforms on demand and thus create entities that offer multifunctionality essential for biological function and control in specific medical applications. This paradigm has been central to many of the most successful nanotechnology-based innovations.

In this article we highlight selected materials and tools that straddle engineering and medicine. Many of these originated from basic benchtop research at the university level and, in a short period of time, have been the catalyst for the establishment of successful startup companies with products and systems that have received, or are trying to obtain, US Food and Drug Administration (FDA) approval. Hundreds of nanotechnology-based technologies and products have emerged via this developmental pathway (Etheridge et al. 2013). We do not discuss each of these top innovations in depth; instead, we refer the reader to our timeline (Figure 1) and the associated list of resources at the end of this article. As representative examples, we describe one breakthrough material—spherical nucleic acids (SNAs)—and one enabling tool—particle replication in nonwetting templates (PRINT).

Figure 1

SNAs: A Breakthrough Material

SNAs are a highly programmable platform material that typically consist of a nanoparticle core and a densely packed, highly oriented nucleic acid (DNA or RNA) shell. Different types of SNAs can be synthetically engineered by changing the composition and size of the core or the length, sequence, and type of nucleic acid used in a modular fashion; multifunctional versions can be created by using different cores or nucleic acid materials in a single structure, and coreless, hollow SNAs as well as nucleic acid–modified nanostructures with nonspherical cores can also be synthesized.

SNAs are one of the most impressive examples of the power and importance of nanotechnology. Just as fullerenes revealed that the arrangement of carbon atoms on the nanometer scale has profound influences on the properties of carbon-based materials, SNAs have shown that arrangement on the nanoscale of perhaps the most important molecules ever synthesized by chemists—DNA and RNA—can dramatically influence the properties of the nucleic acid. Indeed, with the novel three-dimensional arrangement of nucleic acids on their surface, individual SNAs bind single-stranded DNA (ssDNA) approximately 100 times more tightly than free linear ssDNA of the same sequence and, due to their cooperative melting profiles, can be used to discriminate single-base mismatches in diagnostic schemes (Rosi and Mirkin 2005).

Although cell walls are almost impenetrable to linear nucleic acids, SNAs have the extraordinary ability to enter cells of almost any type (>50 cell lines demonstrated to date) in high quantities without the use of toxic transfection agents. Once inside cells, the SNAs are not degraded and do not trigger a significant immune response. These properties allow researchers to use SNAs to carry large payloads of nucleic acids into cells without secondary transfection agents, and are therefore the basis for many intracellular detection and gene regulation strategies (Choi et al. 2013; Cutler et al. 2012).

SNA-based extracellular or intracellular diagnostic and therapeutic schemes offer solutions to many of the pitfalls of currently used technologies, often providing more sensitive, selective, and efficacious alternatives. Colorimetric, electrical, fluorescent, and scanometric diagnostic assays have been developed based on different types of SNAs. The SNAs have been used to create high-sensitivity screening tools and amplification schemes for many types of analytes, including small molecules, proteins, and metal ions.

The scanometric assay, which uses an SNA with a gold nanoparticle core as both a labeling entity and an amplification agent, has opened the door for low-cost, point-of-care, and massively multiplexed DNA and RNA detection. It is the basis for the first commercialized nanotechnology-based molecular medical diagnostic platform, the Verigene System™ (Nanosphere, Inc., Northbrook, IL), which is now sold in over 20 countries. Because the technique does not require polymerase chain reaction (PCR) or other enzymatic amplification schemes, it enables simultaneous detection of many targets in a single sample, proteins and nucleic acids on one platform, and many targets below the titer level required by conventional diagnostic systems. In addition to being useful as a medical screening tool, it has helped identify new molecular markers for Alzheimer’s disease, HIV, cardiovascular disease, and prostate cancer.

SNAs are also the basis for SmartFlares™ (EMD Millipore, Billerica, MA), the only known structures that can naturally enter cells and, when coupled with imaging tools or flow cytometers, yield a measure of genetic content in live cells. SmartFlares consist of gold nanoparticle-based SNAs with short fluorophore-labeled oligonucleotides hybridized to them; the gold quenches their fluorescence. When the SmartFlare enters a cell and binds to a target messenger RNA (mRNA) sequence of interest, it releases the fluorophore-labeled sequence, turning on fluorescence that can be detected by confocal microscopy and flow cytometry (Seferos et al. 2007). There are now over 500 different types of SmartFlares commercially available, and they provide the only way to sort live cells based on genetic content. They are being used to study mRNA expression as a function of disease, to identify circulating tumor or stem cells, and as high-throughput labels for pharmaceutical screening.

Finally, SNAs have proven to be powerful single-entity gene regulation platforms in antisense and RNA interference (RNAi) pathways that may be used to treat any disease with a genetic basis. Because they do not require polymeric delivery agents and can cross therapeutically formidable biological barriers such as the stratum corneum and the blood-brain barrier, they are candidates for many promising new therapeutics. In an academic setting, they have proven effective for the treatment of brain cancers and skin disorders in small animals, and these studies have paved the way for clinical human trials, which are currently under way.

PRINT: An Enabling Tool

Particle replication in nonwetting templates, or PRINT, was inspired by advances in polymer chemistry and traditional lithographic techniques from the microelectronics industry. It was developed as a platform nano-molding technology to fabricate rationally designed, highly uniform nanoparticles (Rolland et al. 2005).

The creation of “calibration-quality” nanoparticles requires independent control over geometry and composition, and PRINT molds, fabricated using soft-lithography techniques, result in a uniform array of cavities with well-defined features, ranging in size from ~20 nm to tens of microns. These molds can be filled with the material that will ultimately constitute the nanoparticle, which is then “solidified” in the cavities. The solidification process is dependent on the material being molded and includes vitrification (e.g., production of glassy materials such as copolymers of lactic acid and glycolic acid), crystallization, and gelation (formation of cross-linked hydrogel particles). Newly formed particles are easily liberated from the PRINT mold, yielding monodisperse replicates of the geometry defined in the mold features.

PRINT technology highlights the increasing influence of engineering in nanotechnology, especially when considering the numerous design features required for navigating biological barriers. PRINT enables the fabrication of a diverse range of particle geometries, including rods of varying aspect ratio and shapes inspired through biomimicry (e.g., filamentous particles, pathogen mimics, and pollen spore mimics), and is compatible with a wide range of relevant materials, including small molecule active pharmaceutical ingredients (APIs), protein biologics, small interfering RNA (siRNA), and both hydrophilic and hydrophobic polymers. The ability to control composition also conveys the ability to fine-tune particle deformability, degradation, surface chemistry, and cargo release through the use of elastomers, targeting and stealthing ligands, or acid- or enzymatically degradable materials (Garcia et al. 2012).

With so many knobs to turn using PRINT’s toolbox, physical and chemical features of nanoparticles can be independently isolated and investigated to develop particle designs for a given application. Engineering tools like these create opportunities to develop new materials through a creative lens. As an example, PRINT particles have been fabricated to mimic the physical dimensions of bacteria to produce more efficacious vaccines. Through such efforts with PRINT and other nanoparticle technologies, engineering is making sizable contributions to the growing body of nanomedicine research tasked with optimizing nanoparticle designs.

PRINT also illustrates the opportunities for manufacturing and scale-up in nanotechnology. In its infancy, PRINT was performed using molds created from the surface area of a single silicon wafer. Liquidia Technologies (Durham, NC), founded in 2004, has successfully converted the PRINT platform into a scalable, roll-to-roll process.1 Furthermore, the technology is intrinsically dry and has minimal batch-to-batch variability, which contributed to its Current Good Manufacturing Practice (cGMP) designation. This designation is a landmark classification for any nanomanufacturing technique and enabled Liquidia to bring its first product, a seasonal influenza vaccine based on PRINT particles, to clinical trials. As in many other examples of enabling nanotechnology tools, engineering ingenuity fostered this scale-up.

Processes that address both manufacturing and regulatory hurdles will be increasingly important to bring technologies from inception to product development. Reinforcing the notion of a technology’s manufacturability as key to its sustainability, a new spray-assisted, layer-by-layer coating technology developed at MIT was recently combined with the PRINT technology to quickly mass-produce tailored nanoparticles specially coated for specific applications in medicines and electronics, among other areas (Morton et al. 2013). This example highlights both the options for new combinations of existing technologies and the influence of manufacturing on nanotechnology successes.

Other Promising Possibilities

Nanotechnology continues to promise a sustained wave of advancement that will affect many different areas of medical science (Figure 2). As an example, one promising area lies at the interface of the human immune system and nanoscience. Nanoparticles interact differently with immune-specific cells than small molecules, offering unique opportunities to modulate immune responses. This has a very powerful implication in nanomedicine: inert particles can be programmed to stimulate the immune system and recognize and eliminate cancer cells or to produce protective antibodies against an infectious disease. In addition, nanomedicines capable of immunomodulation could be designed to retrain the immune system as a way to treat autoimmune diseases, such as multiple sclerosis and diabetes.

Figure 2

As nanoparticles in general become more advanced, many routes of administration (e.g., inhalation, nasal, dermal, and oral) will be leveraged to deliver them to specific sites in the body. Most clinical applications have been designed for intravenous administration, but different routes of administration will enable nanoparticle access to new tissue sites; promising preclinical data in pulmonary and ocular nanoparticle delivery are already emerging (Araújo et al. 2009; Mansour et al. 2009). Given the many administration alternatives, nanomedicine has just begun to scratch the surface of potential applications.

To realize these ambitious goals, considerable efforts from engineers, chemists, material scientists, biologists, pharmacologists, physicians, entrepreneurs, and regulators will be required to converge on a similar set of objectives. Indeed, a widespread call to unify these disciplines and rise to the challenge is under way.

Technical Challenges in Nanomaterials

SNA nanostructures and those fabricated via PRINT are engineered structures that can be made with a high level of control in a well-defined manner. For this and many other reasons, both technologies have advanced quickly from promising benchtop research to drivers of new and exciting areas in the medical field.

But the nanomedicine development road is not paved solely with success stories. As in other fields, many advances showed early signs of success but, in the long run, met major impediments. For example, early attempts to use cadmium-based quantum dots and fullerenes in biological systems were derailed, in part because of concerns regarding toxicity. Lipoplexes are another important class of nanomaterials that show promise for drug delivery applications, especially with respect to gene regulation therapies. But the utility of such materials thus far has been severely limited, in part because of poor biodistribution profiles, and so they have been restricted to a relatively narrow set of diseases.

A primary limitation in this field has been the inability to engineer nanomaterials in such a way that one can control properties, dispersion, and manufacturability. Too many nanomaterial systems studied in the context of biology and medicine suffer from major challenges to polydispersity and scale-up and the inability to engineer them so that they can reproducibly offer advantages over conventional molecule-based approaches.

Although one can easily synthesize kilogram quantities of a single molecule where every molecule is identical, in most traditional cases of nanoparticle fabrication it is impossible to make large quantities where any two particles are identical. For instance, in the late 1980s and early 1990s, the discovery of new carbon nanostructures, with their incredible physical, chemical, electrical, and optical properties, led many researchers to project revolutionary advances for entire industries, including aspects of medicine. Carbon nanotube (CNT) technologies promised advances when used as inert drug delivery vehicles, contrast agents, and heat sources for photothermal treatments. However, in practice, synthesis and fabrication challenges made it difficult to create monodisperse samples of uniform length and structure, and heavy metal impurities and irregularities in tube structure were linked to toxicity (Lacerda et al. 2006).

At present, there are no CNT-based therapies or diagnostic tools approved or cleared for in vivo medical use and their application in these settings remains controversial. But one CNT-based technology has made progress that is worth noting: an x-ray emission source has advanced to clinical trials for enhanced imaging. It has achieved such success because of the ability to engineer and manufacture macroscopic arrays of CNTs, illustrating our premise that technical success will depend on the ability to address fabrication challenges.

Economic and Other Challenges

Although engineering approaches to scientific study are guiding nanotechnology toward success, future breakthrough materials and enabling tools will still face significant hurdles to their implementation.

Considerable economic obstacles must be overcome. The successful commercialization of a nanomedicine-based therapy requires substantial financial resources, and securing such funding, particularly in the United States, is daunting. The United States is poorly organized in comparison to several countries in Asia in this regard, including China, Singapore, and South Korea, which are investing heavily in science and, in particular, nanotechnology (Bai 2005).

Furthermore, large pharmaceutical companies have been slow to embrace nanotechnology-based products and have left many of the initial studies to startup companies. Taking on such studies burdens these fledgling companies and saddles them with a large amount of risk.

Another very different obstacle involves the general public’s perception of nanotechnology (Scheufele et al. 2008). In general, scientists and engineers, including those in nanomedicine, have failed to accurately and successfully communicate results to a lay audience and to follow through on promised potential technological outcomes.

These obstacles should not be alarming, but rather a call to action. As future efforts converge on solid clinical goals and progress accelerates, nanomedicine as a field would be smart to lead the charge toward improving public communication and accessibility by making better use of abundant media resources. Furthermore, a sustained commitment from federal agencies must accompany nanomedicine development to further grow this new sector of the economy.

Outlook

The fusion of design approaches inherent to engineering with advances in nanotechnology has led to fundamental learning and the development of new technologies that extend well beyond the examples discussed here. Early successes and failures reveal a recurring theme: nanomedicine successes exist only with significant engineering influence intrinsically tied to manufacturability. Universal acknowledgment of this concept will further solidify the relationship between these two fields, and the marriage of engineering and medicine through nanotechnology will continue to strengthen and inspire advances (Sharp and Langer 2011). The field is still young, but the promise of multifunctional “smart” nanotechnologies remains bright.

Nanotechnology will continue to create bridges between the engineering and medical fields for years to come, and new breakthrough nanomaterials and enabling tools will be the result of such collaborations. With each new success, we envision that the link between these fields will become stronger and more enduring.

References

Araújo J, Elisabet G, Egea MA, Garcia ML, Souto EB. 2009. Nanomedicines for ocular NSAIDs: Safety on drug delivery. Nanomedicine: Nanotechnology, Biology, and Medicine 5:394–401.

Bai C. 2005. Ascent of nanoscience in China. Science 309:61–63.

Choi CH, Hao L, Narayan SP, Auyeung E, Mirkin CA. 2013. Mechanism for the endocytosis of spherical nucleic acid nanoparticle conjugates. Proceedings of the National Academy of Sciences U S A 110(19):7625–7630.

Cutler JI, Auyeung E, Mirkin CA. 2012. Spherical nucleic acids. Journal of the American Chemical Society 134(3):1376–1391.

Etheridge ML, Campbell SA, Erdman AG, Haynes CL, Wolf SM, McCullough J. 2013. The big picture on nanomedicine: The state of investigational and approved nanomedicine products. Nanomedicine 9(1):1–14.

Garcia A, Mack P, Williams S, Fromen CA, Shen TW, Tully J, Pillai P, Kuehl P, Napier ME, DeSimone JM, Maynor BW. 2012. Microfabricated engineered particle systems for respiratory drug delivery and other pharmaceutical applications. Journal of Drug Delivery 2012: 941243.

Lacerda L, Bianco A, Prato M, Kostarelos K. 2006. Carbon nanotubes as nanomedicines: From toxicology to pharmacology. Advanced Drug Delivery Reviews 58(14):1460–1470.

Mansour HM, Rhee Y, Wu X. 2009. Nanomedicine in pulmonary delivery. International Journal of Nanomedicine 4:299–319.

Morton SW, Herlihy KP, Shopsowitz KE, Deng ZJ, Chu KS, Bowerman CJ, DeSimone JM, Hammond PT. 2013. Scalable manufacture of built-to-order nanomedicine: Spray-assisted layer-by-layer functionalization of PRINT nanoparticles. Advanced Materials, in press; doi: 10.1002/adma.201302025.

Rolland JP, Maynor BW, Euliss LE, Exner AE, Denison GM, DeSimone JM. 2005. Direct fabrication and harvesting of monodisperse shape-specific nanobiomaterials. Journal of the American Chemical Society 127(28):10097–10100.

Rosi NL, Mirkin CA. 2005. Nanostructures in biodiagnostics. Chemical Reviews 105(4):1547–1562.

Scheufele DA, Corley EA, Shih T, Kajsa D, Ho SS. 2008. Religious beliefs and public attitudes towards nanotechnology in Europe and the United States. Nature Nanotechnology 4:91–94.

Seferos DS, Giljohann DA, Hill HD, Prigodich AE, Mirkin CA. 2007. Nano-flares: Probes for transfection and mRNA detection in living cells. Journal of the American Chemical Society 129(50):15477–15479.

Sharp PA, Langer R. 2011. Promoting convergence in biomedical science. Science 333(6042):527.

Watson JD, Crick FHC. 1953. A structure for deoxyribose nucleic acid. Nature 171:737–738.

Categorized Resources and Citations

This list complements the events illustrated in Figure 1.

Enabling Tools

Scanning Tunneling Microscopy (STM)

Key publication: Binnig G, Rohrer H, Gerber C, Weibel E. 1982. Tunneling through a controllable vacuum gap. Applied Physics Letters 40(2):178–180.

1986 Nobel Prize awarded to Binnig and Rohrer.

Image available online at http://en.wikipedia.org/wiki/Image:Atomic_resolution_Au100. JPG.

Atomic Force Microscopy (AFM)

Key publication: Binnig G, Quate CF. 1986. Atomic force microscope. Physical Review Letters 56(9):930–933.

1988 Park Scientific Instruments (now Park Systems) founded; 1989 first AFM commercially available.

Image available online at www.xintek.com/images/afm_2.jpg.

Cell Sorting

1989 Miltenyi Biotec founded to commercialize micro and nano magnetic beads.

1974 First fluorescent-activated sorting (FACS) developed.

Image available online at www.abcam.com/ps/CMS/Images/FACS live cells1.jpg.

Cell Differentiation

Key publication: Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR. 1999. Multilineage potential of adult human mesenchymal stem cells. Science 284(5411):143–147.

Image available online at www.systembio.com/images/graphic_diffReport1.gif.

Dip Pen Nanolithography/Molecular Printing

Key publication: Piner RD, Zhu J, Xu F, Hong S, Mirkin CA. 1999. “Dip-pen” nanolithography. Science 283(5402):661–663.

Review: Senaratne W, Andruzzi L, Ober CK. 2005. Self-assembled monolayers and polymer brushes in biotechnology: Current applications and future perspectives. Biomacromolecules 6(5):2427–2448.

 2002 NanoInk Inc. founded.

Images available online at www.nanoink.com.

Imprinting (PRINT)

Key publication: Rolland JP, Maynor BW, Euliss LE, Exner AE, Denison GM, DeSimone JM. 2005. Direct fabrication and harvesting of monodisperse shape-specific nanobiomaterials. Journal of the American Chemical Society 127(28):10097–10100.

Review: Perry JL, Herlihy KP, Napier ME, DeSimone JM. 2011. PRINT: A novel platform toward shape and size specific nanoparticle theranostics. Accounts of Chemical Research 44:990–998.

2004 Liquidia Technologies Founded.

Images available online at www.liquidia.com.

Nano-Flares

Key publication: Seferos DS, Gilohann DA, Hill HD, Prigodich AE, Mirkin CA. 2007. Nano-flares: Probes for transfection and mRNA detection in living cells. Journal of the American Chemical Society 129(50):15477–15479.

Image reproduced with permission from Seferos et al. (2007). Additional images available online at www.millipore.com.

High-throughput Biochemical Assays

Reviews:

Cunningham BT, Laing LG. 2008. Advantages and application of label-free detetection assays in drug screening. Expert Opinion on Drug Discovery 3(8):891–901.

Fang Y. 2006. Label-free cell-based assays with optical biosensors in drug discovery. Assay and Drug Development Technologies 4(5):583–595.

2011 SAMDI Tech, Inc. founded.

Images available online at www.samdi.com.

Representative Nanostructures

Colloidal Gold

Key publication: Faraday M. 1857. The Bakerian Lecture: Experimental relations of gold (and other metals) to light. Philosophical Transactions of the Royal Society of London 147:145–181.

Image available online at www.rsc.org/ej/FD/2008/b800086g/b800086g-f6.gif.

Quantum Dots

Key publication: Ekimov AI, Onushchenko AA. 1981. Quantum size effects in three-dimensional microscopic semiconductor crystals. Journal of Experimental and Theoretical Physics Letters 34(6):345–349.

Review: Bruchez M Jr, Moronne M, Gin P, Weiss S, Alivisatos AP. 1998. Semiconductor nanocrystals as fluorescent biological labels. Science 281(5385):2013–2016.

Image available online at www.kurzweilai.net/images/Quantum_dots_glowing.jpg.

Fullerenes

Key publication: Kroto HW, Heath JR, O’Brien SC, Curl RF, Smalley RE. 1985. C60: Buckminsterfullerene. Nature 318(14):162–163.

Image available online at http://nanotechnologyuniverse.com/wp-content/uploads/2011/ 10/buckyball.jpg.

Carbon Nanotubes

Key publication: Iijama S. 1991. Helical microtubules of graphitic carbon. Nature 354(6348):56–58.

Review: Lacerda L, Bianco A, Prato M, Kostarelos K. 2006. Carbon nanotubes as nanomedicines: From toxicology to pharmacology. Advanced Drug Delivery Reviews 58(14):1460–1470.

Image available online at www.physics.ox.ac.uk/nanotech/research/nanotubes/nanotube. jpg.

Breakthrough Materials

SNAs

Key publication: Mirkin CA, Letsinger RL, Mucic RC, Storhoff JJ. 1996. A DNA-based method for rationally assembling nanoparticles in macroscopic materials. Nature 382:607–609.

Review: Cutler JI, Auyeung E, Mirkin CA. 2012. Spherical nucleic acids. Journal of the American Chemical Society 134(3):1376–1391.

2000 Nanosphere founded; 2009 AuraSense; 2011 AuraSense Therapeutics.

Image reprinted with permission from Cutler et al. (2012). Additional images available online at www.nanosphere.us and www.aurasensetherapeutics.com.

Quantum Dot Bioconjugates

1998 Quantum Dot Corporation founded; 2002 Qdots commercially available; 2005 Life Technologies acquires Qdot technology.

Reference available online at www.lbl.gov/tt/success_stories/articles/quantumdots.html.

Images available online at www.invitrogen.com/.

Nanoshells

2002 Nanospectra Biosciences, Inc. founded.

Review: Lai S, Clare SE, Halas NJ. 2008. Nanoshell-enabled photothermal cancer therapy: Impending clinical impact. Accounts of Chemical Research 41(12):1842–1851.

Images available online at www.ahc.umn.edu/consortlv/AR11/img/silica-particles.jpg and www.nanospectra.com/.

RNA Particles

2008 First clinical trials by Calando Pharmaceuticals.

Reviews:

Davis ME, Chen Z. 2008. Nanoparticle therapeutics: An emerging treatment modality for cancer. Nature Reviews 7:771–782.

Davis ME. 2009. The first targeted delivery of siRNA in humans via a self-assembling cyclodexterin polymer-based nanoparticle: From concept to clinic. Molecular Pharmaceutics 6(3):659–668.

2005 Calando Pharmaceuticals founded (now a majority-owned subsidiary of Arrowhead Research Corporation); 2006 Cerulean Pharmaceuticals founded.

Image reprinted with permission from Davis (2009). Additional images available online at www.calandopharma.com and ceruleanrx.com.

Polymeric Particles

Reviews:

Torchillin VP. 2006. Multifunctional nanocarriers. Advanced Drug Delivery Reviews 58(14):1532–1555.

Pridgen EM, Langer R, Farokhzad OC. 2007. Biodegradable, polymeric nanoparticle delivery systems for cancer therapy. Nanomedicine 2(5):669–680.

1995 Doxil® first nanodrug approved by FDA.

2007 Bind Therapeutics founded.

Images available online at www.bindtherapeutics.com.

Metallic Particles

Review: Seil JT, Webster TJ. 2012. Antimicrobial applications of nanotechnology: Methods and literature. International Journal of Nanomedicine 7:2767–2781.

2008 I-Flow Corp. acquires AcryMed (2004 SilvaGard™ product developed).

2001 NUCRYST Pharmaceuticals and Smith & Nephew develop Acticoat™ (1998 SILCRYST™ developed).

2006 T2 Biosystems, Inc. founded; 1997 MagForce AG founded.

Images available online at www.acrymed.com/medical.html and www.t2biosystems.com.

FOOTNOTES

 1 Joe DeSimone is the founder of Liquidia Technologies and scientific advisor on the company’s management team.

About the Author:Sarah Hurst Petrosko is a research assistant professor in the Department of Chemistry and International Institute for Nanotechnology at Northwestern University. Catherine A. Fromen is a graduate student in the Department of Chemical and Biomolecular Engineering at North Carolina State University. Evelyn Auyeung is a graduate student in the Department of Materials Science and Engineering at Northwestern University. Joseph M. DeSimone (NAS/NAE) is William R. Kenan Jr. Distinguished Professor in the Department of Chemical and Biomolecular Engineering at North Carolina State University; and Chancellor’s Eminent Professor in the Department of Chemistry and Director of the Frank Hawkins Kenan Institute of Private Enterprise at the University of North Carolina at Chapel Hill. Chad A. Mirkin (NAS/NAE/IOM) is director of the International Institute for Nanotechnology (IIN), George B. Rathmann Professor of Chemistry, and professor of chemical & biological engineering, biomedical engineering, mat