The design and use of materials in the nanoscale size range for addressing medical and health-related issues continues to receive increasing interest. Research in nanomedicine spans a multitude of areas, including drug delivery, vaccine development, antibacterial, diagnosis and imaging tools, wearable devices, implants, high-throughput screening platforms, etc. using biological, nonbiological, biomimetic, or hybrid materials. Many of these developments are starting to be translated into viable clinical products. Here, we provide an overview of recent developments in nanomedicine and highlight the current challenges and upcoming opportunities for the field and translation to the clinic.

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Diverse Applications of Nanomedicine

Photoacoustic imaging (PAI) is an emerging tool that bridges the traditional depth limits of ballistic optical imaging and the resolution limits of diffuse optical imaging. Using the acoustic waves generated in response to the absorption of pulsed laser light, it provides noninvasive images of absorbed optical energy density at depths of several centimeters with a resolution of ∼100 μm. This versatile and scalable imaging modality has now shown potential for molecular imaging, which enables visualization of biological processes with systemically introduced contrast agents. Understanding the relative merits of the vast range of contrast agents available, from small-molecule dyes to gold and carbon nanostructures to liposome encapsulations, is a considerable challenge. Here we critically review the physical, chemical and biochemical characteristics of the existing photoacoustic contrast agents, highlighting key applications and present challenges for molecular PAI.

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Contrast agents for molecular photoacoustic imaging

Lanthanide Nanoparticles: From Design toward Bioimaging and Therapy

The emerging inverse electron demand Diels–Alder (IEDDA) reaction stands out from other bioorthogonal reactions by virtue of its unmatchable kinetics, excellent orthogonality and biocompatibility. With the recent discovery of novel dienophiles and optimal tetrazine coupling partners, attention has now been turned to the use of IEDDA approaches in basic biology, imaging and therapeutics. Here we review this bioorthogonal reaction and its promising applications for live cell and animal studies. We first discuss the key factors that contribute to the fast IEDDA kinetics and describe the most recent advances in the synthesis of tetrazine and dienophile coupling partners. Both coupling partners have been incorporated into proteins for tracking and imaging by use of fluorogenic tetrazines that become strongly fluorescent upon reaction. Selected notable examples of such applications are presented. The exceptional fast kinetics of this catalyst-free reaction, even using low concentrations of coupling partners, make it amenable for in vivo radiolabelling using pretargeting methodologies, which are also discussed. Finally, IEDDA reactions have recently found use in bioorthogonal decaging to activate proteins or drugs in gain-of-function strategies. We conclude by showing applications of the IEDDA reaction in the construction of biomaterials that are used for drug delivery and multimodal imaging, among others. The use and utility of the IEDDA reaction is interdisciplinary and promises to revolutionize chemical biology, radiochemistry and materials science.

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Inverse electron demand Diels–Alder reactions in chemical biology

Theranostics for in vivo cancer diagnosis and treatment generally requires well-designed nanoscale platforms with multiple integrated functionalities. In this study, we uncover that functionalized iron oxide nanoparticles (IONPs) could be self-assembled on the surface of two-dimensional MoS2 nanosheets via sulfur chemistry, forming MoS2-IO nanocomposites, which are then modified with two types of polyethylene glycol (PEG) to acquire enhanced stability in physiological environments. Interestingly, 64Cu, a commonly used positron-emitting radioisotope, could be firmly adsorbed on the surface of MoS2 without the need of chelating molecules, to enable in vivo positron emission tomography (PET) imaging. On the other hand, the strong near-infrared (NIR) and superparamagnetism of MoS2-IO-PEG could also be utilized for photoacoustic tomography (PAT) and magnetic resonance (MR) imaging, respectively. Under the guidance by such triple-modal imaging, which uncovers efficient tumor retention of MoS2-IO-(d)PEG upon int...

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Iron Oxide Decorated MoS2 Nanosheets with Double PEGylation for Chelator-Free Radiolabeling and Multimodal Imaging Guided Photothermal Therapy

Development of reporter genes for multimodality molecular imaging is highly important. In contrast to the conventional strategies which have focused on fusing several reporter genes together to serve as multimodal reporters, human tyrosinase (TYR) – the key enzyme in melanin production – was evaluated in this study as a stand-alone reporter gene for in vitro and in vivo photoacoustic imaging (PAI), magnetic resonance imaging (MRI) and positron emission tomography (PET). Human breast cancer cells MCF-7 transfected with a plasmid that encodes TYR (named as MCF-7-TYR) and non-transfected MCF-7 cells were used as positive and negative controls, respectively. Melanin targeted N-(2-(diethylamino)ethyl)-18F-5-fluoropicolinamide was used as a PET reporter probe. In vivo PAI/MRI/PET imaging studies showed that MCF-7-TYR tumors achieved significant higher signals and tumor-to-background contrasts than those of MCF-7 tumor. Our study demonstrates that TYR gene can be utilized as a multifunctional reporter gene for PAI/MRI/PET both in vitro and in vivo.

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Tyrosinase as a multifunctional reporter gene for Photoacoustic/MRI/PET triple modality molecular imaging

Development of multifunctional nanoparticle-based probes for dual T1- and T2-weighted magnetic resonance imaging (MRI) could allow us to image and diagnose the tumors or other abnormalities in an exceptionally accurate and reliable manner. In this study, by fusing distinct nanocrystals via solid-state interfaces, we built hybrid heteronanostructures to combine both T1 and T2- weighted contrast agents together for MRI with high accuracy and reliability. The resultant hybrid heterotrimers showed high stability in physiological conditions and could induce both simultaneous positive and negative contrast enhancements in MR images. Small animal positron emission tomography imaging study revealed that the hybrid heterostructures displayed favorable biodistribution and were suitable for in vivo imaging. Their potential as dual contrast agents for T1 and T2-weighted MRI was further demonstrated by in vitro and in vivo imaging and relaxivity measurements.

Hybrid nanotrimers for dual T1 and T2-weighted magnetic resonance imaging

The epidermal growth factor receptor (EGFR) serves as an attractive target for cancer molecular imaging and therapy. Our previous positron emission tomography (PET) studies showed that the EGFR-targeting affibody molecules 64Cu-DOTA-ZEGFR:1907 and 18F-FBEM-ZEGFR:1907 can discriminate between high and low EGFR-expression tumors and have the potential for patient selection for EGFR-targeted therapy. Compared with 64Cu, 18F may improve imaging of EGFR-expression and is more suitable for clinical application, but the labeling reaction of 18F-FBEM-ZEGFR:1907 requires a long synthesis time. The aim of the present study is to develop a new generation of 18F labeled affibody probes (Al18F-NOTA-ZEGFR:1907 and 18F-CBT-ZEGFR:1907) and to determine whether they are suitable agents for imaging of EGFR expression. The first approach consisted of conjugating ZEGFR:1907 with NOTA and radiolabeling with Al18F to produce Al18F-NOTA-ZEGFR:1907. In a second approach the prosthetic group 18F-labeled-2-cyanobenzothiazole (18F-...

https://pubs.acs.org/doi/pdf/10.1021/mp5003043

Comparison of two site-specifically (18)F-labeled affibodies for PET imaging of EGFR positive tumors.

Extracellular matrix (ECM) accumulation in liver fibrosis is caused by the activation of hepatic stellate cells (HSCs). The goal of this study was to develop a 99mTc-labeled N-acetylglucosamine (GlcNAc) that specifically interacts with desmin and vimentin expressed on activated HSCs to monitor the progression and prognosis of liver fibrosis using single-photon emission computed tomography (SPECT) imaging. Methods: GlcNAc-conjugated polyethylenimine (PEI) was first prepared and radiolabeled with 99mTc. Noninvasive SPECT imaging with 99mTc-GlcNAc-PEI was used to assess liver fibrosis in a carbon tetrachloride (CCl4) mouse model. The liver uptake value (LUV) of 99mTc-GlcNAc-PEI was measured by drawing the region of interest (ROI) of the whole liver as previously suggested. The LUV of the CCl4 groups was compared with that of the olive oil group. Next, we estimated the correlation between the results of SPECT imaging and physiological indexes. After treatment with clodronate liposome, the LUV of 99mTc-GlcNAc-PEI in fibrotic mice was compared with that in control mice. Results:99mTc-GlcNAc-PEI is a hydrophilic compound with high radiochemical purity (>98%) and good stability. It could specifically target desmin and vimentin on the surface of activated HSCs with high affinity (the Kd values were 53.75 ± 9.50 nM and 20.98 ± 3.56 nM, respectively). The LUV of 99mTc-GlcNAc-PEI was significantly different between the CCl4 and control groups as early as 4 weeks of CCl4 administration (3.30 ± 0.160 vs 2.34 ± 0.114%/cc; P ˂ 0.05). There was a strong correlation between the LUV and Sirius Red quantification (R = 0.92, P ˂ 0.001). Compared with control, clodronate liposome treatment reduced the LUV of 99mTc-GlcNAc-PEI (4.62 ± 0.352 vs 2.133 ± 0.414%/cc; P ˂ 0.05). Conclusion:99mTc-GlcNAc-PEI SPECT/CT was useful in assessing liver fibrosis and monitoring the treatment response.

Desmin- and vimentin-mediated hepatic stellate cell-targeting radiotracer 99mTc-GlcNAc-PEI for liver fibrosis imaging with SPECT.

The insulin-like growth factor 1 receptor (IGF-1R) serves as an attractive target for cancer molecular imaging and therapy. Previous single photon emission computerized tomography (SPECT) studies showed that the IGF-1R-targeting Affibody molecules 99mTc-ZIGF1R:4551-GGGC, [99mTc(CO)3]+-(HE)3-ZIGF1R:4551 and 111In-DOTA-ZIGF1R:4551 can discriminate between high and low IGF-1R-expression tumors and have the potential for patient selection for IGF-1R-targeted therapy. Compared with SPECT, positron emission tomography (PET) may improve imaging of IGF-1R-expression, because of its high sensitivity, high spatial resolution, strong quantification ability. The aim of the present study was to develop the 64Cu-labeled NOTA-conjugated Affibody molecule ZIGF-1R:4:40 as a PET probe for imaging of IGF-1R-positive tumor. An Affibody analogue (Ac-Cys-ZIGF-1R:4:40) binding to IGF-1R was site-specifically conjugated with NOTA and labeled with 64Cu. Binding affinity and specificity of 64Cu-NOTA-ZIGF-1R:4:40 to IGF-1R were evaluated using human glioblastoma U87MG cells. Small-animal PET, biodistribution, and metabolic stability studies were conducted on mice bearing U87MG xenografts after the injection of 64Cu-NOTA-ZIGF-1R:4:40 with or without co-injection of unlabeled Affibody proteins. The radiosynthesis of 64Cu-NOTA-ZIGF-1R:4:40 was completed successfully within 60 min with a decay-corrected yield of 75 %. 64Cu-NOTA-ZIGF-1R:4:40 bound to IGF-1R with low nanomolar affinity (KD = 28.55 ± 3.95 nM) in U87MG cells. 64Cu-NOTA-ZIGF-1R:4:40 also displayed excellent in vitro and in vivo stability. In vivo biodistribution and PET studies demonstrated targeting of U87MG gliomas xenografts was IGF-1R specific. The tumor uptake was 5.08 ± 1.07 %ID/g, and the tumor to muscle ratio was 11.89 ± 2.16 at 24 h after injection. Small animal PET imaging studies revealed that 64Cu-NOTA-ZIGF-1R:4:40 could clearly identify U87MG tumors with good contrast at 1–24 h after injection. This study demonstrates that 64Cu-NOTA-ZIGF-1R:4:40 is a promising PET probe for imaging IGF-1R positive tumor.

Xinhui Su

Papers

Tyrosinase as a multifunctional reporter gene for Photoacoustic/MRI/PET triple modality molecular imaging

Hybrid nanotrimers for dual T1 and T2-weighted magnetic resonance imaging

Comparison of two site-specifically (18)F-labeled affibodies for PET imaging of EGFR positive tumors.

Desmin- and vimentin-mediated hepatic stellate cell-targeting radiotracer 99mTc-GlcNAc-PEI for liver fibrosis imaging with SPECT.

PET imaging of insulin-like growth factor type 1 receptor expression with a 64Cu-labeled Affibody molecule.