Publications by authors named "Xiaoyuan Chen"

937 Publications

Synthesis and Bioapplications of Ag S Quantum Dots with Near-Infrared Fluorescence.

Adv Mater 2021 Jun 12:e2007768. Epub 2021 Jun 12.

Yong Loo Lin School of Medicine and Faculty of Engineering, National University of Singapore, Singapore, 117597, Singapore.

Quantum dots (QDs) with near-infrared fluorescence (NIR) are an emerging class of QDs with unique capabilities owing to the deeper tissue penetrability of NIR light compared with visible light. NIR light also effectively overcomes organism autofluorescence, making NIR QDs particularly attractive in biological imaging applications for disease diagnosis. Considering latest developments, Ag S QDs are a rising star among NIR QDs due to their excellent NIR fluorescence properties and biocompatibility. This review presents the various methods to synthesize NIR Ag S QDs, and systematically discusses their applications in biosensing, bioimaging, and theranostics. Major challenges and future perspectives concerning the synthesis and bioapplications of NIR Ag S QDs are discussed.
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http://dx.doi.org/10.1002/adma.202007768DOI Listing
June 2021

A Fluorinated Ionic Liquid-Based Activatable F MRI Platform Detects Biological Targets.

Chem 2020 May 24;6(5):1134-1148. Epub 2020 Feb 24.

Department of Chemical Biology, State Key Laboratory of Physical Chemistry of Solid Surfaces, The MOE Key Laboratory of Spectrochemical Analysis & Instrumentation, The Key Laboratory for Chemical Biology of Fujian Province, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, China.

F magnetic resonance imaging (F MRI) is a promising technique for molecular imaging and clinical diagnosis, benefiting from its negligible background and unlimited tissue penetration depth. However, the development of F probes with good water solubility and versatile functions for bioresponsive and practical applications remains a challenge. Here, we report fluorinated ion liquids (ILs) as a new type of fluorine agents and build a fluorinated ionic liquid-based activatable F MRI platform (FILAMP), which relies on the phase transition of ILs. Upon exposure to environmental stimulation, coating polymer dissolves or degrades to release the fluorinated ILs payload, which rapidly enhances F signal. This "turn-on" response is verified by the successful detection of biological targets (for example, dysregulated pH and MMP overexpression) at the cellular level and in mice, demonstrating the potential of FILAMP as a robust activatable F probe for diagnosis and monitoring of biological and pathological processes.
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http://dx.doi.org/10.1016/j.chempr.2020.01.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8171808PMC
May 2020

A hypoxia responsive nanoassembly for tumor specific oxygenation and enhanced sonodynamic therapy.

Biomaterials 2021 May 3;275:120822. Epub 2021 May 3.

State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Science, University of Macau, Avenida da Universidade, Taipa, Macau, China. Electronic address:

The hypoxic tumor microenvironment (TME) and non-specific distribution of sonosensitizers are two major obstacles that limit practical applications of sonodynamic therapy (SDT) in combating tumors. Here we report a hypoxia-responsive nanovesicle (hMVs) as delivery vehicles of a sonosensitizer to enhance the efficacy of SDT via specific payload release and local oxygenation in the tumor. The nanovesicles are composed of densely packed manganese ferrite nanoparticles (MFNs) embedded in hypoxia-responsive amphiphilic polymer membranes. With δ-aminolevulinic acid (ALA) loaded in the hollow cavities, the hMVs could rapidly dissociate into discrete nanoparticles in the hypoxic TME to release the payload and induce the generation of reactive oxygen species (ROS) under ultrasound (US) radiation. Meanwhile, the released MFNs could catalytically generate O to overcome the hypoxic TME and thus enhance the efficacy of SDT. After treatment, the dissociated MFNs could be readily excreted from the body via renal clearance to reduce long term toxicity. In vitro and in vivo experiments displayed effective tumor inhibition via hMVs-mediated SDT, indicating the great potential of this unique nanoplatform in effective SDT by generating sufficient ROS in deep-seated hypoxic tumors that are not readily accessible by conventional photodynamic therapy.
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http://dx.doi.org/10.1016/j.biomaterials.2021.120822DOI Listing
May 2021

Supramolecular Polymerization-Induced Nanoassemblies for Self-Augmented Cascade Chemotherapy and Chemodynamic Therapy of Tumour.

Angew Chem Int Ed Engl 2021 May 26. Epub 2021 May 26.

University of Macau, Institute of Chinese Medical Sciences, CHINA.

The clinical application of chemodynamic therapy is impeded by the insufficient intracellular H 2 O 2 level in tumour tissues. Herein, we developed a supramolecular nanoparticle via a simple one-step supramolecular polymerization-induced self-assembly process using platinum (IV) complex-modified β-cyclodextrin-ferrocene conjugates as supramolecular monomers. The supramolecular nanoparticles could dissociate rapidly upon exposure to endogenous H 2 O 2 in the tumour and release hydroxyl radicals as well as platinum (IV) prodrugs in situ , which is reduced into cisplatin to significantly promote the generation of H 2 O 2 in the tumour tissue. Thus, the supramolecular nanomedicine overcomes the limitation of conventional chemodynamic therapy via the self-augmented cascade radical generation and drug release. In addition, the dissociated supramolecular nanoparticles could be readily excreted from the body via renal clearance to effectively avoid systemic toxicity and ensure long term biocompatibility of the nanomedicine. This work may provide new insights on the design and development of novel supramolecular nanoassemblies for cascade chemo/chemodynamic therapy.
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http://dx.doi.org/10.1002/anie.202103721DOI Listing
May 2021

Photodynamic-Chemodynamic Cascade Reactions for Efficient Drug Delivery and Enhanced Combination Therapy.

Adv Sci (Weinh) 2021 05 8;8(10):2002927. Epub 2021 Apr 8.

Departments of Diagnostic Radiology, Chemical and Biomolecular Engineering, and Biomedical Engineering National University of Singapore Singapore 117545 Singapore.

Nanomedicines with photodynamic therapy and reactive oxygen species (ROS)-triggered drug release capabilities are promising for cancer therapy. However, most of the nanomedicines based on ROS-responsive nanocarriers still suffer from serious ROS consumption during the triggered drug release process. Herein, a photodynamic-chemodynamic cascade strategy for the design of drug delivery nanosystem is proposed. A doxorubicin hydrochloride-loaded ROS-responsive polymersome (DOX-RPS) is prepared via the self-assembly of amphiphilic poly(ethylene glycol)-poly(linoleic acid) and poly(ethylene glycol)-(2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-α)-iron chelate (PEG-HPPH-Fe). The RPS can effectively deliver a drug to tumor site through passive targeting effect. Upon laser irradiation, the photosensitizer HPPH can efficiently generate ROS, which further causes in situ oxidation of linoleic acid chain and subsequent RPS structural destruction, permitting triggered drug release. Intriguingly, catalyzed by HPPH-Fe, ROS will be regenerated from linoleic acid peroxide through a chemodynamic process. Therefore, ROS-triggered drug release can be achieved without ROS over-consumption. The in vitro and in vivo results confirmed ROS generation, triggered drug release behavior, and potent antitumor effect of the DOX-RPS. This photodynamic-chemodynamic cascade strategy provides a promising approach for enhanced combination therapy.
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http://dx.doi.org/10.1002/advs.202002927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8132047PMC
May 2021

Extracellular vesicles as a drug delivery system:A systematic review of preclinical studies.

Adv Drug Deliv Rev 2021 May 18. Epub 2021 May 18.

Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, 119228 Singapore, Singapore; Cardiovascular Research Institute (CVRI), National University Heart Centre Singapore (NUHCS), 117599 Singapore, Singapore; Nanomedicine Translational Research Programme, the Centre for NanoMedicine, Yong Loo Lin School of Medicine, National University of Singapore, 117609 Singapore, Singapore; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore. Electronic address:

During the past decades, EVs have emerged as attractive drug delivery systems. Here, we assess their pre-clinical applications, in the form of a systematic review. For each study published during the past decade, disease models, animal species, EV donor cell types, active pharmaceutical ingredients (APIs), EV surface modifications, API loading methods, EV size and charge, estimation of EV purity, presence of biodistribution studies and administration routes were qualitatively analyzed in a defined and reproducible way. We have interpreted the trends we observe over the past decade, to define the niches where to apply EVs for drug delivery in the future and to provide a basis for regulatory guidelines.
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http://dx.doi.org/10.1016/j.addr.2021.05.011DOI Listing
May 2021

Beyond Photo: Xdynamic Therapies in Fighting Cancer.

Adv Mater 2021 May 13:e2007488. Epub 2021 May 13.

Departments of Diagnostic Radiology and Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore.

Reactive oxygen species (ROS)-related therapeutic approaches are developed as a promising modality for cancer treatment because the aberrant increase of intracellular ROS level can cause cell death due to nonspecific oxidation damage to key cellular biomolecules. However, the most widely considered strategy, photodynamic therapy (PDT), suffers from critical limitations such as limited tissue-penetration depth, high oxygen dependence, and phototoxicity. Non-photo-induced ROS generation strategies, which are defined as Xdynamic therapies (X = sono, radio, microwave, chemo, thermo, and electro), show good potential to overcome the drawbacks of PDT. Herein, recent advances in the development of Xdynamic therapies, including the design of systems, the working mechanisms, and examples of cancer therapy application, are introduced. Furthermore, the approaches to enhance treatment efficiency of Xdynamic therapy are highlighted. Finally, the perspectives and challenges of these strategies are also discussed.
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http://dx.doi.org/10.1002/adma.202007488DOI Listing
May 2021

Rationally Programming Nanomaterials with DNA for Biomedical Applications.

Adv Sci (Weinh) 2021 04 24;8(8):2003775. Epub 2021 Feb 24.

Yong Loo Lin School of Medicine and Faculty of Engineering National University of Singapore Singapore 117597 Singapore.

DNA is not only a carrier of genetic information, but also a versatile structural tool for the engineering and self-assembling of nanostructures. In this regard, the DNA template has dramatically enhanced the scalability, programmability, and functionality of the self-assembled DNA nanostructures. These capabilities provide opportunities for a wide range of biomedical applications in biosensing, bioimaging, drug delivery, and disease therapy. In this review, the importance and advantages of DNA for programming and fabricating of DNA nanostructures are first highlighted. The recent progress in design and construction of DNA nanostructures are then summarized, including DNA conjugated nanoparticle systems, DNA-based clusters and extended organizations, and DNA origami-templated assemblies. An overview on biomedical applications of the self-assembled DNA nanostructures is provided. Finally, the conclusion and perspectives on the self-assembled DNA nanostructures are presented.
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http://dx.doi.org/10.1002/advs.202003775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8061415PMC
April 2021

Base Composition and Host Adaptation of the SARS-CoV-2: Insight From the Codon Usage Perspective.

Front Microbiol 2021 6;12:548275. Epub 2021 Apr 6.

College of Veterinary Medicine, South China Agricultural University, Guangzhou, China.

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been spreading rapidly all over the world and has raised grave concern globally. The present research aims to conduct a robust base compositional analysis of SARS-CoV-2 to reveal adaptive intricacies to the human host. Multivariate statistical analysis revealed a complex interplay of various factors including compositional constraint, natural selection, length of viral coding sequences, hydropathicity, and aromaticity of the viral gene products that are operational to codon usage patterns, with compositional bias being the most crucial determinant. UpG and CpA dinucleotides were found to be highly preferred whereas, CpG dinucleotide was mostly avoided in SARS-CoV-2, a pattern consistent with the human host. Strict avoidance of the CpG dinucleotide might be attributed to a strategy for evading a human immune response. A lower degree of adaptation of SARS-CoV-2 to the human host, compared to Middle East respiratory syndrome (MERS) coronavirus and SARS-CoV, might be indicative of its milder clinical severity and progression contrasted to SARS and MERS. Similar patterns of enhanced adaptation between viral isolates from intermediate and human hosts, contrasted with those isolated from the natural bat reservoir, signifies an indispensable role of the intermediate host in transmission dynamics and spillover events of the virus to human populations. The information regarding avoided codon pairs in SARS-CoV-2, as conferred by the present analysis, promises to be useful for the design of vaccines employing codon pair deoptimization based synthetic attenuated virus engineering.
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http://dx.doi.org/10.3389/fmicb.2021.548275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8057303PMC
April 2021

The circACC1/miR-29c-3p/FOXP1 network plays a key role in gastric cancer by regulating cell proliferation.

Biochem Biophys Res Commun 2021 Jun 19;557:221-227. Epub 2021 Apr 19.

The Department of Ultrasound Medicine, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, China. Electronic address:

Although substantial progress has been made in early detection and treatment of GC, this disease remains a major burden worldwide. CircRNAs have potential as prognostic and diagnostic biomarkers in tumorigenesis. Therefore, we aimed to clarify the role and mechanism of circACC1 in GC cell proliferation. The expression levels of circACC1, miR-29c-3p and FOXP1 were validated in GC tissue samples and adjacent tissue samples. The impact of circACC1 and miR-29c-3p on overall survival was evaluated in GC specimens. A functional study was performed on MKN-45 and BGC823 cells transfected with different vectors. Cell proliferation was assayed by CCK-8 and colony formation assays. The interactions among circACC1, miR-29c-3p and FOXP1 were tested by RNA immunoprecipitation and luciferase reporter assays. This study demonstrated that circACC1 is upregulated in GC tissues, and its upregulation predicts poorer OS in GC patients. Upregulation of circACC1 promoted GC cell proliferation, as indicated by CCK-8 and colony formation assays. A mechanistic study revealed that the pro-oncogenic effect of circACC1 was mainly caused by binding to miR-29c-3p, thus regulating expression of its downstream target FOXP1. The circACC1/miR-29c-3p/FOXP1 network plays a key role in gastric cancer by regulating cell proliferation.
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http://dx.doi.org/10.1016/j.bbrc.2021.04.028DOI Listing
June 2021

Polyphenol-Containing Nanoparticles: Synthesis, Properties, and Therapeutic Delivery.

Adv Mater 2021 Jun 19;33(22):e2007356. Epub 2021 Apr 19.

Yong Loo Lin School of Medicine and Faculty of Engineering, National University of Singapore, Singapore, 119077, Singapore.

Polyphenols, the phenolic hydroxyl group-containing organic molecules, are widely found in natural plants and have shown beneficial effects on human health. Recently, polyphenol-containing nanoparticles have attracted extensive research attention due to their antioxidation property, anticancer activity, and universal adherent affinity, and thus have shown great promise in the preparation, stabilization, and modification of multifunctional nanoassemblies for bioimaging, therapeutic delivery, and other biomedical applications. Additionally, the metal-polyphenol networks, formed by the coordination interactions between polyphenols and metal ions, have been used to prepare an important class of polyphenol-containing nanoparticles for surface modification, bioimaging, drug delivery, and disease treatments. By focusing on the interactions between polyphenols and different materials (e.g., metal ions, inorganic materials, polymers, proteins, and nucleic acids), a comprehensive review on the synthesis and properties of the polyphenol-containing nanoparticles is provided. Moreover, the remarkable versatility of polyphenol-containing nanoparticles in different biomedical applications, including biodetection, multimodal bioimaging, protein and gene delivery, bone repair, antibiosis, and cancer theranostics is also demonstrated. Finally, the challenges faced by future research regarding the polyphenol-containing nanoparticles are discussed.
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http://dx.doi.org/10.1002/adma.202007356DOI Listing
June 2021

Singlet Oxygen Generation in Dark-Hypoxia by Catalytic Microenvironment-Tailored Nanoreactors for NIR-II Fluorescence-Monitored Chemodynamic Therapy.

Angew Chem Int Ed Engl 2021 Jun 24;60(27):15006-15012. Epub 2021 May 24.

Departments of Diagnostic Radiology, Chemical and Biomolecular Engineering, and Biomedical Engineering, Yong Loo Lin School of Medicine and Faculty of Engineering, National University of Singapore, Singapore, 117597, Singapore.

Singlet oxygen ( O ) has a potent anticancer effect, but photosensitized generation of O is inhibited by tumor hypoxia and limited light penetration depth. Despite the potential of chemodynamic therapy (CDT) to circumvent these issues by exploration of O -producing catalysts, engineering efficient CDT agents is still a formidable challenge since most catalysts require specific pH to function and become inactivated upon chelation by glutathione (GSH). Herein, we present a catalytic microenvironment-tailored nanoreactor (CMTN), constructed by encapsulating MoO catalyst and alkaline sodium carbonate within liposomes, which offers a favorable pH condition for MoO -catalyzed generation of O from H O and protects MoO from GSH chelation owing to the impermeability of liposomal lipid membrane to ions and GSH. H O and O can freely cross the liposomal membrane, allowing CMTN with a built-in NIR-II ratiometric fluorescent O sensor to achieve monitored tumor CDT.
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http://dx.doi.org/10.1002/anie.202102097DOI Listing
June 2021

Pathogenicity and transmissibility of a novel respirovirus isolated from a Malayan pangolin.

J Gen Virol 2021 04;102(4)

Center for Emerging and Zoonotic Diseases, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, PR China.

The identification of SARS-CoV-2-like viruses in Malayan pangolins () has focused attention on these endangered animals and the viruses they carry. We successfully isolated a novel respirovirus from the lungs of a dead Malayan pangolin. Similar to murine respirovirus, the full-length genome of this novel virus was 15 384 nucleotides comprising six genes in the order 3'-(leader)-NP-P-M-F-HN-l-(trailer)-5'. Phylogenetic analysis revealed that this virus belongs to the genus and is most closely related to murine respirovirus. Notably, animal infection experiments indicated that the pangolin virus is highly pathogenic and transmissible in mice, with inoculated mice having variable clinical symptoms and a fatality rate of 70.37 %. The virus was found to replicate in most tissues with the exception of muscle and heart. Contact transmission of the virus was 100 % efficient, although the mice in the contact group displayed milder symptoms, with the virus mainly being detected in the trachea and lungs. The isolation of a novel respirovirus from the Malayan pangolin provides new insight into the evolution and distribution of this important group of viruses and again demonstrates the potential infectious disease threats faced by endangered pangolins.
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http://dx.doi.org/10.1099/jgv.0.001586DOI Listing
April 2021

Capturing Cytokines with Advanced Materials: A Potential Strategy to Tackle COVID-19 Cytokine Storm.

Adv Mater 2021 May 10;33(20):e2100012. Epub 2021 Apr 10.

Institute of Biomedical Health Technology and Engineering, Shenzhen Bay Laboratory, Shenzhen, 518132, China.

The COVID-19 pandemic, induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused great impact on the global economy and people's daily life. In the clinic, most patients with COVID-19 show none or mild symptoms, while approximately 20% of them develop severe pneumonia, multiple organ failure, or septic shock due to infection-induced cytokine release syndrome (the so-called "cytokine storm"). Neutralizing antibodies targeting inflammatory cytokines may potentially curb immunopathology caused by COVID-19; however, the complexity of cytokine interactions and the multiplicity of cytokine targets make attenuating the cytokine storm challenging. Nonspecific in vivo biodistribution and dose-limiting side effects further limit the broad application of those free antibodies. Recent advances in biomaterials and nanotechnology have offered many promising opportunities for infectious and inflammatory diseases. Here, potential mechanisms of COVID-19 cytokine storm are first discussed, and relevant therapeutic strategies and ongoing clinical trials are then reviewed. Furthermore, recent research involving emerging biomaterials for improving antibody-based and broad-spectrum cytokine neutralization is summarized. It is anticipated that this work will provide insights on the development of novel therapeutics toward efficacious management of COVID-19 cytokine storm and other inflammatory diseases.
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http://dx.doi.org/10.1002/adma.202100012DOI Listing
May 2021

Bombesin-Tethered Reactive Oxygen Species (ROS)-Responsive Nanoparticles for Monomethyl Auristatin F (MMAF) Delivery.

Bioengineering (Basel) 2021 Mar 29;8(4). Epub 2021 Mar 29.

Yong Loo Lin School of Medicine and Faculty of Engineering, National University of Singapore, Singapore 117597, Singapore.

Dolastatin derivatives, represented by monomethylauristatin E (MMAE), have been translated in clinic with a form of antibody-drug conjugate; however, their potential in nanoparticle systems has not been well established due to the potential risk of immature release of extremely high cytotoxic dolastatin drugs during blood circulation. Herein, we rationally propose monomethylauristatin F (MMAF), a dolastatin-derived, loaded nanoparticle system composed of bombesin (BBN)-tethered ROS-responsive micelle system (BBN-PEG-PPADT) to achieve efficient anticancer therapy with targeted and efficient delivery of MMAF. The developed MMAF-loaded BBN-PEG-PPADT micelles ([email protected]) exhibited improved cellular uptake via interactions between BBN and gastrin-releasing peptide receptors on the cancer cells and the intracellular burst release of MMAF, owing to the ROS-responsive disruption, which allowed the efficient anticancer effects of MMAF in vitro. This study suggests the potential of nanoparticle systems in the delivery of dolastatin drugs.
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http://dx.doi.org/10.3390/bioengineering8040043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066503PMC
March 2021

Rational design of semiconducting polymer brushes as cancer theranostics.

Mater Horiz 2020 06 14;7(6):1474-1494. Epub 2020 Feb 14.

Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland 20892, USA.

Photonic theranostics (PTs) generally contain optical agents for the optical sensing of biomolecules and therapeutic components for converting light into heat or chemical energy. Semiconducting polymer nanoparticles (SPNs) as advanced PTs possessing good biocompatibility, stable photophysical properties, and sensitive and tunable optical responses from the ultraviolet to near-infrared (NIR) II window (300-1700 nm) have recently aroused great interest. Although semiconducting polymers (SPs) with various building blocks have been synthesized and developed to meet the demands of biophotonic applications, most of the SPNs were made by a nanoprecipitation method that used amphiphilic surfactants to encapsulate SPs. Such binary SP micelles usually exhibit weakened photophysical properties of SPs and undergo dissociation SP brushes (SPBs) are products of functional post-modification of SP backbones, which endows unique features to SPNs enhanced optical properties and multiple chemical reaction sites for the conjunction of organic/inorganic imaging agents and therapeutics). Furthermore, the SPB-based SPNs can be highly stable due to supramolecular self-assembly and/or chemical crosslinking. In this review, we highlight the recent progress in the development of SPBs for advanced theranostics.
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http://dx.doi.org/10.1039/d0mh00012dDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990392PMC
June 2020

Cascade Drug-Release Strategy for Enhanced Anticancer Therapy.

Matter 2021 Jan 6;4(1):26-53. Epub 2021 Jan 6.

Yong Loo Lin School of Medicine and Faculty of Engineering, National University of Singapore, Singapore, 117597, Singapore.

Chemotherapy serves as one of the most effective approaches in numerous tumor treatments but also suffers from the limitations of low bioavailability and adverse side effects due to premature drug leakage. Therefore, it is crucial to realize accurate on-demand drug release for promoting the application of chemotherapeutic agents. To achieve this, stimuli-responsive nanomedicines that can be activated by delicately designed cascade reactions have been developed in recent years. In general, the nanomedicines are triggered by an internal or external stimulus, generating an intermediate stimulus at tumor site, which can intensify the differences between tumor and normal tissues; the drug release process is then further activated by the intermediate stimulus. In this review, the latest progress made in cascade reactions-driven drug-release modes, based on the intermediate stimuli of heat, hypoxia, and reactive oxygen species, is systematically summarized. The perspectives and challenges of cascade strategy for drug delivery are also discussed.
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http://dx.doi.org/10.1016/j.matt.2020.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7945719PMC
January 2021

Targeted Dual Small Interfering Ribonucleic Acid Delivery via Non-Viral Polymeric Vectors for Pulmonary Fibrosis Therapy.

Adv Mater 2021 Mar 19;33(12):e2007798. Epub 2021 Feb 19.

Yong Loo Lin School of Medicine and Faculty of Engineering, National University of Singapore, Singapore, 119228, Singapore.

Inhibiting the myofibroblast differentiation of lung-resident mesenchymal stem cells (LR-MSCs) is a promising yet challenging approach for pulmonary fibrosis (PF) therapy. Here, micelles formed by a graft copolymer of multiple PEGs modified branched polyethylenimine are used for delivering runt-related transcription factor-1 (RUNX1) small interfering RNA (siRNA) (siRUNX1) to the lung, aiming to inhibit the myofibroblast differentiation of LR-MSCs. LR-MSC targeting is achieved by functionalizing the micelle surface with an anti-stem-cell antigen-1 antibody fragment (Fab'). Consequently, therapeutic benefits are obtained by successful suppression of myofibroblast differentiation of LR-MSCs in bleomycin-induced PF model mice treated with siRUNX1-loaded micelles. Furthermore, an excellent synergistic effect of PF therapy is achieved for this micelle system loaded siRUNX1 and glioma-associated oncogene homolog-1 (Gli1) small interfering RNA (siGli1), a traditional anti-PF siRNA of glioma-associated oncogene homolog-1. Hence, this work not only provides RUNX1 as a novel PF therapeutic target, but also as a promising dual siRNA-loaded nanocarrier system for the therapy of PF.
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http://dx.doi.org/10.1002/adma.202007798DOI Listing
March 2021

Biphasic synthesis of biodegradable urchin-like mesoporous organosilica nanoparticles for enhanced cellular internalization and precision cascaded therapy.

Biomater Sci 2021 Apr 17;9(7):2584-2597. Epub 2021 Feb 17.

Department of Chemistry & Biological Engineering, Beijing Key Laboratory for Bioengineering and Sensing Technology, Daxing Research Institute, University of Science & Technology Beijing, Beijing 100083, China.

It is widely accepted that a small particle size and rough surface can enhance tumor tissue accumulation and tumor cellular uptake of nanoparticles, respectively. Herein, sub-50 nm urchin-inspired disulfide bond-bridged mesoporous organosilica nanoparticles (UMONs) featured with a spiky surface and glutathione (GSH)-responsive biodegradability were successfully synthesized by a facile one-pot biphasic synthesis strategy for enhanced cellular internalization and tumor accumulation. l-Arginine (LA) is encapsulated into the mesopores of UMONs, whose outer surface is capped with the gatekeeper of ultrasmall gold nanoparticles, i.e., UMONs-LA-Au. On the one hand, the mild acidity-activated uncapping of ultrasmall gold can realize a tumor microenvironment (TME)-responsive release of LA. On the other hand, the unique natural glucose oxidase (GOx)-mimicking catalytic activity of ultrasmall gold can catalyze the decomposition of intratumoral glucose to produce acidic hydrogen peroxide (HO) and gluconic acid. Remarkably, these products can not only further facilitate the release of LA, but also catalyze the LA-HO reaction for an increased nitric oxide (NO) yield, which realizes synergistic catalysis-enhanced NO gas therapy for tumor eradication. The judiciously fabricated UMONs-LA-Au present a paradigm of TME-responsive nanoplatforms for both enhanced cellular uptake and tumor-specific precision cascaded therapy, which broadens the range of practical biomedical applications and holds a significant promise for the clinical translation of silica-based nanotheranostics.
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http://dx.doi.org/10.1039/d1bm00015bDOI Listing
April 2021

Imaging of Insulinoma by Targeting Glucagonlike Peptide-1 Receptor.

PET Clin 2021 Apr 12;16(2):205-217. Epub 2021 Feb 12.

Yong Loo Lin School of Medicine and Faculty of Engineering, National University of Singapore, Singapore 117597, Singapore. Electronic address:

"Glucagonlike peptide-1 (GLP-1) receptor imaging, using radiolabeled exendin-4, was recently established for detecting insulinoma in patients with hyperinsulinemic hypoglycemia. It has proven to be a sensitive and specific method for preoperative localization of insulinoma. This review introduces the development, clinical research, and perspective of GLP-1 receptor imaging mainly in insulinoma.
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http://dx.doi.org/10.1016/j.cpet.2020.12.008DOI Listing
April 2021

Resection and survival data from a clinical trial of glioblastoma multiforme-specific IRDye800-BBN fluorescence-guided surgery.

Bioeng Transl Med 2021 Jan 31;6(1):e10182. Epub 2020 Aug 31.

Laboratory of Molecular Imaging and Nanomedicine (LOMIN) National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH) Bethesda Maryland USA.

Supra-maximum surgical tumor resection without neurological damage is highly valuable for treatment and prognosis of patients with glioblastoma multiforme (GBM). We developed a GBM-specific fluorescence probe using IRDye800CW (peak absorption/emission, 778/795 nm) and bombesin (BBN), which (IRDye800-BBN) targets the gastrin-releasing peptide receptor, and evaluated the image-guided resection efficiency, sensitivity, specificity, and survivability. Twenty-nine patients with newly diagnosed GBM were enrolled. Sixteen hours preoperatively, IRDye800-BBN (1 mg in 20 ml sterile water) was intravenously administered. A customized fluorescence surgical navigation system was used intraoperatively. Postoperatively, enhanced magnetic resonance images were used to assess the residual tumor volume, calculate the resection extent, and confirm whether complete resection was achieved. Tumor tissues and nonfluorescent brain tissue in adjacent noneloquent boundary areas were harvested and assessed for diagnostic accuracy. Complete resection was achieved in 82.76% of patients. The median extent of resection was 100% (range, 90.6-100%). Eighty-nine samples were harvested, including 70 fluorescence-positive and 19 fluorescence-negative samples. The sensitivity and specificity of IRDye800-BBN were 94.44% (95% CI, 85.65-98.21%) and 88.24% (95% CI, 62.25-97.94%), respectively. Twenty-five patients were followed up (median, 13.5 [3.1-36.0] months), and 14 had died. The mean preoperative and immediate and 6-month postoperative Karnofsky performance scores were 77.9 ± 11.8, 71.3 ± 19.2, and 82.6 ± 14.7, respectively. The median overall and progression-free survival were 23.1 and 14.1 months, respectively. In conclusion, GBM-specific fluorescent IRDye800-BBN can help neurosurgeons identify the tumor boundary with sensitivity and specificity, and may improve survival outcomes.
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http://dx.doi.org/10.1002/btm2.10182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823121PMC
January 2021

Effects of Various Rice-Based Raw Materials on Enhancement of Volatile Aromatic Compounds in Vinegar.

Molecules 2021 Jan 28;26(3). Epub 2021 Jan 28.

Hubei International Scientific and Technological Cooperation Base of Traditional Fermented Foods, Huazhong Agricultural University, Wuhan 430070, China.

vinegar (MV), during whose brewing process spp. and polished rice (PR) are normally used as the starter and the raw material, respectively, is one of the traditional vinegars in China. In this study, the effects of three raw materials, including PR, unhusked rice (UR), and germinated UR (GR), on MV volatile compounds have been investigated. The results revealed that MV of GR (GMV), and its intermediate wine (GMW), exhibited the highest amount of aroma, not only in the concentrations but also in the varieties of the aromatic compounds mainly contributing to the final fragrance. Especially after three years of aging, the contents of benzaldehyde and furfural in GMV could reach to 13.93% and 0.57%, respectively, both of which can coordinate synergistically on enhancing the aroma. We also found that the filtering efficiency was significantly improved when UR and GR were applied as the raw materials, respectively. Therefore, GR might be more suitable raw materials for MV.
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http://dx.doi.org/10.3390/molecules26030687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866154PMC
January 2021

Supramolecular cancer nanotheranostics.

Chem Soc Rev 2021 Feb 1;50(4):2839-2891. Epub 2021 Feb 1.

State Key Laboratory of Chemical Engineering, Center for Chemistry of High-Performance & Novel Materials, Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. China.

Among the many challenges in medicine, the treatment and cure of cancer remains an outstanding goal given the complexity and diversity of the disease. Nanotheranostics, the integration of therapy and diagnosis in nanoformulations, is the next generation of personalized medicine to meet the challenges in precise cancer diagnosis, rational management and effective therapy, aiming to significantly increase the survival rate and improve the life quality of cancer patients. Different from most conventional platforms with unsatisfactory theranostic capabilities, supramolecular cancer nanotheranostics have unparalleled advantages in early-stage diagnosis and personal therapy, showing promising potential in clinical translations and applications. In this review, we summarize the progress of supramolecular cancer nanotheranostics and provide guidance for designing new targeted supramolecular theranostic agents. Based on extensive state-of-the-art research, our review will provide the existing and new researchers a foundation from which to advance supramolecular cancer nanotheranostics and promote translationally clinical applications.
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http://dx.doi.org/10.1039/d0cs00011fDOI Listing
February 2021

Pnictogen Semimetal (Sb, Bi)-Based Nanomaterials for Cancer Imaging and Therapy: A Materials Perspective.

ACS Nano 2021 02 23;15(2):2038-2067. Epub 2021 Jan 23.

State Key Lab of Metal Matrix Composites, School of Materials Science and Engineering, Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China.

Innovative multifunctional nanomaterials have attracted tremendous interest in current research by facilitating simultaneous cancer imaging and therapy. Among them, antimony (Sb)- and bismuth (Bi)-based nanoparticles are important species with multifunction to boost cancer theranostic efficacy. Despite the rapid development, the extensive previous work treated Sb- and Bi-based nanoparticles as mutually independent species, and therefore a thorough understanding of their relationship in cancer theranostics was lacking. We propose here that the identical chemical nature of Sb and Bi, being semimetals, provides their derived nanoparticles with inherent multifunction for near-infrared laser-driven and/or X-ray-based cancer imaging and therapy as well as some other imparted functions. An overview of recent progress on Sb- and Bi-based nanoparticles for cancer theranostics is provided to highlight the relationship between chemical nature and multifunction. The understanding of Sb- and Bi-based nanoparticles in this way might shed light on the further design of smart multifunctional nanoparticles for cancer theranostics.
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http://dx.doi.org/10.1021/acsnano.0c07899DOI Listing
February 2021

A hybrid semiconducting organosilica-based O nanoeconomizer for on-demand synergistic photothermally boosted radiotherapy.

Nat Commun 2021 01 22;12(1):523. Epub 2021 Jan 22.

Yong Loo Lin School of Medicine and Faculty of Engineering, National University of Singapore, 117597, Singapore, Singapore.

The outcome of radiotherapy is significantly restricted by tumor hypoxia. To overcome this obstacle, one prevalent solution is to increase intratumoral oxygen supply. However, its effectiveness is often limited by the high metabolic demand for O by cancer cells. Herein, we develop a hybrid semiconducting organosilica-based O nanoeconomizer pHPFON-NO/O to combat tumor hypoxia. Our solution is twofold: first, the pHPFON-NO/O interacts with the acidic tumor microenvironment to release NO for endogenous O conservation; second, it releases O in response to mild photothermal effect to enable exogenous O infusion. Additionally, the photothermal effect can be increased to eradicate tumor residues with radioresistant properties due to other factors. This "reducing expenditure of O and broadening sources" strategy significantly alleviates tumor hypoxia in multiple ways, greatly enhances the efficacy of radiotherapy both in vitro and in vivo, and demonstrates the synergy between on-demand temperature-controlled photothermal and oxygen-elevated radiotherapy for complete tumor response.
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http://dx.doi.org/10.1038/s41467-020-20860-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822893PMC
January 2021

Lu-DOTA-EB-TATE, a Radiolabeled Analogue of Somatostatin Receptor Type 2, for the Imaging and Treatment of Thyroid Cancer.

Clin Cancer Res 2021 Mar 22;27(5):1399-1409. Epub 2020 Dec 22.

Metabolic Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland.

Purpose: The goal of this study was to analyze the role of somatostatin receptor type 2 (SSTR2) as a molecular target for the imaging and treatment of thyroid cancer through analysis of SSTR2 expression and its epigenetic modulation and testing tumor uptake of different radiolabeled SSTR2 analogues.

Experimental Design: We analyzed SSTR2 expression by immunostaining of 92 thyroid cancer tissue samples and quantified standard uptake values (SUV) of SSTR2 analogue, Ga-DOTA-TATE, by PET/CT imaging in 25 patients with metastatic thyroid cancer. We utilized human thyroid cancer cell lines characterized by differential SSTR2 expression (TT, BCPAP, and FTC133) and rat pancreatic cell line (AR42J) with intrinsically high SSTR2 expression for functional studies. SSTR2-high (AR42J) and SSTR2-low (FTC133) xenograft mouse models were used to test the uptake of radiolabeled SSTR2 analogues and their therapeutic efficacy .

Results: Thyroid cancer had a higher SSTR2 expression than normal thyroid. Hurthle cell thyroid cancer was characterized by the highest Ga-DOTA-TATE uptake [median SUV, 16.5 (7.9-29)] than other types of thyroid cancers. studies demonstrated that radiolabeled DOTA-EB-TATE is characterized by significantly higher tumor uptake than DOTA-TATE ( < 0.001) and DOTA-JR11 ( < 0.001). Treatment with Lu-DOTA-EB-TATE extended survival and reduced tumor size in a mouse model characterized by high somatostatin (SST) analogues uptake (SUV, 15.16 ± 4.34), but had no effects in a model with low SST analogues uptake (SUV, 4.8 ± 0.27).

Conclusions: A novel SST analogue, Lu-DOTA-EB-TATE, has the potential to be translated from bench to bedside for the targeted therapy of patients characterized by high uptake of SST analogues in metastatic lesions.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3453DOI Listing
March 2021

Decoding Human Megakaryocyte Development.

Cell Stem Cell 2021 03 18;28(3):535-549.e8. Epub 2020 Dec 18.

State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China; CAMS Center for Stem Cell Medicine, PUMC Department of Stem Cell and Regenerative Medicine, Tianjin 300020, China. Electronic address:

Despite our growing understanding of embryonic immune development, rare early megakaryocytes (MKs) remain relatively understudied. Here we used single-cell RNA sequencing of human MKs from embryonic yolk sac (YS) and fetal liver (FL) to characterize the transcriptome, cellular heterogeneity, and developmental trajectories of early megakaryopoiesis. In the YS and FL, we found heterogeneous MK subpopulations with distinct developmental routes and patterns of gene expression that could reflect early functional specialization. Intriguingly, we identified a subpopulation of CD42bCD14 MKs in vivo that exhibit high expression of genes associated with immune responses and can also be derived from human embryonic stem cells (hESCs) in vitro. Furthermore, we identified THBS1 as an early marker for MK-biased embryonic endothelial cells. Overall, we provide important insights and invaluable resources for dissection of the molecular and cellular programs underlying early human megakaryopoiesis.
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http://dx.doi.org/10.1016/j.stem.2020.11.006DOI Listing
March 2021

New Opportunities in Cancer Immunotherapy and Theranostics.

Acc Chem Res 2020 12;53(12):2763-2764

Yonsei University.

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http://dx.doi.org/10.1021/acs.accounts.0c00724DOI Listing
December 2020

Size-transformable antigen-presenting cell-mimicking nanovesicles potentiate effective cancer immunotherapy.

Sci Adv 2020 Dec 11;6(50). Epub 2020 Dec 11.

Laboratory of Molecular Imaging and Nanomedicine (LOMIN), National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH), Bethesda, MD 20892, USA.

Artificial antigen-presenting cells (aAPCs) can stimulate CD8 T cell activation. While nanosized aAPCs (naAPCs) have a better safety profile than microsized (maAPCs), they generally induce a weaker T cell response. Treatment with aAPCs alone is insufficient due to the lack of autologous antigen-specific CD8 T cells. Here, we devised a nanovaccine for antigen-specific CD8 T cell preactivation in vivo, followed by reactivation of CD8 T cells via size-transformable naAPCs. naAPCs can be converted to maAPCs in tumor tissue when encountering preactivated CD8 T cells with high surface redox potential. In vivo study revealed that naAPC's combination with nanovaccine had an impressive antitumor efficacy. The methodology can also be applied to chemotherapy and photodynamic therapy. Our findings provide a generalizable approach for using size-transformable naAPCs in vivo for immunotherapy in combination with nanotechnologies that can activate CD8 T cells.
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http://dx.doi.org/10.1126/sciadv.abd1631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732193PMC
December 2020