Chemical Research in Chinese Universities

Themed Issue on Nanomolecular Imaging and Biosensing

GUO Zijian, FAN Chunhai, TIAN Yang, WANG Qiangbin

2021, 37(4): 1-2.

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Electrochemical Sensors Applied for In vitro Diagnosis

LI Duo, WU Chao, TANG Xuehui, ZHANG Yue, WANG Tie

2021, 37(4): 803-822. doi:10.1007/s40242-021-0387-0

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Electrochemical sensing technology has received extensive attention from researchers for its unique detection and analysis methods as well as the promising applications in clinical diagnosis. Compared with other detection methods, such as capillary electrophoresis, high-performance liquid chromatography and liquid chromatography-tandem mass spectrometry, the electrochemical sensor overcomes the disadvantages of expensive cost and complicated operation, as an ideal device for in vitro detection. In this article, we mainly introduce some methods for the detection of biologically important compounds and cancer biomarkers, and briefly summarize the characteristics of these methods at first. And then, we also focus on the latest research progress in the application of electrochemical sensing technology to biologically important compounds' and cancer biomarkers' detection. Finally, the development trend and challenges of electrochemical sensing technology for in vitro diagnosis are also prospected.

Bioimaging Based on Nucleic Acid Nanostructures

HAN Lin, WANG Yuang, TANG Wantao, LIU Jianbing, DING Baoquan

2021, 37(4): 823-828. doi:10.1007/s40242-021-1055-0

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Nucleic acid nanostructures with structural programmability, spatial addressability and excellent biocompatibility have drawn much attention in various biomedical applications, such as bioimaging, biosensing and drug delivery. In this review, we summarize the recent research progress in the field of bioimaging based on nucleic acid nanostructures with different imaging models, including fluorescent imaging(FI), magnetic resonance imaging(MRI), photoacoustic imaging(PAI) and positron emission tomography/computed tomography(PET/CT) imaging. We also discuss the remaining challenges and further opportunities involved in the bioimaging research based on nucleic acid nanostructures.

Conventional Molecular and Novel Structural Mechanistic Insights into Orderly Organelle Interactions

XU Haijiao, WANG Hongda

2021, 37(4): 829-839. doi:10.1007/s40242-021-1191-6

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The orderly organelle interaction network is prerequisite for normal life activity of cell, ensuring a balance between communication and uniqueness of organelles. Disorder organelle interaction is implicated in the occurrence and development of many diseases. An in-depth understanding of mechanisms of orderly organelle interaction helps to reveal the pathogenesis of related diseases. Chemical and genetic tools have identified the roles of specific proteins in orderly organelle interaction; however, little is known about the modes, functions and mechanisms of orderly interaction between organelles. With rapid development of imaging tools, deep-going insights into the structure feature of cell membranes have substantially improved our understanding of the mechanisms of ordered organelle interactions. This review summarizes the conventional molecular mechanism of orderly organelle interactions, and highlights the new progress regarding membrane structure and the novel structural mechanism of orderly organelle transport.

Advanced Nanomaterials for Multimodal Molecular Imaging

YUAN Hui, LIANG Hanyu, HOU Peidong, LI Juan

2021, 37(4): 840-845. doi:10.1007/s40242-021-1196-1

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The development of multimodal molecular imaging contrast agents based on versatile nanomaterials has recently attracted much attention in disease diagnosis and therapeutic delivery. Contrast agents made from nanoparticles and used for multimodal imaging in vivo provide a multidimensional pathophysiological overview of diseases. This review summarizes recently developed advanced nanomaterials for multimodal molecular imaging. We comprehensively discuss these nanoparticle contrast agents in terms of their targeting modalities, limitations in clinical translation and future directions.

Dip-Pen Nanolithography(DPN): from Micro/Nano-patterns to Biosensing

LI Haonan, WANG Zhao, HUO Fengwei, WANG Shutao

2021, 37(4): 846-854. doi:10.1007/s40242-021-1197-0

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Dip-pen nanolithography is an emerging and attractive surface modification technique that has the capacity to directly and controllably write micro/nano-array patterns on diverse substrates. The superior throughput, resolution, and registration enable DPN an outstanding candidate for biological detection from the molecular level to the cellular level. Herein, we overview the technological evolution of DPN in terms of its advanced derivatives and DPN-enabled versatile sensing patterns featuring multiple compositions and structures for biosensing. Benefitting from uniform, reproducible, and large-area array patterns, DPN-based biosensors have shown high sensitivity, excellent selectivity, and fast response in target analyte detection and specific cellular recognition. We anticipate that DPN-based technologies could offer great potential opportunities to fabricate multiplexed, programmable, and commercial array-based sensing biochips.

In vivo Self-assembled Peptide Nanoprobes for Disease Diagnosis

YANG Jia, ZHENG Rui, AN Hongwei, WANG Hao

2021, 37(4): 855-869. doi:10.1007/s40242-021-1130-6

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In vivo imaging is creating great opportunities for disease diagnosis as a research tool. Probes are usually used to observe physiological structures in vivo clearly. Recent progresses of nanoprobes are important for the generation of high resolution and high contrast images required by accurate and precision disease diagnosis. In vivo self-assembled peptide(SAP) nanoprobes are playing major roles in in vivo imaging by modularity of design, high imaging contrast, response to the location of the lesion, and long-time retention in the lesion. And the response to lesion and long-term retention in there can enhance imaging sensitivity and specificity of in vivo SAP nanoprobes. Therefore, in vivo SAP nanoprobes are simple ancillary contrast entities to optimize the imaging effect. In this review, the recent progress of in vivo SAP nanoprobes for in vivo imaging, from molecular design of peptides to biomedical and clinical applications including disease diagnosis and disease-related molecular imaging is systematically summarized. We evaluate their ability, including sensitivity and specificity to provide relevant information under preoperative and during surgery circumstances and critically their likelihood to be clinically translated. Finally, a brief outlook on remaining challenges and potential directions for future research in this area is presented.

A Pretargeting Strategy Enabled by Bioorthogonal Reactions Towards Advanced Nuclear Medicines: Application and Perspective

GAO Yun, CHEN Lei, GE Jianxian, CUI Jiabin, ZENG Jianfeng, GAO Mingyuan

2021, 37(4): 870-879. doi:10.1007/s40242-021-1179-2

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Pretargeting is an innovative and promising approach in nuclear medicine for targeted-imaging/therapy through the following bioorthogonal reactions. It requires two reactive participants, one of which is a targeting vector and the other is a small radiolabeled probe capable of specifically coupling through bioorthogonal reactions with the targeting vector accumulated in the disease site. Compared to the conventional direct targeting approach, such a two-step scheme conceptually can achieve a higher imaging contrast and an improved therapeutic effect owing to the suppressed non-specific targeting. In this review, we will first give a brief introduction on pretargeting systems and the history of bioorthogonal reactions, and then focus on some important works about radionuclide delivering through the bioorthogonal reaction based pretargeting strategy. Finally, we will discuss the steps forward in respect to the future clinical translation and truly hope that this methodology would continue to make contributions to nuclear medicines.

Fluorescent Silicon-based Nanomaterials Imaging Technology in Diseases

CHU Binbin, WANG Houyu, HE Yao

2021, 37(4): 880-888. doi:10.1007/s40242-021-1180-9

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Fluorescence imaging analysis of microscale dynamic process (e.g., metabolism, mitosis, endocytosis, exocytosis, etc.) is of particular significance to study the related pathogenesis and design the intracellular drug delivery systems. Owing to unique physical, chemical and/or biological properties, silicon(Si)-based nanomaterials have been employed to design and construct diffe-rent types of nanoprobes for the imaging analysis of diseases. Thus, we herein present an overview of recent advances in fluorescent silicon nanomaterials imaging technology for analyzing and diagno-sing diseases. Firstly, we mainly introduce the construction of Si nanomaterials-based bioprobes for long-term fluorescence imaging analysis of cancer-related biological information, such as tumour cells, biomarkers and nanocarriers. Afterwards, we focus on the Si nanomaterials-based imaging technology for monitoring the dynamic process of pathological changes of various ocular diseases (e.g., ocular angiogenesis, bacterial keratitis, etc.). Then, we outline the construction of Si-based nanoprobes and their applications in simultaneously imaging and treating the bacteria-induced diseases caused by broad-spectrum bacteria-related pathogens. Finally, we further discuss the major challenges and prospects for developing silicon-based fluorescence imaging technology.

In situ Activatable Peptide-based Nanoprobes for Tumor Imaging

LIU Zhiyu, LIANG Gaolin, ZHAN Wenjun

2021, 37(4): 889-899. doi:10.1007/s40242-021-1181-8

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Owing to its excellent biological properties, peptide has been widely used in the design of nanoprobes capable of enhancing tumor imaging signals. In recent years, a number of peptide-based nanoprobes with strong loading capacity and great biocompatibility have been developed for precision tumor imaging by coupling peptide motifs with different imaging agents. It is worth noting that, compared with "always on" mode, the use of stimulus-mediated in situ activatable mode to design and control the self-assembly or nanostructure transformation of peptide-based nanoprobes in vivo can achieve the significant improvement of imaging efficiency. Herein, we summarize the recent progress of in situ activatable peptide-based nanoprobes for tumor imaging in diverse imaging modes, including magnetic resonance imaging(MRI), fluorescence imaging(FI), photoacoustic imaging(PAI), radionuclide imaging(RI) and multimodal imaging. Finally, we briefly prospect the challenges and potential development directions of this field.

Surface-enhanced Raman Scattering Technology Based on WO₃ Film for Detection of VEGF

LIU Xiaoyan, ZHOU Yan, ZHENG Tingting, TIAN Yang

2021, 37(4): 900-905. doi:10.1007/s40242-021-1192-5

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With the advancement of nanomaterials for surface-enhanced Raman scattering(SERS) detection, a deeper understanding of the chemical mechanism(CM) and further applications has been achieved. Herein, we prepared a porous tungsten trioxide(WO₃) film by the pulse electrodeposition method, and constructed a WO₃ film SERS aptasensor. With methylene blue(MB) as the adsorption molecule, the developed WO₃ film SERS aptasensor revealed remarkable Raman activity. Through experimental data and theoretical calculations, we found that the significant SERS enhancement[enhancement factor(EF)=1.5×10⁶] was due to the CM based on charge transfer and molecular resonance. Utilizing the Raman response of MB on the WO₃ film and specific aptamers, we successfully developed the aptamer sensor by covalently attaching the MB modified aptamer to the WO₃ film. The sensor realized the specific and sensitive determination of vascular endothelial growth factor(VEGF) with the detection limit down to 8.7 pg/mL. In addition, the developed aptasensor indicated the excellent selectivity among other interferences, such as metal ions, reactive oxygen species(ROS), and proteins. This WO₃ film SERS aptasensor not only contributed to the study of the enhancement mechanism of semiconductor material, but also provided a powerful platform for the sensitive detection of VEGF, possessing a great potential in the real-time monitoring of biomarkers of glioblastoma in vitro.

A Combinatorial Approach Based on Nucleic Acid Assembly and Electrostatic Compression for siRNA Delivery

REN Yiqing, LIU Xinlong, GE Huan, GUO Yuanyuan, ZHANG Qiushuang, XIE Miao, WANG Ping, ZHU Xinyuan, ZHANG Chuan

2021, 37(4): 906-913. doi:10.1007/s40242-021-1168-5

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Acombinatorial strategy based on nucleic acid assembly and electrostatic complexation is developed for efficient small interfering ribonucleic acid(siRNA) delivery. In this approach, siRNAs are first loaded into a well-defined nanotube through programmable nucleic acid self-assembly. Compared to small rigid siRNA duplex, the obtained siRNA-bearing nanotube with large architecture is more readily to complex with cationic and ionizable poly(β-amino ester), resulting in the formation of a novel platform for efficient siRNA delivery.

Catalytic DNA Origami-based Chiral Plasmonic Biosensor

LIU Zhenyu, DONG Jinyi, PAN Jiahao, ZHOU Chao, FAN Chunhai, WANG Qiangbin

2021, 37(4): 914-918. doi:10.1007/s40242-021-1115-x

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Plasmonic circular dichroism(CD) has been emerged as a pro-mising signal for building biosensors due to its high sensitivity and specificity. In the past years, DNA nanotechnology enabled diverse chiral plasmonic devices, which can response biomolecules and then generate dynamic plasmonic CD signals at the visible range. Although some of them have been successfully employed as biosensors, the detection sensitivity is still relatively low. Herein we report a chiral plasmonic sensor with an improved detection sensitivity by integrating catalytic hairpin assembly circuits into DNA origami structures. We tested two kinds of tumor marker RNA sequences as detection targets and it turns out that the detection limit is below 10 pmol/L, improving one order of magnitude compared to previous work. The chiral plasmonic sensor with internal signal amplification circuits can stimulate a variety of smart nano-sensors for biological detection and offer a promising strategy for pathogenic RNA detection with plasmonic CD output.

DNA Framework-based Topological Aptamer for Differentiating Subtypes of Hepatocellular Carcinoma Cells

YIN Fangfei, CAO Nan, XIANG Xuelin, FENG Hao, LI Fan, LI Min, XIA Qiang, ZUO Xiaolei

2021, 37(4): 919-924. doi:10.1007/s40242-021-1159-6

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Hepatocellular carcinoma(HCC) remains a global health challenge with a growing incidence worldwide. The accurate identification of liver HCC cell subtypes plays crucial roles in precision medicine and prognosis. Nevertheless, simple and efficient methods for cell subtype discrimination still remain an issue to be studied. In this study, we construct topological probes by using a tetrahedral DNA framework(TDF) to topologically engineer the spatial orientations of the aptamers. The three vertexes of a TDF were algebraic topologically anchored with aptamers targeting epithelial cell adhesion molecule(EpCAM), which may express differently on different subtypes of HCC cells. Using the TDF-based topological aptamer(TDF-TA), we accomplish the differentiation of HCC cell subtypes, including high-metastatic, low-metastatic HCC and normal cells based on flow cytometry(FCM) and fluorescence microscope imaging. By replacing the fluorescent indicator modified on aptamers with photoacoustic dyes, we achieve the discrimination of different HCC cells using photoacoustic imaging technology, further demonstrating the feasibility of the TDF-based topological probe for HCC cell subtype discrimination. This TDF-based topolo-gical engineering strategy thus provides a flexible means for subtype cell discrimination, which may provide new ideas for achieving accurate diagnosis of HCC.

A Cyanine-based Liposomal Nanophotosensitizer for Enhanced Cancer Chemo-Photodynamic Therapy

LI Mengqi, MA He, SHI Chao, ZHANG Han, LONG Saran, SUN Wen, DU Jianjun, FAN Jiangli, PENG Xiaojun

2021, 37(4): 925-933. doi:10.1007/s40242-021-1186-3

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Currently, chemotherapy is one of the most important treatment modalities for malignant tumors in the clinic, however, it exhibits some shortcomings, such as poor selectivity, limited efficacy and serious adverse effects. Therefore, synergistic therapy and accurate drug delivery at tumor sites become a promising strategy for achieving tumor eradication. Herein, a smart NIR fluorescence imaging-guided nanoliposome was fabricated by encapsulating a chemotherapeutic drug(doxorubicin, DOX), liposomes(L) and a near-infrared(NIR) photosensitizer(CY) to form L@CY@DOX, which could realize enhanced therapeutic efficacy of chemo-PDT in cancer therapy(PDT=photodynamic therapy). L@CY@DOX can induce mitochondrial apoptosis and produce severe toxicity at the cellular level, and L@CY@DOX can enrich in the tumor site, which significantly induces tumor death. In vitro and in vivo studies demonstrated that L@CY@DOX exhibited great antitumor efficacy compared with each one of these monotherapies, indicating that the combination of chemotherapy and PDT possessed potential development prospects and is anticipated in clinical application.

Theranostic Gold Nanoclusters for NIR-II Imaging and Photodynamic Therapy

TANG Lin, ZENG Xiaodong, ZHOU Hui, GUI Conghao, LUO Qiulin, ZHOU Wenyi, WU Jing, LI Qianqian, LI Yang, XIAO Yuling

2021, 37(4): 934-942. doi:10.1007/s40242-021-1117-3

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Fluorescence imaging in the second near-infrared window(NIR-II, 1000-1700 nm) has demonstrated tremendous promise for biomedical applications, with its extraordinarily high resolution and deep tissue penetration. Ultrasmall gold nanoclusters(AuNCs) have shown unique features for NIR-II imaging, such as photostability and biocompatibility, as compared to organic NIR-II molecules or other inorganic NIR-II nanoparticles. Here, we report the first-in-class protein-capped ultrasmall AuNCs(BSA-AuNCs, BSA=bovine serum albumin) for simultaneous NIR-II imaging and photodynamic therapy. The BSA-AuNCs show a uniform size, high quantum yield and excellent photostability, display a high accumulation and long retention in 4T1 tumor, and are used for clear imaging of blood vessels and lymph nodes. Moreover, laser irradiation of these AuNCs can rapidly trigger ROS generation, leading to effective inhibition of tumor cell growth in vitro and in vivo. This study demonstrates the feasibility of a protein-capped ultrasmall AuNCs platform for theranostic applications by combining NIR-II imaging and photodynamic cancer therapy.

Rare-earth Doped Nanoparticles with Narrow NIR-II Emission for Optical Imaging with Reduced Autofluorescence

LU Feng, ZHAO Ting, SUN Xiaojun, WANG Zuqiang, FAN Quli, HUANG Wei

2021, 37(4): 943-950. doi:10.1007/s40242-021-1172-9

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Fluorescence imaging in the second near-infrared region(900-1700 nm, NIR-II) with a high resolution and penetration depth due to the significantly reduced tissue scattering and autofluorescence has emerged as a useful tool in biomedical fields. Recently, many efforts have been devoted to the development of fluorophores with an emission band covering the long-wavelength end of NIR-II region(1500-1700 nm) to eliminate the autofluorescence. Alternatively, we believe imaging with a narrow bandwidth could also reduce the autofluorescence. As a proof of concept, NaYF₄:Yb,Nd@NaYF₄ downconversion nanoparticles(DCNPs) with sharp NIR-II emission were synthesized. The luminescence of DCNPs showed a half-peak width of 49 nm centered at 998 nm, which was perfectly matched with a (1000±25) nm bandpass filter. With this filter, we were able to retain most of the emissions from the nanoparticles, while the autofluorescence was largely reduced. After PEGylation, the DCNPs exhibited great performance for blood vessel and tumor imaging in living mice with significantly reduced autofluorescence and interference signals. This work provided an alternative way for the low-autofluorescence imaging and emphasized the importance of narrow emitting rare-earth doped nanoparticles for NIR-II imaging.

Near-infrared Aza-BODIPY Dyes Through Molecular Surgery for Enhanced Photothermal and Photodynamic Antibacterial Therapy

YU Qing, HUANG Xuan, ZHANG Tian, WANG Weili, YANG Dongliang, SHAO Jinjun, DONG Xiaochen

2021, 37(4): 951-959. doi:10.1007/s40242-021-1190-7

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The widespread use of high-dose antibiotics will not only lead to the rapid acquisition of antibiotic resistance and increased incidence of drug-resistant bacterial infections, but also produce toxic side effects on normal tissues. Herein, two near-infrared dyes BDP-4PTZ and BDP-4DPA were synthesized, and the electron donors of diphenylamine and phenothiazine with the only difference of sulphur(S)-lock between the two phenyl rings were introduced onto the electron acceptor aza-dipyrromethene boron difluoride(aza-BODIPY) through molecular surgery. Through co-precipitation into nanoparticles(NPs), BDP-4PTZ NPs and BDP-4DPA NPs were fabricated with good biocompatibility. Upon 660 nm photoirradiation, BDP-4PTZ NPs and BDP-4DPA NPs showed excellent photothermal conversion efficiency(43% and 50%, respectively) and reactive oxygen species(ROS) production performance(ca. 3.6 and 6 times higher than that of indocyanine green, respectively). In vitro antibacterial experiments indicated that both NPs could effectively destroy the bacteria's membrane to eradicate drug-resistant bacteria. Furthermore, the bacterial abscess was effectively eliminated after treatment with BDP-4DPA NPs under 660 nm photoirradiation without adverse effects. Thus, through molecular surgery, BDP-4DPA without the S-lock demonstrates synergistic photothermal and photodynamic antimicrobial activities, which is promising for further molecular design towards effective neo-antimicrobial phototherapy.

Excimer-based Activatable Fluorescent Sensor for Sensitive Detection of Alkaline Phosphatase

YUAN Fang, LI Yang, CHEN Zhenjuan, ZHANG Jianjian, NING Lulu, YANG Xiao-Feng, PU Kanyi

2021, 37(4): 960-966. doi:10.1007/s40242-021-1194-3

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The accurate detection of related biomarkers at early stage is crucial in diagnosis and therapy of cancer. Small molecule fluorescence probes stand out acting as efficient tools to detect biomolecules, especially biomacromolecules. Herein, a new probe that features excimer formation has been designed to detect cancer-related biomarker alkaline phosphatase(ALP). The probe shows high sensitivity to ALP with a low limit detection of 0.13 U/L and high selectivity with resistance to the interference in the complex physiological system. Furthermore, this probe presents good biocompatibility with negligible cytotoxicity and displays remarkable cell imaging functions, which allows for its application in biosystems.Theoretical simulation validates the high affinity of the probe with ALP and depicts the details of the interaction modes, which provides the possible mechanisms underlying the efficient detection of the probe in atomic level. The study of synthesis, properties and applications of the activatable emissive excimers not only enriches the tools to detect ALP, but also provides a new strategy to comprehend the pathogenic mechanism of enzyme-related diseases.

ICG and Sunitinib-loaded NH₂-MOFs for Folate-mediated Hepatocellular Carcinoma Dual-modal Therapy

ZHANG Zhoujing, LIU Chuang, Ozioma AKAKURU, XU Wenjing, WU Aiguo, ZHANG Yewei

2021, 37(4): 967-974. doi:10.1007/s40242-021-1206-3

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This research investigated a novel folic acid(FA)-modified zirconium core metal-organic framework(MOF) Uio-66 as a nanocarrier to deliver indocyanine green(ICG) and Sunitinib to cancer cells for combination therapy. Platinum-loaded Uio-66 nanoparticles(Pu) were synthesized via a one-pot method, followed by the modification with FA on their surfaces. This afforded FPu that enabled subsequent loading of ICG and Sunitinib to achieve dual-modal cancer therapy. Drug loading/release test and singlet oxygen detection were also conducted in vitro, and the nanoparticles showed considerable drug loading efficiency for both ICG and Sunitinib, coupled with a high singlet oxygen generation rate. Specifically, drug loading and encapsulation efficiency of Sunitinib were 2.30% and 72.67%, while those for ICG were 2.87% and 90.28%, respectively. Additionally, cytotoxicity test on HepG2 human hepatocellular carcinoma cancer cell line revealed that the fully functional nanoparticles possess excellent biocompatibility and as such could be further investigated as a potential drug delivery system for effectual carcinoma cancer treatment.

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