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Review
. 2011 Oct 18;44(10):990-8.
doi: 10.1021/ar2000315. Epub 2011 Aug 2.

PRINT: a novel platform toward shape and size specific nanoparticle theranostics

Jillian L Perry  1 , Kevin P Herlihy, Mary E Napier, Joseph M Desimone
Affiliations
Review

PRINT: a novel platform toward shape and size specific nanoparticle theranostics

Jillian L Perry et al. Acc Chem Res. .

Abstract

Nanotheranostics represents the next generation of medicine, fusing nanotechnology, therapeutics, and diagnostics. By integrating therapeutic and imaging agents into one nanoparticle, this new treatment strategy has the potential not only to detect and diagnose disease but also to treat and monitor the therapeutic response. This capability could have a profound impact in both the research setting as well as in a clinical setting. In the research setting, such a capability will allow research scientists to rapidly assess the performance of new therapeutics in an effort to iterate their designs for increased therapeutic index and efficacy. In the clinical setting, theranostics offers the ability to determine whether patients enrolling in clinical trials are responding, or are expected to respond, to a given therapy based on the hypothesis associated with the biological mechanisms being tested. If not, patients can be more quickly removed from the clinical trial and shifted to other therapeutic options. To be effective, these theranostic agents must be highly site specific. Optimally, they will carry relevant cargo, demonstrate controlled release of that cargo, and include imaging probes with a high signal-to-noise ratio. There are many biological barriers in the human body that challenge the efficacy of nanoparticle delivery vehicles. These barriers include, but are not limited to, the walls of blood vessels, the physical entrapment of particles in organs, and the removal of particles by phagocytic cells. The rapid clearance of circulating particles during systemic delivery is a major challenge; current research seeks to define key design parameters that govern the performance of nanocarriers, such as size, surface chemistry, elasticity, and shape. The effect of particle size and surface chemistry on in vivo biodistribution of nanocarriers has been extensively studied, and general guidelines have been established. Recently it has been documented that shape and elasticity can have a profound effect on the behavior of delivery vehicles. Thus, having the ability to independently control shape, size, matrix, surface chemistry, and modulus is crucial for designing successful delivery agents. In this Account, we describe the use of particle replication in nonwetting templates (PRINT) to fabricate shape- and size-specific microparticles and nanoparticles. A particular strength of the PRINT method is that it affords precise control over shape, size, surface chemistry, and modulus. We have demonstrated the loading of PRINT particles with chemotherapeutics, magnetic resonance contrast agents, and fluorophores. The surface properties of the PRINT particles can be easily modified with "stealth" poly(ethylene glycol) chains to increase blood circulation time, with targeting moieties for targeted delivery or with radiolabels for nuclear imaging. These particles have tremendous potential for applications in nanomedicine and diagnostics.

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Figures

FIGURE 1
FIGURE 1
Schematic illustration of the PRINT process. (A) Delivery sheet casting: A true solution (red) is made and then cast on a PET substrate using a mayer rod. Solvent is removed under heat, generating a solid state solution film referred to as the delivery sheet, as it will deliver the composition to the mold. (B) Particle fabrication: a perfluoropolyether elastomeric mold (green) is brought into contact with a delivery sheet (red), passed through a heated nip (gray), and split. The cavities of the mold are filled. (C) Particle harvesting: a filled mold is brought into contact with a high energy film or excipient layer (yellow) and passed through the heated nip without splitting. After cooling, the mold is removed to reveal an array of particles on the high-energy film or excipient layer. Reprinted with permission from ref . Copyright 2011 American Chemical Society.
FIGURE 2
FIGURE 2
Scanning electron micrograph images of particles fabricated using the PRINT method: (A) degradable 2 μm cubic particles; (B) 10 μm magnetic hydrogel boomerangs; (C) 3 μm hydrogel toroids; (D) 100 × 300 nm hydrogel rods; (E) 200 nm cylindrical hydrogel particles; (F) 80 × 2000 nm filamentous hydrogel particles. Image (A) is reprinted with permission from ref , and Image (C) is reprinted with permission from ref . Copyright American Chemical Society 2008 and 2009. Image (E) is reprinted with permission from ref . Copyright 2007 Elsevier.
FIGURE 3
FIGURE 3
Scanning electron micrographs of PLGA PRINT particles: (A) 80 ×320 nm cylinders, (B) 200 ×200 nm cylinders, (C) 200 ×600 nm cylinders, (D) 1 μm sphere approximates, (E) 2 μm cubes with ridges, and (F) 3 μm particles with center fenestrations. Scale bars: (A) 5 μm, (B) 4 μm, (C) 3 μm, (D) 10 μm, (E) 3 μm, and (F) 20 μm. Reprinted with permission from ref . Copyright 2011 American Chemical Society.
FIGURE 4
FIGURE 4
Confocal laser scanning micrographs of HeLa cells incubated with rapidly degrading hexnut particles (green) and nondegrading hexnut particles (red). Micrographs (A–C) highlight the phases of particle degradation: swelling (a), fragmentation (b), and complete degradation (c). The nondegradable particles showed no change when exposed to intracellular conditions (d). Scale bar represents 10 μm for all images. Reprinted with permission from ref . Copyright 2010 American Chemical Society.
FIGURE 5
FIGURE 5
Confocal laser scanning microscopy micrographs of HeLa cells after a 1 h incubation period at 37 °C with (A) 3 μm cubic, (B) 2 m cubic, (C) 1 × 1 μm cylindrical, and (D) 200 × 200 nm cylindrical particles. Scale bar represents 10 μm in all images. Reprinted with permission from ref . Copyright 2008 National Academy of Science.
FIGURE 6
FIGURE 6
Transferrin receptor-targeted delivery of PRINT nanoparticles to various cancer and noncancer cell lines. (a) Cellular uptake and (b) cytotoxicity of particles. Reprinted with permission from ref . Copyright 2010 American Chemical Society.
FIGURE 7
FIGURE 7
(A) Fluorescence micrograph of RBC mimics and (B) intravital image of blue vasculature and red particles. Reprinted with permission from ref . Copyright 2011 National Academy of Science.
FIGURE 8
FIGURE 8
Biodistribution of RBCMs 2 h post dosing by percent recovered fluorescence normalized for tissue weight. Error bars represent one standard deviation, with n = 3 for each case. Reprinted with permission from ref . Copyright 2011 National Academy of Science.
FIGURE 9
FIGURE 9
Transmission electron microscopy images of PRINT particles (A) 80 × 320 nm and (B) 80 × 2000 nm containing iron oxide nanoparticles. Reprinted with permission from ref . Copyright 2010 American Chemical Society.
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