IGF1 receptor-targeted black TiO2 nanoprobes for MRI-guided synergetic photothermal-chemotherapy in drug resistant pancreatic tumor.

Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest malignant tumors with features of matrix barrier caused poor drug permeability, and susceptibility to drug resistance. Herein, a PDAC and its stromal cell dual-targeted photothermal-chemotherapy strategy is explored to loosen the matrix and reverse drug resistance. To achieve this goal, black TiO2-Gd nanocomposites were conjugated with insulin like growth factor 1 (IGF1), and loaded with gemcitabine (GEM) to construct bTiO2-Gd-IGF1-GEM nanoprobes. In vitro results show that under 808 nm near-infrared irradiation, killing effect of the nanoprobes on drug-resistant MIA PaCa-2 cell is 3.3 times than that of GEM alone. In vivo experiments indicate the synergetic photothermal-chemotherapy not only loosens fibrous matrix of pancreatic tumor model, but also dramatically inhibits tumor growth, and almost completely eradicates the tumor after 12 days of treatment. In addition, relaxation rate of the nanoprobes is 8.2 times than commercial contrast agent Magnevist, therefore boosts the signal of magnetic resonance imaging in pancreatic tumor. In conclusion, our results reinforce that the prepared nanoprobes are promising to break matrix barrier and overcome drug resistance in PDAC.

Porous Gold Nanoshells on Functional NH2 -MOFs: Facile Synthesis and Designable Platforms for Cancer Multiple Therapy.

AuroShell nanoparticles (sealed gold nanoshell on silica) are the only inorganic materials that are approved for clinical trial for photothermal ablation of solid tumors. Based on that, porous gold nanoshell structures are thus critical for cancer multiple theranostics in the future owing to their inherent cargo-loading ability. Nevertheless, adjusting the diverse experimental parameters of the reported procedures to obtain porous gold nanoshell structures is challenging. Herein, a series of amino-functionalized porous metal-organic frameworks (NH2 -MOFs) nanoparticles are uncovered as superior templates for porous gold nanoshell deposition (NH2 -MOFs@Aushell ) by means of a more facile and general one-step method, which combines the enriched functionalities of NH2 -MOFs with those of porous gold nanoshells. Moreover, in order to illustrate the promising applications of this method in biomedicine, platinum nanozymes-encapsulated NH2 -MOFs are further designed with porous gold nanoshell coating and photosensitizer chlorin e6 (Ce6)-loaded nanoparticles with continuous O2 -evolving ability (Pt@UiO-66-NH2 @Aushell -Ce6). The combination of photodynamic and photothermal therapy is then carried out both in vitro and in vivo, achieving excellent synergistic therapeutic outcomes. Therefore, this work not only presents a facile strategy to fabricate functionalized porous gold nanoshell structures, but also illustrates an excellent synergistic tumor therapy strategy.

Engineering magnetic nanosystem for TRPV1 and TRPV4 channel activation.

Recently, physical tools for remotely stimulating mechanical force-sensitive and temperature-sensitive proteins to regulate intracellular pathways have opened up novel and exciting avenues for basic research and clinical applications. Among the numerous modes of physical stimulation, magnetic stimulation is significantly attractive for biological applications due to the advantages of depth penetration and spatial-temporally controlled transduction. Herein, the physicochemical parameters (e.g., shape, size, composition) that influence the magnetic properties of magnetic nanosystems as well as the characteristics of transient receptor potential vanilloid-1 (TRPV1) and transient receptor potential vanilloid-4 (TRPV4) channels are systematically summarized, which offer opportunities for magnetic manipulation of cell fate in a precise and effective manner. In addition, representative regulatory applications involving magnetic nanosystem-based TRPV1 and TRPV4 channel activation are highlighted, both at the cellular level and in animal models. Furthermore, perspectives on the further development of this magnetic stimulation mode are commented on, with emphasis on scientific limitations and possible directions for exploitation. This article is categorized under: Diagnostic Tools > Biosensing Diagnostic Tools > In Vivo Nanodiagnostics and Imaging.

Highly-Efficient Gallium-Interference Tumor Therapy Mediated by Gallium-Enriched Prussian Blue Nanomedicine.

Prussian blue (PB)-based nanomedicines constructed from metal ion coordination remain restricted due to their limited therapeutic properties, and their manifold evaluation complexity still needs to be unraveled. Owing to the high similarities of its ionic form to iron (Fe) and the resulting cellular homeostasis disruption performance, physiologically unstable and low-toxicity gallium (Ga) has garnered considerable attention clinically as an anti-carcinogen. Herein, Ga-based nanoparticles (NPs) with diverse Ga contents are fabricated in one step using PB with abundant Fe sites as a substrate for Ga substitution, which aims to overcome the deficiencies of both and develop an effective nanomedicine. A systematic comparison of their physicochemical properties effectively reveals the saturated Ga introduction state during the synthesis process, further identifying the most Ga-enriched PB NPs with a substitution content of >50% as a nanomedicine for subsequent exploration. It is verified that the Ga interference mechanisms mediated by the most Ga-enriched PB NPs are implicated in metabolic disorders, ionic homeostasis disruption, cellular structure dysfunction, apoptosis, autophagy, and target activation of the mammalian target of the rapamycin (mTOR) and mitogen-activated protein kinase (MAPK) pathways. This study provides significant guidance on exploiting clinically approved agents for Ga interference and lays the foundation for the next generation of PB-based theranostic agents.

Navigating zinc-involved nanomedicine in oncotherapy.

Zinc (Zn), extolled as "the flower of life" in modern medicine, has been extensively highlighted with its physiological functions to maintain growth, development, and metabolism homeostasis. Driven by the substantial advancement of nanotechnology and oncology, Zn-involved nanomedicines integrating the intrinsic bioactivity of Zn species and the physiochemical attributes of Zn-composed nanosystems have blazed a highly efficient and relatively biosafe antineoplastic path. In this review, we aim to highlight and discuss the recent representative modalities of emerging Zn-involved oncology nanomedicine, mainly emphasizing the rational design, biological effect and biosafety, and therapeutic strategies. In addition, we provide the underlying critical obstacles and future perspectives of Zn-involved oncology nanomedicines, primarily focusing on the chances and challenges of clinical translation. Furthermore, we hope the review can give rise to opportunities within oncology nanomedicine and other biomedical fields, promoting the prosperity and progress of the "Zincic Age".

Magneto-mechanical therapeutic effects and associated cell death pathways of magnetic nanocomposites with distinct geometries.

Recent years have witnessed important developments in the emerging field of magneto-mechanical therapies. While such approaches have been demonstrated as a highly efficient route to augment, complement, or entirely replace other therapeutic strategies, important aspects are still poorly understood. Among these, the dependence between the cell death pathway and the geometry of magnetic nanocomposites enabling magneto-mechanical therapies under a low-frequency rotating magnetic field (RMF) is yet to be deciphered. To provide insights into this important problem, we evaluate the cell death pathway for two magnetic nanocomposites with highly distinct geometries: Zn0.2Fe2.8O4-PLGA magnetic nanospheres (MNSs) and Zn0.2Fe2.8O4-PLGA magnetic nanochains (MNCs). We show that under exposure to an RMF, the MNSs and the MNCs exhibit a corkscrewed circular propulsion mode and a steering propulsion mode, respectively. This distinct behavior, with important implications for the associated magneto-mechanical forces exerted by these nanomaterials on surrounding structures (e.g., the cellular membrane), depends on their specific geometries. Next, using numerical simulations and cell viability experiments, we demonstrate that the field strength of the RMF and the rotating speed of the MNSs or MNCs have strong implications for their magneto-mechanical therapeutic performance. Last, we reveal that the magneto-mechanical effects of MNSs are more prone to induce cell apoptosis, whereas those of the MNCs favor instead cell necrosis. Overall, this work enhances the current understanding of the dependences existing between the magneto-mechanical therapeutic effects of magnetic nanocomposites with different geometries and associated cell death pathways, paving the way for novel functionalization routes which could enable significantly enhanced cures and biomedical tools. STATEMENT OF SIGNIFICANCE.

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.

Using host-guest interactions at the interface of quantum dots to load drug molecules for biocompatible, safe, and effective chemo-photodynamic therapy against cancer.

Combining photodynamic therapy (PDT) and chemotherapy (CHT) by loading an anti-cancer drug and a photosensitizer (PS) into the same delivery nanosystem has been proposed as an effective approach to achieve synergistic effects for a safe cancer treatment. However, exploring an ideal delivery nanosystem has been challenging, because the noncovalent interactions must be maintained between the multiple components to produce a stable yet responsive nanostructure that takes into account the encapsulation of drug molecules. We addressed this issue by engineering the interfacial interaction between Ag2S quantum dots (QDs) using a pillararene derivative to direct the co-self-assembly of the entire system. The high surface area-to-volume ratio of the Ag2S QDs provided ample hydrophobic space to accommodate the anti-drug molecule doxrubicine. Moreover, Ag2S QDs served as PSs triggered by 808 nm near-infrared (NIR) light and also as carriers for high-efficiency delivery of drug molecules to the tumor site. Drug release experiments showed smart drug release under the acidic microenvironments (pH 5.5) in tumor cells. Additionally, the Ag2S QDs demonstrated outstanding PDT ability under NIR light, as confirmed by extracellular and intracellular reactive oxygen species generation. Significant treatment efficacy of the chemo-photodynamic synergistic therapy for cancer using the co-delivery system was demonstrated via in vitro and in vivo studies. These findings suggest that our system offers intelligent control of CHT and PDT, which will provide a promising strategy for constructing hybrid systems with synergistic effects for advanced applications in biomedicine, catalysis, and optoelectronics.

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.

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.

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.

Living Sample Viability Measurement Methods from Traditional Assays to Nanomotion.

Living sample viability measurement is an extremely common process in medical, pharmaceutical, and biological fields, especially drug pharmacology and toxicology detection. Nowadays, there are a number of chemical, optical, and mechanical methods that have been developed in response to the growing demand for simple, rapid, accurate, and reliable real-time living sample viability assessment. In parallel, the development trend of viability measurement methods (VMMs) has increasingly shifted from traditional assays towards the innovative atomic force microscope (AFM) oscillating sensor method (referred to as nanomotion), which takes advantage of the adhesion of living samples to an oscillating surface. Herein, we provide a comprehensive review of the common VMMs, laying emphasis on their benefits and drawbacks, as well as evaluating the potential utility of VMMs. In addition, we discuss the nanomotion technique, focusing on its applications, sample attachment protocols, and result display methods. Furthermore, the challenges and future perspectives on nanomotion are commented on, mainly emphasizing scientific restrictions and development orientations.

Guarding food safety with conventional and up-conversion near-infrared fluorescent sensors.

BACKGROUND: Acknowledged by the World Health Organisation (WHO), over 200 diseases ranging from mild to fatal are linked to the consumption of food products subjected to physical, chemical, or biological contamination. Nevertheless, conventional methods commonly used for the identification of health hazards in foodstuffs have problems coping with the sensitivity requirements imposed by latest-hour regulations in the field. Additionally, their use and availability is wildly limited by aspects such as instrument dimension, prohibitive costs, detection complexity and required operational knowledge. AIM OF REVIEW: This review provides an overview of recent efforts that have focused on the assesment of food contamination based on near infrared (NIR) photoluminescent sensors. Important endeavors that have targeted the precise detection of various inorganic and organic contaminants, including hydrogen sulfide, cyanide anions, mycotoxins, antibiotic residues, etc., are presented and relevant challenges that lie en route as stumbling blocks for such sensors to reach the next level of maturity and to become more available, are systematically discussed and enunciated. KEY SCIENTIFIC CONCEPTS OF REVIEW: Ingenious food contamination sensors that rely on conventional or up-conversion photoluminescence in the NIR region represent an emerging topic. To date, such sensors have been demonstrated as promising detection candidates, possessing important advantages such as: high efficiency, facile implementation, and convenient flexibility, thereby promising significant contributions to expand the current state of the art in food security.

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.

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.

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.

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.

Arsenene Nanodots with Selective Killing Effects and their Low-Dose Combination with ß-Elemene for Cancer Therapy.

Arsenical drugs have achieved hallmark success in treating patients with acute promyelocytic leukemia, but expanding their clinical utility to solid tumors has proven difficult with the contradiction between the therapeutic efficacy and the systemic toxicity. Here, leveraging efforts from materials science, biocompatible PEGylated arsenene nanodots (AsNDs@PEG) with high monoelemental arsenic purity that can selectively and effectively treat solid tumors are synthesized. The intrinsic selective killing effect of AsNDs@PEG is closely related to high oxidative stress in tumor cells, which leads to an activated valence-change of arsenic (from less toxic As0 to severely toxic oxidation states), followed by decreased superoxide dismutase activity and massive reactive oxygen species (ROS) production. These effects occur selectively within cancer cells, causing mitochondrial damage, cell-cycle arrest, and DNA damage. Moreover, AsNDs@PEG when applied in a multi-drug combination strategy with ß-elemene, a plant-derived anticancer drug, achieves synergistic antitumor outcomes, and its newly discovered on-demand photothermal properties facilitate the elimination of the tumors without recurrence, potentially further expanding its clinical utility. In line of the practicability for a large-scale fabrication and negligible systemic toxicity of AsNDs@PEG (even at high doses and with repetitive administration), a new-concept arsenical drug with high therapeutic efficacy for selective solid tumor therapy is provided.