Molecularly Imprinted Polymers as Artificial Recognition and Drug Delivery Media

Molecular recognition and molecular encapsulation are nanoscale processes that offer great potential for applications as diverse as sensors, environmental remediation and targeted drug delivery. Biological receptors and natural materials such as liposomes offer excellent characteristics for such uses. However, these molecules are expensive, complex to produce and are sensitive to chemical and physical environments. Molecular imprinting produces molecule-specific cavities that mimic the behavior of, and may be substituted for, natural receptor binding sites or antibodies, without the temperature sensitivity and high cost of the natural systems.¹ Moreover, these artificial receptors may be synthesized for almost any target molecule.

While several alternative methods exist, the general concept for imprinting, via polymerization, is displayed in Figure 1. The template or target molecule is mixed with monomer. Through self-assembly, the template forms a complex with the functional groups of the monomer. The self-assembled structure is locked into place by polymerization with a crosslinking agent. After polymerization is complete, the template is extracted from the polymer and the molecularly imprinted polymer or MIP is ready for use. The MIP selectively rebinds the template molecule from solution or from the vapor phase.

Figure 1. The synthetic procedure for production of MIPs is shown. The template and monomer are mixed and a pre-polymerization complex is formed. Crosslinker and initiator are added and the complex is “locked” into the polymer. Finally, the template is removed and the MIP is ready for rebinding.

When coupled to a technique that reads out the presence of the analyte, MIPs provide a molecularly specific method of identifying a chemical agent. Molecularly imprinted polymers have been used as solid phase extraction adsorbents and as chromatographic (GC and HPLC) column materials for the separation and determination of a range of targets including environmental contaminants, pharmaceuticals, pesticides, chemical warfare materials and industrial waste streams. Drug detection and drug delivery are additional research fields in which MIPs may play a role.¹ Both larger biological molecules as such as proteins and smaller, commercial therapeutics have been targeted.

The formation of MIPs is often characterized by significant changes in polymer morphology, which are observed using microscopy techniques on the nanoscale.² Figure 2 presents atomic force microcopy (AFM) images of our unimprinted and glucose-imprinted polyvinylphenol polymers. Note that the pores created in the imprinted polymeric material are of the order of a few tens of nanometers.

The formation of the film is controlled by the relative phase separation of the template-polymer host complex from the other components, template-template and polymer-polymer, of the MIP solution. These are images of a thin film of the MIP, with a measured thickness of ~300nm.

Figure 2. AFM images of an unimprinted polyvinylphenol film (left) and a polyvinylphenol film imprinted with glucose (right).

MIPs are of interest as synthetically formed recognition and binding agents for a variety of sensing applications, which are the focus of our current research. As sensors, the key elements of MIPs are the density of active sites, their geometric accessibility governing sensor response speed, and the selectivity they exhibit for the analyte. Thin film materials rather than powders may be used to optimize the density and availability of receptor sites, as they are often formed under non-equilibrium conditions, and, when thin, minimize the diffusion distance necessary for the analyte to traverse during extraction and binding events.

Different sensing mechanisms are employed in various reported sensor devices. For example, Sadeghi³ developed a potentiometric sensor based on a polymer imprinted for the antibiotic levamisole hydrochloride, which was embedded in a polyvinylchloride membrane. The sensor, with a sensitivity in the µM range, a response time of less than 15s and a lifespan of four months, was highly selective to the antibiotic in either pure or tablet formulation. We have reported on a capacitive sensor targeted to solutions of amino acids and hosted in a Nylon-6 film, a true parallel-plate capacitive structure.⁴ Operated in an AC mode, these sensors exhibited significant shifts in the dissipation factor peaks, providing information on whether the target analyte was present in the sensor or had been removed. Moreover, the sensors built for a specific amino acid were insensitive to the adsorption of other, competing amino acids.

More recently, we have focused on chemiresistive sensors. The imprinted polymer solution is spin- or dip-coated onto a silicon chip upon which a set of interdigitated electrodes were lithographically produced. The polymer films are kept very thin, 100-300nm, so that the adsorption event is detected and reported via the change in the conductivity of the device. An important application of this technology is the development of a sensing film to detect the presence of secondhand cigarette smoke by specifically adsorbing nicotine in the ambient air.⁵ This device relies on a conductive polymer film, polyaniline, as the reporting agent. A typical response to the presence of secondhand smoke from a single cigarette is shown in Figure 3. The increase in resistance is immediate and the decease from the maximum occurs as the cigarette is extinguished. Incorporation of such a film in a personal sensor will provide the means to notify those most sensitive to the components of smoldering tobacco that they must take precautions.

Figure 3. The response of a polyaniline-based sensor to secondhand cigarette smoke via the detection of nicotine.

A similar device, employing a different adsorbent layer, but also using polyaniline as the reporting element, has been developed to specifically detect the presence of gaseous formaldehyde at sub-ppm levels.⁶ Again providing a means to ensure the safety of those who might be adversely impacted by exposure.

Both of the resistance-based sensors described above rely on polyaniline as the conductive element. This is a restrictive situation, since the change in conductivity requires that the analyte abstract a proton from the doped polymer. We have developed a more general approach in which the conductive element is single walled carbon nanotubes.⁷ Typically, a fraction of carbon nanotubes have metallic properties and these tubes serve as the reporting agent for adsorption. The MIP is coated onto the nanotubes, which are then deposited across the electrodes. This is a general technique, and while we expect to find numerous uses for the technology, one specific application we have reported is testing for the presence of cotinine in urine. Cotinine is the major metabolite of nicotine and a more sensitive test is required in order to assess exposure to secondhand cigarette smoke in individuals.

References

1. J.J. BelBruno, “Molecularly Imprinted Polymers: Artificial receptors with wide-ranging applications”, Micro and Nanosystems, 1, 163 (2009).
2. S.E. Campbell, M. Collins, L. Xie and J.J. BelBruno “Surface morphology of spin- coated molecularly imprinted polymer films”, Surface and Interface Analysis 41, 347 (2009).
3. S. Sadeghi, F. Fathi and J. Abbasifar, “Potentiometric sensing of levamisole hydrochloride based on molecularly imprinted polymer”, Sensors and Actuators B 122, 158 (2007).
4. J.J. BelBruno, G. Zhang and U.J. Gibson, “Capacitive sensing of amino acids in molecularly imprinted nylon films”, Sensors and Actuators B 155, 915 (2011).
5. Y. Liu, A. Antwi-Boampong, S.E. Tanski, M. Crane and J.J. BelBruno, “Detection of secondhand cigarette smoke via nicotine using conductive polymer films”, Science (submitted, Sept. 2012).
6. S. Antwi-Boampong and J.J. BelBruno, “Detection of formaldehyde vapor using conductive polymer films”, Sensors and Actuators B, (submitted, Aug. 2012).
7. S.W.R. Dunbar and J.J. BelBruno, “Molecularly imprinted polymer-carbon nanotube sensor targeted to cotinine”, Chemical Sensors, in press (2012).

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