A novel dual-function SERS-based identification strategy for preliminary screening and accurate diagnosis of circulating tumor cells.

Non-specific adsorption of bioprobes based on surface-enhanced Raman spectroscopy (SERS) technology inevitably endows white blood cells (WBC) in the peripheral blood with Raman signals, which greatly interfere the identification accuracy of circulating tumor cells (CTCs). In this study, an innovative strategy was proposed to effectively identify CTCs by using SERS technology assisted by a receiver operating characteristic (ROC) curve. Firstly, a magnetic Fe3O4-Au complex SERS bioprobe was developed, which could effectively capture the triple negative breast cancer (TNBC) cells and endow the tumor cells with distinct SERS signals. Then, the ROC curve obtained based on the comparison of SERS intensity of TNBC cells and WBC was used to construct a tumor cell identification model. The merit of the model was that the detection sensitivity and specificity could be intelligently switched according to different identification purposes such as accurate diagnosis or preliminary screening of tumor cells. Finally, the difunctional recognition ability of the model for accurate diagnosis and preliminary screening of tumor cells was further validated by using the healthy human blood added with TNBC cells and blood samples of real tumor patients. This novel difunctional identification strategy provides a new perspective for identification of CTCs based on the SERS technology.

Latest advances and perspectives of liquid biopsy for cancer diagnostics driven by microfluidic on-chip assays.

Microfluidic-based lab-on-a-chip technology is a multidisciplinary approach, which has evolved rapidly in the past decade and remains a hot research topic as a promising microanalysis platform for a plethora of biomedical applications. Microfluidic chips have been successfully applied in cancer diagnosis and monitoring, given that they can lead to the effective separation and analysis of cancer-derived substances such as extracellular vesicles (EVs), circulating tumour cells (CTCs) and circulating DNA (ctDNA), proteins and other metabolites. In particular, EVs and CTCs are two outstanding objects for cancer liquid biopsy, which share similar membrane structures but possess different sizes. Through molecular typing and concentration detection of EVs, CTCs and ctDNA, disease-related information can be well-learned, including the development stage and prognosis of cancer. However, the conventional separation and detection methods are often time-consuming with limited efficiency. In comparison, the use of microfluidic platforms can effectively simplify the separation and enrichment process and improve the detection efficiency significantly. Although review papers have been published on the application of microfluidic chips for the analysis of objects of liquid biopsy, generally they focused on a specific detection target, lacking a descriptive extraction of the commonality of LOC devices used in liquid biopsy. Thus, few of them present a comprehensive overview and outlook on the design and application of microfluidic chips for liquid biopsy. This motivated us to prepare this review paper, which is divided into 4 parts. The first part aims to elucidate the material selection and fabrication approaches of microfluidic chips. In the second part, the important separation strategies, including physical methods and biological methods, are discussed. The third part highlights the advanced on-chip technologies for the detection of EVs, CTCs and ctDNA by providing practical examples. In the fourth part, novel on-chip applications of single cells/exosomes are introduced. Finally, the prospective outlook and challenges for the long-term development of on-chip assays are envisioned and discussed.

Gold nanorods with iron oxide dual-modal bioprobes in SERS-MRI enable accurate programmed cell death ligand-1 expression detection in triple-negative breast cancer.

The efficiency of immunotherapy for triple-negative breast cancer (TNBC) is relatively low due to the difficulty in accurately detecting immune checkpoints. The detection of TNBC-related programmed cell death ligand-1 (PD-L1) expression is important to guide immunotherapy and improve treatment efficiency. Surface-enhanced Raman spectroscopy (SERS) and magnetic resonance (MR) imaging exhibit great potential for early TNBC diagnosis. SERS, an optical imaging mode, has the advantages of high detection sensitivity, good spatial resolution, and "fingerprint" spectral characteristics; however, the shallow detection penetration of SERS bioprobes limits its application in vivo. MR has the advantages of allowing deep penetration with no radiation; however, its spatial resolution needs to be improved. SERS and MR have complementary imaging features for tumor marker detection. In this study, gold nanorod and ultrasmall iron oxide nanoparticle composites were developed as dual-modal bioprobes for SERS-MRI to detect PD-L1 expression. Anti-PD-L1 (aPD-L1) was utilized to improve the targeting ability and specificity of PD-L1 expression detection. TNBC cells expressing PD-L1 were accurately detected via the SERS imaging mode in vitro, which can image at the single-cell level. In addition, bioprobe accumulation in PD-L1 expression-related tumor-bearing mice was simply and dynamically monitored and analyzed in vivo using MR and SERS. To the best of our knowledge, this is the first time a SERS-MRI dual-modal bioprobe combined with a PD-L1 antibody has been successfully used to detect PD-L1 expression in TNBC. This work paves the way for the design of high-performance bioprobe-based contrast agents for the clinical immunotherapy of TNBC.

Dual-infinite coordination polymer-engineered nanomedicines for dual-ion interference-mediated oxidative stress-dependent tumor suppression.

Recently, nanomedicine design has shifted from simple nanocarriers to nanodrugs with intrinsic antineoplastic activities for therapeutic performance optimization. In this regard, degradable nanomedicines containing functional inorganic ions have blazed a highly efficient and relatively safe ion interference paradigm for cancer theranostics. Herein, given the potential superiorities of infinite coordination polymers (ICPs) in degradation peculiarity and functional integration, a state-of-the-art dual-ICP-engineered nanomedicine is elaborately fabricated via integrating ferrocene (Fc) ICPs and calcium-tannic acid (Ca-TA) ICPs. Thereinto, Fc ICPs, and Ca-TA ICPs respectively serve as suppliers of ferrous iron ions (Fe2+) and calcium ions (Ca2+). After the acid-responsive degradation of ICPs, released TA from Ca-TA ICPs facilitated the conversion of released ferric iron (Fe3+) from Fc ICPs into highly active Fe2+. Owing to the dual-path oxidative stress and neighboring effect mediated by Fe2+ and Ca2+, such a dual-ICP-engineered nanomedicine effectively induces dual-ion interference against triple-negative breast cancer (TNBC). Therefore, this work provides a novel antineoplastic attempt to establish ICP-engineered nanomedicines and implement ion interference-mediated synergistic therapy.

Effective Separation of Cancer-Derived Exosomes in Biological Samples for Liquid Biopsy: Classic Strategies and Innovative Development.

Liquid biopsy has remarkably facilitated clinical diagnosis and surveillance of cancer via employing a non-invasive way to detect cancer-derived components, such as circulating tumor DNA and circulating tumor cells from biological fluid samples. The cancer-derived exosomes, which are nano-sized vesicles secreted by cancer cells have been investigated in liquid biopsy as their important roles in intracellular communication and disease development have been revealed. Given the challenges posed by the complicated humoral microenvironment, which contains a variety of different cells and macromolecular substances in addition to the exosomes, it has attracted a large amount of attention to effectively isolate exosomes from collected samples. In this review, the authors aim to analyze classic strategies for separation of cancer-derived exosomes, giving an extensive discussion of advantages and limitations of these methods. Furthermore, the innovative multi-strategy methods to realize efficient isolation of cancer-derived exosomes in practical applications are also presented. Additionally, the possible development trends of exosome separation in to the future is discussed in this review.

TiO2-based Surface-Enhanced Raman Scattering bio-probe for efficient circulating tumor cell detection on microfilter.

Circulating tumor cell (CTC) detection as a burgeoning detection strategy can identify the tumor lesion in the early stage, and facilitates the understanding of tumorigenesis, tumor progression, metastasis, and drug-resistance. Herein, we present a novel strategy for in situ isolating and directly detecting CTCs from peripheral blood at single-cell resolution using black TiO2 (B-TiO2)-based Surface-Enhanced Raman Scattering (SERS) bio-probe on a microfilter. CTCs were isolated from blood by microfilter based on the size and deformation difference. The SERS bio-probe was composed of crystal-amorphous core-shell B-TiO2 nanoparticles (NPs), alizarin red (AR) as Raman reporter molecules, and a thin protective layer of NH2-PEG2000-COOH (PEG), which provided sufficient binding sites for target molecule of folic acid (FA). Demonstrated by three cell lines of MCF-7 (folate receptor (FR) positive), A549 and Raw264.7 (FR negative), SERS bio-probe of B-TiO2-AR-PEG-FA could distinguish FR positive CTCs from peripheral blood cells efficiently by targeting FR on CTC membranes and ruling out false positive interference of white blood cells (WBCs) with reliability and specificity. Benefiting by these advantages, this strategy enhanced the detection efficiency and veracity, which reduced the detection time within 1.5 h and make the LOD of detection reduced to 2 cells/mL. These features also facilitated successful CTC detection in several clinical cancer patient bloods which illustrates that the integration of microfluidic isolation and SERS detection may open new paths for liquid biopsy.

Magnetomechanical force: an emerging paradigm for therapeutic applications.

Mechanical forces, which play a profound role in cell fate regulation, have prompted the rapid development and popularization of mechanobiology. More recently, magnetic fields in combination with intelligent materials featuring magnetic responsiveness have been identified as a spatially and time-controlled transducing paradigm to generate magnetomechanical forces and induce a therapeutic effect. Herein, recent magnetic materials and magnetic regulation systems are summarized, which offer opportunities for magnetomechanical force manipulation in a precise manner. Additionally, promising applications based on magnetomechanical force including drug controlled release, cancer therapy, and regenerative medicine are highlighted, with respect to both in vitro and in vivo. Furthermore, perspectives on the further development of magnetomechanical force are commented on, mainly emphasizing scientific restrictions and exploitation directions.

A TiO2-based bioprobe enabling excellent SERS activity in the detection of diverse circulating tumor cells.

Circulating tumor cells (CTCs) can be the seeds of tumor metastasis and are closely linked to cancer-related death. Fast and effective detection of CTCs is important for the early diagnosis of cancer and the evaluation of micrometastasis. However, the extreme rarity and heterogeneity of CTCs in peripheral blood make sensitive detection of CTCs a big challenge. In this paper, a TiO2-based surface-enhanced Raman scattering (SERS) bioprobe is reported for the first time with outstanding ultrasensitive specificity, excellent stability of the signal, and good biocompatibility for the detection of CTCs. The TiO2 NPs were encoded with alizarin red (AR) and functionalized with reduced bovine serum protein (rBSA) and folic acid (FA). The limit of detection (LOD) for 4-mercaptobenzoic acid (4-MBA) and AR molecules adsorbed on the TiO2 SERS substrate is 5 × 10-7 M. The designed TiO2-based SERS bioprobe can be effectively utilized in detecting four diverse types of cancer cells in rabbit blood, which shows good sensitivity of the SERS detection technology. Finally, precise targeting of CTCs based on the SERS bioprobe with the function of fluorescence imaging is also confirmed by the fluorescence colouration test. This work offers a novel strategy for CTC detection and the development of non-noble metal semiconductor-based SERS platforms for tumor diagnosis.

Ultrahigh SERS activity of the TiO2@Ag nanostructure leveraged for accurately detecting CTCs in peripheral blood.

Circulating tumor cells (CTCs) usually shed from primary and metastatic tumors serve as an important tumor marker, and easily cause fatal distant metastasis in cancer patients. Accurately and effectively detecting CTCs in a peripheral blood sample is of great significance in early tumor diagnosis, efficacy evaluation, and postoperative condition monitoring. In this work, a TiO2@Ag nanostructure is structured as a SERS substrate, rhodamine 6G (R6G) is used as a Raman signal molecule, the reduced bovine serum protein (rBSA) acts as a protective agent, and folic acid (FA) acts as a target molecule to specifically recognize cancer cells. A TiO2@Ag-based SERS bioprobe is successfully prepared with the feature of ultrahigh sensitivity, good specificity, low toxicity, and high accuracy in CTC detection. The remarkable SERS activity of the TiO2@Ag nanostructure is synergistically contributed by surface plasmon resonance and photon-induced charge transfer mechanism. The limit of detection for rhodamine 6G (R6G) molecules adsorbed on the TiO2@Ag SERS substrate is 5 × 10-14 M, and the corresponding SERS enhancement factor can reach 7.61 × 107. The designed TiO2@Ag-R6G-rBSA-FA SERS bioprobe is effectively utilized in detecting various cancer cells in rabbit blood, and the limit of detection (LOD) for the target cancer cell is 1 cell per mL. Notably, CTCs in peripheral blood of six clinical liver cancer patients are successfully recognized via the TiO2@Ag-based SERS bioprobe. Accurately recognizing CTCs in peripheral blood based on the TiO2@Ag-R6G-rBSA-FA SERS bioprobe is also carefully verified by in situ immunofluorescence staining experiments, which directly supports the CTC detection accuracy of the SERS strategy. These results demonstrate that the TiO2@Ag-based SERS bioprobe has great application potential in early screening and diagnosis of tumors.

Nanoplatform-mediated calcium overload for cancer therapy.

Mitochondria, as the "the power plants" of cells, have been extensively studied because of their biological functions of providing energy and participating in signaling pathways. In parallel, calcium (Ca2+) plays a vital role in the homeostasis balance and function coordination of mitochondria, especially in cancer cells which metabolize frequently to maintain their growth. On this basis, Ca2+ overload has been an efficient, yet safe theranostic model for cancer therapy, by activating mitochondrial apoptosis pathways to achieve cancer suppression. However, the integration of functional units mediating Ca2+ overload into the nanoplatform remains a difficult but significant task. This review aims to highlight meaningful designs of nanoplatforms for Ca2+ overload, including monotherapy and combination therapy. In addition, perspectives on further development of Ca2+ overload are provided, mainly emphasizing scientific restrictions and future exploitation directions.

Octahedral silver oxide nanoparticles enabling remarkable SERS activity for detecting circulating tumor cells.

The detection of circulating tumor cells (CTCs) is a crucial tool for early cancer diagnosis, prognosis, and postoperative evaluation. However, detection sensitivity remains a major challenge because CTCs are extremely rare in peripheral blood. To effectively detect CTCs, octahedral Ag2O nanoparticles (NPs) with high dispersibility, good biocompatibility, remarkable surface-enhanced Raman scattering (SERS) enhancement, and obvious enhancement selectivity are designed as an SERS platform. Ag2O NPs with many oxygen vacancy defects are successfully synthesized, which exhibit an ultra-high SERS enhancement factor (1.98×106) for 4-mercaptopyridine molecules. The remarkable SERS activity of octahedral Ag2O NPs is derived from the synergistic effect of the surface defect-promoted photo-induced charge transfer (PICT) process and strong vibration coupling resonance in the Ag2O-molecule SERS complex, greatly amplifying the molecular Raman scattering cross-section. The promoted PICT process is confirmed using ultraviolet-visible (UV-Vis) absorption spectroscopy, demonstrating that obvious PICT resonance occurs in Ag2O SERS system under visible light. An additional growth step of SERS bioprobe is proposed by modifying the Raman signal molecules and functional biological molecules on Ag2O NPs for CTC detection. The Ag2O-based SERS bioprobe exhibits excellent detection specificity for different cancer cells in rabbit blood. Importantly, the high-sensitivity Ag2O-based SERS bioprobe satisfies the requirement for rare CTC detection in the peripheral blood of cancer patients, and the detection limit can reach 1 cell per mL. To our knowledge, this study is the first time that a semiconductor SERS substrate has been successfully utilized in CTC detection. This work provides new insights into CTC detection and the development of novel semiconductor-based SERS platforms for cancer diagnosis.

Boosting Chemodynamic Therapy via a Synergy of Hypothermal Ablation and Oxidation Resistance Reduction.

Chemodynamic therapy (CDT), deemed as a cutting-edge antineoplastic therapeutic tactics, efficaciously suppresses tumors via catalytically yielding hydroxyl radicals (•OH) in tumor regions. Nevertheless, its biomedical applications are often restricted by the limited hydrogen peroxide (H2O2) level and upregulated antioxidant defense. Herein, a versatile nanoreactor is elaborately designed via integrating Cu2-xS and MnO2 for T1-weighted magnetic resonance (MR) imaging-guided CDT, synergistically enhanced through hypothermal ablation and oxidation resistance reduction, thereby displaying splendid antitumor efficiency as well as suppression on pulmonary metastasis. The as-synthesized Cu2-xS@MnO2 nanoreactors afford acid-dependent Cu-based and glutathione (GSH)-activated Mn-based catalytic properties for bimodal CDT. Owing to excellent absorbance at the second near-infrared (NIR-II) window, the Cu2-xS furnishes hypo-photo-thermal therapy (PTT) against tumor growth and ameliorates the catalytic performance for thermal-enhanced CDT. Additionally, MnO2 significantly downregulates GSH and glutathione peroxidase 4, which synergistically boosts CDT via promoting oxidative stress, simultaneously generating Mn2+ for MR contrast improvement and activatable tumor imaging. Therefore, this study proffers a new attempt centered on the collaborative strategy integrating NIR-II hypothermal PTT and synergistically enhanced CDT for tumor eradication.

An intelligent tumor microenvironment responsive nanotheranostic agent for T1/T2 dual-modal magnetic resonance imaging-guided and self-augmented photothermal therapy.

Photothermal therapy (PTT), as a promising antineoplastic therapeutic strategy, has been harnessed to restrain tumor growth through near-infrared (NIR) irradiation mediated thermal ablation. Nevertheless, its biological applications are hampered by thermal diffusion and up-regulated heat shock proteins (HSPs). Herein, a versatile nanotheranostic agent is developed via integrating Zn0.2Fe2.8O4 nanoparticles (NPs), polydopamine (PDA), and MnO2 NPs for T1/T2 dual-modal magnetic resonance (MR) imaging-guided and self-augmented PTT. The as-designed Zn0.2Fe2.8O4@PDA@MnO2 NPs adequately serve as a PTT agent to realize effective photothermal conversion and obtain local hyperthermia. Additionally, the Zn0.2Fe2.8O4@PDA@MnO2 NPs can significantly consume overexpressed glutathione (GSH) and generate Mn2+ in the tumor microenvironment (TME), thus destroying redox homeostasis and catalytically generating hydroxyl radicals (˙OH) for HSP suppression and PTT enhancement. Meanwhile, Mn2+ and Zn0.2Fe2.8O4 NPs significantly strengthen T1- and T2-weighted MR contrast for tumor imaging and PTT guidance. Hence, this study offers proof of concept for self-augmented PTT and T1/T2 dual-modal MR imaging for tumor elimination.

Research progress and mechanism of nanomaterials-mediated in-situ remediation of cadmium-contaminated soil: A critical review.

Cadmium contamination of soil is a global issue and in-situ remediation technology as a promising mitigation strategy has attracted more and more attention. Many nanomaterials have been applied for the in-situ remediation of cadmium-contaminated soil due to their excellent properties of the nano-scale size effect. In this work, recent research progress of various nanomaterials, including carbon nanomaterials, metal-based nanomaterials and nano mineral materials, in the removal of cadmium and in-situ remediation of cadmium-contaminated soil were systematically discussed. Additional emphases were particularly laid on both laboratory and field restoration effects. Moreover, the factors which can affect the stability of cadmium, main interaction mechanisms between nanomaterials and cadmium in the soil, and potential future research direction were also provided. Therefore, it is believed that this work will ultimately contribute to the myriad of environmental cleanup advances, and further improve human health and sustainable development.

Public-Health-Driven Microfluidic Technologies: From Separation to Detection.

Separation and detection are ubiquitous in our daily life and they are two of the most important steps toward practical biomedical diagnostics and industrial applications. A deep understanding of working principles and examples of separation and detection enables a plethora of applications from blood test and air/water quality monitoring to food safety and biosecurity; none of which are irrelevant to public health. Microfluidics can separate and detect various particles/aerosols as well as cells/viruses in a cost-effective and easy-to-operate manner. There are a number of papers reviewing microfluidic separation and detection, but to the best of our knowledge, the two topics are normally reviewed separately. In fact, these two themes are closely related with each other from the perspectives of public health: understanding separation or sorting technique will lead to the development of new detection methods, thereby providing new paths to guide the separation routes. Therefore, the purpose of this review paper is two-fold: reporting the latest developments in the application of microfluidics for separation and outlining the emerging research in microfluidic detection. The dominating microfluidics-based passive separation methods and detection methods are discussed, along with the future perspectives and challenges being discussed. Our work inspires novel development of separation and detection methods for the benefits of public health.

Rational design of nanomedicine for photothermal-chemodynamic bimodal cancer therapy.

Given the diversity, complexity, and heterogeneity of persistent tumors, traditional nanoscale monotherapeutic systems suffer from dissatisfactory curative efficiency with incidence of metastasis or relapse. In parallel, the trend of clinical research on the basis of nanomedicines has increasingly shifted from monotherapy toward combinatorial therapy for admirable synergetic performances. In this regard, cutting-edge nanomedicines harnessing photothermal-chemodynamic bimodal therapy (PTT/CDT) have opened up a highly-efficient and relatively-safe cancer theranostic paradigm. Still, the integration of PTT/CDT functional units into one nanomedicine remains a herculean but meaningful task to achieve notable super-additive effects. This review aims to elucidate underlying synergistic interactions of PTT/CDT and highlight intriguing designs of nanomedicines for PTT/CDT including nanomaterial selection, performance optimization, multimodal therapy, visualization strategies, and targeting strategies. Furthermore, an outlook on further improvements of PTT/CDT is provided, emphasizing significant scientific issues that require remediation for clinical translation. This article is categorized under: Diagnostic Tools > in vivo Nanodiagnostics and Imaging Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Microfluidic applications on circulating tumor cell isolation and biomimicking of cancer metastasis.

The prognosis of malignant tumors is challenged by insufficient means to effectively detect tumors at early stage. Liquid biopsy using circulating tumor cells (CTCs) as biomarkers demonstrates a promising solution to tackle the challenge, because CTCs play a critical role in cancer metastatic process via intravasation, circulation, extravasation, and formation of secondary tumor. However, the effectiveness of the solution is compromised by rarity, heterogeneity, and vulnerability associated with CTCs. Among a plethora of novel approaches for CTC isolation and enrichment, microfluidics leads to isolation and detection of CTCs in a cost-effective and operation-friendly way. Development of microfluidics also makes it feasible to model the cancer metastasis in vitro using a microfluidic system to mimick the in vivo microenvironment, thereby enabling analysis and monitor of tumor metastasis. This paper aims to review the latest advances for exploring the dual-roles microfluidics has played in early cancer diagnosis via CTC isolation and investigating the role of CTCs in cancer metastasis; the merits and drawbacks for dominating microfluidics-based CTC isolation methods are discussed; biomimicking cancer metastasis using microfluidics are presented with example applications on modelling of tumor microenvironment, tumor cell dissemination, tumor migration, and tumor angiogenesis. The future perspectives and challenges are discussed.

Design and fabrication of human skin by three-dimensional bioprinting.

Three-dimensional (3D) bioprinting, a flexible automated on-demand platform for the free-form fabrication of complex living architectures, is a novel approach for the design and engineering of human organs and tissues. Here, we demonstrate the potential of 3D bioprinting for tissue engineering using human skin as a prototypical example. Keratinocytes and fibroblasts were used as constituent cells to represent the epidermis and dermis, and collagen was used to represent the dermal matrix of the skin. Preliminary studies were conducted to optimize printing parameters for maximum cell viability as well as for the optimization of cell densities in the epidermis and dermis to mimic physiologically relevant attributes of human skin. Printed 3D constructs were cultured in submerged media conditions followed by exposure of the epidermal layer to the air-liquid interface to promote maturation and stratification. Histology and immunofluorescence characterization demonstrated that 3D printed skin tissue was morphologically and biologically representative of in vivo human skin tissue. In comparison with traditional methods for skin engineering, 3D bioprinting offers several advantages in terms of shape- and form retention, flexibility, reproducibility, and high culture throughput. It has a broad range of applications in transdermal and topical formulation discovery, dermal toxicity studies, and in designing autologous grafts for wound healing. The proof-of-concept studies presented here can be further extended for enhancing the complexity of the skin model via the incorporation of secondary and adnexal structures or the inclusion of diseased cells to serve as a model for studying the pathophysiology of skin diseases.