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Template synthesis of test tube nanoparticles using nondestructive replication


Nanoparticles have gained a great deal of attention as delivery vehicles for therapeutics including small drug molecules, peptides, DNA, proteins, and enzymes. One promising type of nanoparticle under development for delivery of therapeutics is the nano test tube. Nano test tubes have high surface areas and the ability to protect cargo from the environment by sequestering it within the tube. The presence of a single small opening at the end of elongated nano test tubes provides an opportunity for controlling diffusion of molecules into and out of the tubes. This makes nano test tubes a particularly attractive platform for enzyme immobilization since enzymes inside a nano test tube might be protected from the environment while still allowing diffusion of enzymatic substrates and products.

This concept of a “bionanoreactor” has proven effective for the protection of enzymes inside spherical particles as well as tubes in a two dimensional array. Free floating nanotest tubes should provide similar protection for enzymes, but facile synthesis of nano test tube particles remains a challenge. Template-based synthesis methods have been devised using porous alumina templates (AAO) for test tube manufacture. AAO templates allow nm-scale control over pore diameter and length and thus over the dimensions of the tube. This is important since size is a critical parameter for nanoparticle behavior in the circulation. Particles between 10 nm and 200 nm in diameter are considered preferable for long-circulating particles. The elongated shape of the tubes insures they will have high surface area and tunable cell uptake dynamics. Template synthesis also allows for tubes with disparate chemical functionalization on the inner and outer surfaces. For example, protein conjugation can be targeted within the core, and the outer surface can be PEGylated to improve stability or inertness to immune response.

Many different core-shell compositions are possible for template synthesized tubes including a wide variety of metals and biodegradable polymers. Although template synthesis allows considerable control over nano tube parameters, current methods are limited in scale up for high volume manufacturing. Porous alumina templates of suitably uniform pore size and appropriate length are not commercially available. Synthesizing the templates is laborious and includes depositing thick layers of metal followed by long anodization in acid. Once the desired materials are infiltrated, the alumina template is dissolved with strong etchants, which are incompatible with many desired tube materials. Destroying the template means re-making a new template for every batch of tubes. The template synthesis method is essentially a 2-dimensional synthesis, requiring large amounts of surface area (~20 m2) to produce gr. quantities. Therefore, the resources and labor that would be required to manufacture therapeutic quantities of nano test tubes is prohibitive. In order to manufacture enough nano tubes to be therapeutically useful, it is necessary to find more efficient methods of nanotubule synthesis.

IGERT student, Jonathan Wagner used the application of nondestructive template replication to quickly and easily synthesize test tube shaped nanoparticles (See Figure). In this new approach, the pores of a hard template are used to produce pillar like structures in a polymer material, which can subsequently be coated to make the nano tubes without alteration of the original template. These nanoparticles provide a customizable platform for drug delivery that can be manufactured in volumes sufficient for therapeutic use.

Address Goals

Nano test tubes are a promising delivery vehicle for a range of therapeutics including small molecule drugs and biologics. However, current template synthesis methods of producing nano test tubes are prohibitively expensive and time consuming. In this study non-destructive template replication was used to increase nano test tube yield from porous alumina by more than a hundredfold. These nano test tubes should find application as delivery vehicles for therapeutics, particularly for processive “bionanoreactors” loaded with enzymes.