Nanomedicine has the potential to transform clinical care in the 21(st) century. However, a precise understanding of how nanomaterial design parameters such as size, shape and composition affect the mammalian immune system is a prerequisite for the realization of nanomedicine's translational promise. Herein, we make use of the recently developed Particle Replication in Non-wetting Template (PRINT) fabrication process to precisely fabricate particles across and the nano- and micro-scale with defined shapes and compositions to address the role of particle design parameters on the murine innate immune response in both in vitro and in vivo settings. We find that particles composed of either the biodegradable polymer poly(lactic-co-glycolic acid) (PLGA) or the biocompatible polymer polyethylene glycol (PEG) do not cause release of pro-inflammatory cytokines nor inflammasome activation in bone marrow-derived macrophages. When instilled into the lungs of mice, particle composition and size can augment the number and type of innate immune cells recruited to the lungs without triggering inflammatory responses as assayed by cytokine release and histopathology. Smaller particles (80×320 nm) are more readily taken up in vivo by monocytes and macrophages than larger particles (6 µm diameter), yet particles of all tested sizes remained in the lungs for up to 7 days without clearance or triggering of host immunity. These results suggest rational design of nanoparticle physical parameters can be used for sustained and localized delivery of therapeutics to the lungs.

The particle fabrication technique PRINT® was used to fabricate monodisperse size and shape specific poly(lactide-co-glycolide) particles loaded with the chemotherapeutic Docetaxel. The pharmacokinetics of two cylindrical shaped particles with diameter=80nm; height=320nm (PRINT-Doc-80×320) and d=200nm; h=200nm (PRINT-Doc-200×200) were compared to Docetaxel in mice bearing human ovarian carcinoma SKOV-3 flank xenografts. The Docetaxel plasma exposure was ~20-fold higher for both particles compared to docetaxel. Additionally, the volume of distribution (Vd) of Docetaxel in PRINT formulations was ~18-fold (PRINT-Doc-80×320) and ~33-fold (PRINT-Doc-200×200) lower than Docetaxel. The prolonged duration of Docetaxel in plasma when dosed with PRINT formulations subsequently led to increased tumor exposure of Docetaxel from 0 to 168h (~53% higher for PRINT-Doc-80×320 and ~76% higher for PRINT-Doc-200×200 particles). PRINT-Doc-80×320 had lower exposures in the liver, spleen and lung compared with PRINT-Doc-200×200. Thus, the use of particles with smaller feature size may be preferred to decrease clearance by organs of the mononuclear phagocyte system. FROM THE CLINICAL EDITOR:In this study, the plasma, tumor, and tissue pharmacokinetics of different Docetaxel nanoparticles of precise shape and size were characterized in mice with human ovarian carcinoma xenograft. It is concluded that the use of particles with smaller feature size may be preferred to decrease clearance by organs of the mononuclear phagocyte system.

Nanotechnology can provide a critical advantage in developing strategies for cancer management and treatment by helping to improve the safety and efficacy of novel therapeutic delivery vehicles. This paper reports the fabrication of poly(lactic acid-co-glycolic acid)/siRNA nanoparticles coated with lipids for use as prostate cancer therapeutics made via a unique soft lithography particle molding process called Particle Replication In Nonwetting Templates (PRINT). The PRINT process enables high encapsulation efficiency of siRNA into neutral and monodisperse PLGA particles (32-46% encapsulation efficiency). Lipid-coated PLGA/siRNA PRINT particles were used to deliver therapeutic siRNA in vitro to knockdown genes relevant to prostate cancer.

A three-channel spectrometer (3CS) based on a commercial digital camera was developed to distinguish among tens of large (>100 nm), anisotropic plasmonic particles with various shapes, orientations, and compositions on a surface simultaneously. Using band pass filters and polarizers, the contrast of 3CS images could be enhanced to identify specific orientation and composition characteristics of gold and gold-silver nanopyramids and as well as the direction of the longest arm of gold nanostars.

Small structural changes in the shape of nanostructures have profound effects on their optical properties. As the tip of Au nanopyramidal shells is removed, the complex plasmon modes shifted to lower wavelengths.

This Letter describes how gold pyramidal nanoshells (nanopyramids) can be assembled into low- and high-order structures by varying the rate of solvent evaporation and surface wettability. Single-particle and individual-cluster dark field scattering spectra on isolated, dimers and trimers of nanopyramids were compared. We found that the short wavelength resonances blue-shifted as the particles assembled; the magnitude of this shift was greater for high-order structures. To test which assembled architecture supported a larger Raman-active volume, we compared their surface enhanced Raman scattering (SERS) response of the resonant Raman molecule methylene blue (λ(ex) = 633 nm). We discovered that high-order structures exhibited more Raman scattering compared to low-order assemblies. Finite-difference time-domain modeling of nanopyramid assemblies revealed that the highest electromagnetic field intensities were localized between adjacent particle faces, a result that was consistent with the SERS observations. Thus, the local spatial arrangement of the same number of nanoparticles in assembled clusters is an important design parameter for optimizing nanoparticle-based SERS sensors.

This paper describes the fabrication and characterization of nested Au pyramidal nanoshells. These particles exhibited two plasmon resonances at visible and near-infrared wavelengths that could be manipulated depending on the size of the gap between inner and outer pyramidal shells. We found that larger gaps (30 nm) exhibited much larger Raman scattering responses compared to smaller gaps (5 nm) in the nested pyramidal shells. The SERS-activity of these anisotropic particles can be optimized by adjusting the distances between the inner and outer Au shells.

This review focuses on nanofabrication tools, based on soft lithography, which can generate a wide range of noble-metal structures with exceptional optical properties. These techniques offer a scalable and practical approach for producing arrays of complementary plasmonic structures (nanoholes and nanoparticles) and, in addition, expand the possible architectures of plasmonic materials because the metal building blocks can be organized over multiple length scales. We describe the preparation and characterization of five different systems: subwavelength nanohole arrays, finite arrays of nanoholes, microscale arrays of nanoholes, multiscale arrays of nanoparticles, and pyramidal particles. We also discuss how the surface plasmon resonances of these structures can be tuned across visible and near-infrared wavelengths by varying different parameters. Applications and future prospects of these nanostructured metals are addressed.

This paper describes an approach to fabricate anisotropic core-shell particles by assembling dielectric beads within fabricated noble metal pyramidal structures. Particles with gold (Au) shells and different dielectric cores were generated, and their optical properties were characterized by single particle spectroscopy. Because of their unique geometry, these particles exhibit multiple plasmon resonances from visible to near-IR wavelengths.

This paper investigates how structural features of noble metal nanoparticles affect their photothermal properties. Using PEEL, we fabricated a range of Au nanopyramid-like particles with surface plasmon resonances tunable from visible to near-infrared wavelengths. By systematically varying geometric parameters including size, shell thickness, and presence or absence of tips, we determined which factors were most important in heat generation. For solutions with the same Au content, we discovered that pyramidal particles with thin shells and having sharp tips showed the largest photothermal response.

This paper describes three ways to tune the multipolar surface plasmon resonances of Au pyramidal particles: (1) by varying their thickness; (2) by controlling their relative orientation on a surface; and (3) by changing the refractive index of the surrounding media. We found that as the index of the medium was increased that the plasmon resonances red-shifted linearly from visible to near-infrared wavelengths. By screening the different geometric parameters, we found that 25-nm thick pyramids in a tip-up orientation produced the largest refractive index sensitivities.

This review focuses on nanofabrication tools, based on soft lithography, which can generate a wide range of noble-metal structures with exceptional optical properties. These techniques offer a scalable and practical approach for producing arrays of complementary plasmonic structures (nanoholes and nanoparticles) and, in addition, expand the possible architectures of plasmonic materials because the metal building blocks can be organized over multiple length scales. We describe the preparation and characterization of five different systems: subwavelength nanohole arrays, finite arrays of nanoholes, microscale arrays of nanoholes, multiscale arrays of nanoparticles, and pyramidal particles. We also discuss how the surface plasmon resonances of these structures can be tuned across visible and near-infrared wavelengths by varying different parameters. Applications and future prospects of these nanostructured metals are addressed.

This Account explores nanofabricated pyramids, a new class of nanoparticles with tunable optical properties at visible and near-infrared wavelengths. This system is ideally suited for designing multifunctional plasmonic materials for use in diagnostics, imaging, sensing, and therapeutics. The nanofabrication scheme that we developed (called PEEL) for these asymmetric metal particles is extremely versatile and offers several advantages over synthetic methodologies. The PEEL approach yields pyramids with variable sizes, thicknesses, and multimetal compositions, as well as blunt or ultrasharp tips or no tips. In addition, we have prepared pyramids with site-specific chemical and biological functionality on different portions of the pyramids. This is an important design feature for biological applications, as suggested by the generation of amphiphilic gold pyramids functionalized with alkanethiols on the hydrophobic portions and DNA on the hydrophilic portions. The optical characteristics of these pyramids depend on particle orientation, wavevector direction, and polarization direction and can be tuned. Using the multipolar surface plasmon resonances of large (>250 nm) pyramids, imaging and spectral identification of pyramid orientation in condensed media was possible. We were also able to direct pyramids to assemble into one- and two-dimensional arrays with interesting optical properties. Furthermore, modification of the PEEL fabrication scheme allowed the production of multimaterial pyramidal structures with complex attributes, highlighting the power of this platform for exacting nanometer-scale control over particle structure and composition.

[GRAPHICS]Multifunctional Nanoparticles: A facile approach to create multi-functional nanopyramids has been demonstrated. The surfaces of bi-material Au/Ni nanopyramids were differentially modified with chemical and biological moieties. Dye-labeled nanopyramids were used as probes for dual-mode optical imaging (scattering and fluorescence). Under a magnetic field, these multi-functional Au/Ni NPs also assembled into 1D chains that exhibited polarization-dependent optical properties.