Sangho Cho

Copper‐64‐Alloyed Gold Nanoparticles for Cancer Imaging: Improved Radiolabel Stability and Diagnostic Accuracy

Gold nanoparticles, especially positron-emitter- labeled gold nanostructures, have gained steadily increasing attention in biomedical applications. Of the radionuclides used for nanoparticle positron emission tomography imaging, radiometals such as (64) Cu have been widely employed. Currently, radiolabeling through macrocyclic chelators is the most commonly used strategy. However, the radiolabel stability may be a limiting factor for further translational research. We report the integration of (64) Cu into the structures of gold nanoparticles. With this approach, the specific radioactivity of the alloyed gold nanoparticles could be freely and precisely controlled by the addition of the precursor (64) CuCl2 to afford sensitive detection. The direct incorporation of (64) Cu into the lattice of the gold nanoparticle structure ensured the radiolabel stability for accurate localization in vivo. The superior pharmacokinetic and positron emission tomography imaging capabilities demonstrate high passive tumor targeting and contrast ratios in a mouse breast cancer model, as well as the great potential of this unique alloyed nanostructure for preclinical and translational imaging.

Nanoscopic Cylindrical Dual Concentric and Lengthwise Block Brush Terpolymers as Covalent Preassembled High-Resolution and High-Sensitivity Negative-Tone Photoresist Materials

We describe a high-resolution, high-sensitivity negative-tone photoresist technique that relies on bottom-up preassembly of differential polymer components within cylindrical polymer brush architectures that are designed to align vertically on a substrate and allow for top-down single-molecule line-width imaging. By applying cylindrical diblock brush terpolymers (DBTs) with a high degree of control over the synthetic chemistry, we achieved large areas of vertical alignment of the polymers within thin films without the need for supramolecular assembly processes, as required for linear block copolymer lithography. The specially designed chemical compositions and tuned concentric and lengthwise dimensions of the DBTs enabled high-sensitivity electron-beam lithography of patterns with widths of only a few DBTs (sub-30 nm line-width resolution). The high sensitivity of the brush polymer resists further facilitated the generation of latent images without postexposure baking, providing a practical approach for controlling acid reaction/diffusion processes in photolithography.

Directing Self-Assembly of Nanoscopic Cylindrical Diblock Brush Terpolymers into Films with Desired Spatial Orientations: Expansion of Chemical Composition Scope

Diblock brush terpolymers (DBTs) with different fluorinated methacrylate-based block segments are synthesized through sequential ring-opening metathesis polymerizations and are used to prepare polymer thin films with predictable film thicknesses. These DBTs exhibit preferable substrate vertical alignments within the films, induced by the relatively lower surface energy of the fluorinated structural components, together with the overall cylindrical morphology of the brush architecture.

Gold Nanoclusters Doped with 64Cu for CXCR4 Positron Emission Tomography Imaging of Breast Cancer and Metastasis

As an emerging class of nanomaterial, nanoclusters hold great potential for biomedical applications due to their unique sizes and related properties. Herein, we prepared a (64)Cu doped gold nanocluster ((64)CuAuNC, hydrodynamic size: 4.2 ± 0.5 nm) functionalized with AMD3100 (or Plerixafor) for targeted positron emission tomography (PET) imaging of CXCR4, an up-regulated receptor on primary tumor and lung metastasis in a mouse 4T1 orthotopic breast cancer model. The preparation of targeted (64)CuAuNCs-AMD3100 (4.5 ± 0.4 nm) was done via one-step reaction with controlled conjugation of AMD3100 and specific activity, as well as improved colloid stability. In vivo pharmacokinetic evaluation showed favorable organ distribution and significant renal and fecal clearance within 48 h post injection. The expression of CXCR4 in tumors and metastasis was characterized by immunohistochemistry, Western blot, and reverse transcription polymerase chain reaction analysis. PET imaging with (64)CuAuNCs-AMD3100 demonstrated sensitive and accurate detection of CXCR4 in engineered tumors expressing various levels of the receptor, while competitive receptor blocking studies confirmed targeting specificity of the nanoclusters. In contrast to nontargeted (64)CuAuNCs and (64)Cu-AMD3100 alone, the targeted (64)CuAuNCs-AMD3100 detected up-regulated CXCR4 in early stage tumors and premetastatic niche of lung earlier and with greater sensitivity. Taken together, we believe that (64)CuAuNCs-AMD3100 could serve as a useful platform for early and accurate detection of breast cancer and metastasis providing an essential tool to guide the treatment.

Aldehyde-functional polycarbonates as reactive platforms

Ozonolysis of allyl-functional polycarbonates provides aldehyde-functional polycarbonates that have potential to be reactive platforms for transformation into diverse active materials.

Bottom-up/top-down, high-resolution, high-throughput lithography using vertically assembled block bottle brush polymers

Abstract. We describe a novel deterministic bottom-up/top-down approach to sub-30-nm photolithography using a film composed of assembled block brush polymers of highly uniform composition and chain length. The polymer architecture consists of a rigid backbone of polymerized norbornene, each linked to flexible short side brush chains. The resultant bottle brush topology has a cylindrical shape with short brush chains arranged concentrically around the backbone, in which the cylinder radius is determined by the number of monomers within the brush fragment, while the cylinder length is determined by the degree of backbone polymerization. The modularity of the synthetic system allows a wide diversity of lithographically useful monomers, sequencing, dimension, and property variation. Sequential grafting of presynthesized blocks allows for facile formation of either concentric or lengthwise block copolymers. Placement of brush chains of different compositions along different regions of the cylinder, along with variation of the relative concentric and lengthwise dimensions, provides mechanisms to align and control placement of the cylinders. These polymers are compatible with photoacid generators and crosslinker functionality. Our results are consistent with a model that the bottle brush polymers assemble (bottom-up) in the film to yield a forest of vertically arranged cylindrical block brush polymers, with the film thickness determined by the coherence lengths of the cylinders. Subsequent imaging via electron beam (e-beam) or optical radiation yields a (top-down) mechanism for acid catalyzed crosslinking of adjacent cylinders. Uncrosslinked cylinders are removed in developer to yield negative photoresist patterns. Exposure doses are very low and throughputs are amenable to the requirements of extreme ultraviolet lithography. The limiting resolution with e-beam exposure is potentially about two cylinder diameters width (<8  nm), with the smallest observed patterns approaching 10 nm.

Bottom-up/top-down high resolution, high throughput lithography using vertically assembled block bottle brush polymers

We describe a novel deterministic bottom-up / top-down approach to sub-30 nm photolithography using a film composed of assembled block brush polymers of highly uniform composition and chain length. The polymer architecture consists of a rigid backbone of polymerized norbornene, each linked to flexible short side brush chains. The resultant ‘bottle brush’ topology has a cylindrical shape with short brush chains arranged concentrically around the backbone, in which the cylinder radius is determined by the number of monomers within the brush fragment, while the cylinder length is determined by the degree of backbone polymerization. The modularity of the synthetic system allows a wide diversity of lithographically useful monomers, sequencing, dimension and property variation. Sequential grafting of pre-synthesized blocks allows for facile formation of either concentric or lengthwise block copolymers. Placement of brush chains of different compositions along different regions of the cylinder, along with variation of the relative concentric and lengthwise dimensions, provides mechanisms to align and control placement of the cylinders. These polymers are compatible with photoacid generators (PAGs) and crosslinker functionality. Our results are consistent with a model that the bottle brush polymers assemble (bottom-up) in the film to yield a ‘forest’ of vertically arranged cylindrical block brush polymers, with the film thickness determined by the coherence lengths of the cylinders. Subsequent imaging via electron beam (EB or ebeam) or optical radiation yields a (top-down) mechanism for acid catalyzed crosslinking of adjacent cylinders. Uncrosslinked cylinders are removed in developer to yield negative photoresist patterns. Exposure doses are very low and throughputs are amenable to the requirements of Extreme Ultraviolet (EUV) lithography. The limiting resolution with ebeam exposure is potentially about two cylinder diameters width (< 8 nm), with the smallest observed patterns approaching 10 nm.

A Vinyl Ether-Functional Polycarbonate as a Template for Multiple Postpolymerization Modifications

A highly-reactive vinyl ether-functionalized aliphatic polycarbonate and its block copolymer were developed as templates for multiple post-polymerization conjugation chemistries. The vinyl ether-functional six-membered cyclic carbonate monomer was synthesized by a well-established two-step procedure starting from 2,2-bis(hydroxymethyl)propionic acid. An organobase-catalyzed ring-opening polymerization of the synthesized monomer afforded polycarbonates with pendant vinyl ether functionalities (PMVEC). The vinyl ether moieties on the resulting polymers were readily conjugated with hydroxyl- or thiol-containing compounds via three different post-polymerization modification chemistries - acetalization, thio-acetalization, and thiol-ene reaction. Acetal-functionalized polycarbonates were studied in depth to exploit their acid-labile acetal functionalities. Acetalization of the amphiphilic diblock copolymer of poly(ethylene glycol) methyl ether (mPEG) and PMVEC, mPEG113-b-PMVEC13, with the model hydroxyl compound 4- methylbenzyl alcohol resulted in a maximum of 42% acetal and 58% hydroxyl side chain groups. Nonetheless, the amphiphilicity of the block polymer allowed for its self-assembly in water to afford nanostructures, as characterized via dynamic light scattering and transmission electron microscopy. The kinetics of acetal cleavage within the block polymer micelles were examined in acidic buffered solutions (pH 4 and 5). In addition, mPEG-b-PMVEC and its hydrolyzed polymer mPEG-b-PMHEC (i.e., after full cleavage of acetals) exhibited minimal cytotoxicity to RAW 264.7 mouse macrophages, indicating that this polymer system represents a biologically non-hazardous material with pH-responsive activity.