Evaluation of Anti-Inflammatory Effects of Celery Leaf and Stem Extracts in LPS-Induced RAW 264.7 Cells Using Nitric Oxide Assay and LC-MS Based Metabolomics.

The present work demonstrated and compared the anti-inflammatory effects of celery leaf (CLE) and stem (CSE) extracts. LC-MS-based metabolomics were an effective approach to achieve the biomarker identification and pathway elucidation associated with the reduction in inflammatory responses. The celery extracts suppressed LPS-induced NO production in RAW 264.7 cells, and CLE was five times more effective than CSE. Distinct differences were revealed between the control and celery-treated samples among the 24 characteristic metabolites that were identified. In celery-treated LPS cells, reversals of intracellular (citrulline, proline, creatine) and extracellular (citrulline, lysine) metabolites revealed that the therapeutic outcomes were closely linked to arginine metabolism. Reversals of metabolites when treated with CLE (aspartate, proline) indicated targeted effects on the TCA and urea cycles, while, in the case of CSE (histidine, glucose), the glycolysis and the pentose phosphate pathways were implicated. Subsequently, apigenin and bergapten in CLE were identified as potential biomarkers mediating the anti-inflammatory response.

Retooling Cancer Nanotherapeutics' Entry into Tumors to Alleviate Tumoral Hypoxia.

Anti-hypoxia cancer nanomedicine (AHCN) holds exciting potential in improving oxygen-dependent therapeutic efficiencies of malignant tumors. However, most studies regarding AHCN focus on optimizing structure and function of nanomaterials with presupposed successful entry into tumor cells. From such a traditional perspective, the main barrier that AHCN needs to overcome is mainly the tumor cell membrane. However, such an oversimplified perspective would neglect that real tumors have many biological, physiological, physical, and chemical defenses preventing the current state-of-the-art AHCNs from even reaching the targeted tumor cells. Fortunately, in recent years, some studies are beginning to intentionally focus on overcoming physiological barriers to alleviate hypoxia. In this Review, the limitations behind the traditional AHCN delivery mindset are addressed and the key barriers that need to be surmounted before delivery to cancer cells and some good ways to improve cell membrane attachment, internalization, and intracellular retention are summarized. It is aimed to contribute to Review literature on this emerging topic through refreshing perspectives based on this work and what is also learnt from others. This Review would therefore assist AHCNs researchers to have a quick overview of the essential information and glean thought-provoking ideas to advance this sub-field in cancer nanomedicine.

Endothelial leakiness elicited by amyloid protein aggregation.

Alzheimer's disease (AD) is a major cause of dementia debilitating the global ageing population. Current understanding of the AD pathophysiology implicates the aggregation of amyloid beta (Aß) as causative to neurodegeneration, with tauopathies, apolipoprotein E and neuroinflammation considered as other major culprits. Curiously, vascular endothelial barrier dysfunction is strongly associated with Aß deposition and 80-90% AD subjects also experience cerebral amyloid angiopathy. Here we show amyloid protein-induced endothelial leakiness (APEL) in human microvascular endothelial monolayers as well as in mouse cerebral vasculature. Using signaling pathway assays and discrete molecular dynamics, we revealed that the angiopathy first arose from a disruption to vascular endothelial (VE)-cadherin junctions exposed to the nanoparticulates of Aß oligomers and seeds, preceding the earlier implicated proinflammatory and pro-oxidative stressors to endothelial leakiness. These findings were analogous to nanomaterials-induced endothelial leakiness (NanoEL), a major phenomenon in nanomedicine depicting the paracellular transport of anionic inorganic nanoparticles in the vasculature. As APEL also occurred in vitro with the oligomers and seeds of alpha synuclein, this study proposes a paradigm for elucidating the vascular permeation, systemic spread, and cross-seeding of amyloid proteins that underlie the pathogeneses of AD and Parkinson's disease.

Shape programmable T1-T2 dual-mode MRI nanoprobes for cancer theranostics.

The shape effect is an important parameter in the design of novel nanomaterials. Engineering the shape of nanomaterials is an effective strategy for optimizing their bioactive performance. Nanomaterials with a unique shape are beneficial to blood circulation, tumor targeting, cell uptake, and even improved magnetism properties. Therefore, magnetic resonance imaging (MRI) nanoprobes with different shapes have been extensively focused on in recent years. Different from other multimodal imaging techniques, dual-mode MRI can provide imaging simultaneously by a single instrument, which can avoid differences in penetration depth, and the spatial and temporal resolution of multiple imaging devices, and ensure the accurate matching of spatial and temporal imaging parameters for the precise diagnosis of early tumors. This review summarizes the latest developments of nanomaterials with various shapes for T1-T2 dual-mode MRI, and highlights the mechanism of how shape intelligently affects nanomaterials' longitudinal or transverse relaxation, namely sphere, hollow, core-shell, cube, cluster, flower, dumbbell, rod, sheet, and bipyramid shapes. In addition, the combination of T1-T2 dual-mode MRI nanoprobes and advanced therapeutic strategies, as well as possible challenges from basic research to clinical transformation, are also systematically discussed. Therefore, this review will help others quickly understand the basic information on dual-mode MRI nanoprobes and gather thought-provoking ideas to advance the subfield of cancer nanomedicine.

Disturbing cytoskeleton by engineered nanomaterials for enhanced cancer therapeutics.

Cytoskeleton plays a significant role in the shape change, migration, movement, adhesion, cytokinesis, and phagocytosis of tumor cells. In clinical practice, some anti-cancer drugs achieve cytoskeletal therapeutic effects by acting on different cytoskeletal protein components. However, in the absence of cell-specific targeting, unnecessary cytoskeletal recombination in organisms would be disastrous, which would also bring about severe side effects during anticancer process. Nanomedicine have been proven to be superior to some small molecule drugs in cancer treatment due to better stability and targeting, and lower side effects. Therefore, this review summarized the recent developments of various nanomaterials disturbing cytoskeleton for enhanced cancer therapeutics, including carbon, noble metals, metal oxides, black phosphorus, calcium, silicon, polymers, peptides, and metal-organic frameworks, etc. A comprehensive analysis of the characteristics of cytoskeleton therapy as well as the future prospects and challenges towards clinical application were also discussed. We aim to drive on this emerging topic through refreshing perspectives based on our own work and what we have also learnt from others. This review will help researchers quickly understand relevant cytoskeletal therapeutic information to further advance the development of cancer nanomedicine.

Engineering tumoral vascular leakiness with gold nanoparticles.

Delivering cancer therapeutics to tumors necessitates their escape from the surrounding blood vessels. Tumor vasculatures are not always sufficiently leaky. Herein, we engineer therapeutically competent leakage of therapeutics from tumor vasculature with gold nanoparticles capable of inducing endothelial leakiness (NanoEL). These NanoEL gold nanoparticles activated the loss of endothelial adherens junctions without any perceivable toxicity to the endothelial cells. Microscopically, through real time live animal intravital imaging, we show that NanoEL particles induced leakiness in the tumor vessels walls and improved infiltration into the interstitial space within the tumor. In both primary tumor and secondary micrometastases animal models, we show that pretreatment of tumor vasculature with NanoEL particles before therapeutics administration could completely regress the cancer. Engineering tumoral vasculature leakiness represents a new paradigm in our approach towards increasing tumoral accessibility of anti-cancer therapeutics instead of further increasing their anti-cancer lethality.

CCR2-overexpressing biomimetic carrier-free nanoplatform for enhanced cascade ferroptosis tumor therapy.

Ferroptosis-based nanoplatforms have shown great potential in cancer therapy. However, they also face issues such as degradation and metabolism. Carrier-free nanoplatforms consisting of active drugs can effectively avoid the security issues associated with additional carrier ingredients. Herein, a biomimetic carrier-free nanoplatform (HESN@CM) was designed to treat cancer by modulating cascade metabolic pathways of ferroptosis. CCR2-overexpressing macrophage membrane-modified HESN can target cancer cells via the CCR2-CCL2 axis. The acidic tumor microenvironment (TME) can disrupt the supramolecular interaction of HESN, releasing hemin and erastin. Then, erastin could induce cancer cells ferroptosis by inhibiting system XC- pathways, while hemin, a vital component of blood to transport oxygen, could be broken down by heme oxygenase-1 (HO-1), increasing the intracellular Fe2+ concentration to induce cancer cells' ferroptosis further. Meanwhile, erastin could enhance the activity of HO-1, further promoting the release of Fe2+ from hemin. As a result, HESN@CM demonstrated superior therapeutic efficacy in both primary and metastatic tumors in vitro and in vivo. The carrier-free HESN@CM provided cascade ferroptosis tumor therapy strategies for potential clinical application. STATEMENT OF SIGNIFICANCE: CCR2-overexpressing biomimetic carrier-free nanoplatform (HESN@CM) was designed for cancer treatment by modulating metabolic pathways of ferroptosis. HESN modified with CCR2-overexpressing macrophage membrane can target tumor cells via the CCR2-CCL2 axis. HESN was composed of hemin and erastin without additional vectors. Erastin could directly induce ferroptosis, while hemin could be broken down by heme oxygenase-1 (HO-1), increasing the intracellular Fe2+ concentration to enhance ferroptosis further. Meanwhile, erastin could improve the activity of HO-1, promoting the release of Fe2+ from hemin. Therefore, HESN@CM with good bioavailability, stability, and simple preparation can realize cascade ferroptosis tumor therapy and have the potential prospect of clinical translation.

Inducible endothelial leakiness in nanotherapeutic applications.

All intravenous delivered nanomedicine needs to escape from the blood vessel to exert their therapeutic efficacy at their designated site of action. Failure to do so increases the possibility of detrimental side effects and negates their therapeutic intent. Many powerful anticancer nanomedicine strategies rely solely on the tumor derived enhanced permeability and retention (EPR) effect for the only mode of escaping from the tumor vasculature. However, not all tumors have the EPR effect nor can the EPR effect be induced or controlled for its location and timeliness. In recent years, there have been exciting developments along the lines of inducing endothelial leakiness at the tumor to decrease the dependence of EPR. Physical disruption of the endothelial-endothelial cell junctions with coordinated biological intrinsic pathways have been proposed that includes various modalities like ultrasound, radiotherapy, heat and even nanoparticles, appear to show good progress towards the goal of inducing endothelial leakiness. This review explains the intricate and complex biological background behind the endothelial cells with linkages on how updated reported nanomedicine strategies managed to induce endothelial leakiness. This review will also end off with fresh insights on where the future of inducible endothelial leakiness holds.

Shield-activated two-way imaging nanomaterials for enhanced cancer theranostics.

Smart nanomaterials with stimuli-responsive imaging enhancement have been widely developed to meet the requirements of accurate cancer diagnosis. However, these imaging nanoenhancers tend to be always on during circulation, which significantly increases the background signal when assessing the imaging performance. To improve unfavorable signal-to-noise ratios, an effective way is to shield the noise signal of these nanoprobes in non-targeted areas. Fortunately, there is a natural mutual shielding effect between some imaging nanomaterials, which provides the possibility of designing engineered nanomaterials with imaging quenching between two different components at the beginning. Once in the tumor microenvironment, the two components will present activated dual-mode imaging ability because of their separation, designated as two-way imaging tuning. This review highlights the design and mechanism of a series of engineered nanomaterials with two-way imaging tuning and their latest applications in the fields of cancer magnetic resonance imaging, fluorescence imaging, and their combination. The challenges and future directions for the improvement of these engineered nanomaterials towards clinical transformation are also discussed. This review aims to introduce the special constraint relationships of imaging components and provide scientists with simpler and more efficient nanoplatform construction ideas, promoting the development of engineered nanomaterials with two-way imaging tuning in cancer theranostics.

A Framework of Paracellular Transport via Nanoparticles-Induced Endothelial Leakiness.

Nanomaterial-induced endothelial leakiness (NanoEL) is an interfacial phenomenon denoting the paracellular transport of nanoparticles that is pertinent to nanotoxicology, nanomedicine and biomedical engineering. While the NanoEL phenomenon is complementary to the enhanced permeability and retention effect in terms of their common applicability to delineating the permeability and behavior of nanoparticles in tumoral environments, these two effects significantly differ in scope, origin, and manifestation. In the current study, the descriptors are fully examined of the NanoEL phenomenon elicited by generic citrate-coated gold nanoparticles (AuNPs) of changing size and concentration, from microscopic gap formation and actin reorganization down to molecular signaling pathways and nanoscale interactions of AuNPs with VE-cadherin and its intra/extracellular cofactors. Employing synergistic in silico methodologies, for the first time the molecular and statistical mechanics of cadherin pair disruption, especially in response to AuNPs of the smallest size and highest concentration are revealed. This study marks a major advancement toward establishing a comprehensive NanoEL framework for complementing the understanding of the transcytotic pathway and for guiding the design and application of future nanomedicines harnessing the myriad functions of the mammalian vasculature.

Phototherapy with layered materials derived quantum dots.

Quantum dots (QDs) originating from two-dimensional (2D) sheets of graphitic carbon nitride (g-C3N4), graphene, hexagonal boron nitride (h-BN), monoatomic buckled crystals (phosphorene), germanene, silicene and transition metal dichalcogenides (TMDCs) are emerging zero-dimensional materials. These QDs possess diverse optical properties, are chemically stable, have surprisingly excellent biocompatibility and are relatively amenable to surface modifications. It is therefore not difficult to see that these QDs have potential in a variety of bioapplications, including biosensing, bioimaging and anticancer and antimicrobial therapy. In this review, we briefly summarize the recent progress of these exciting QD based nanoagents and strategies for phototherapy. In addition, we will discuss about the current limitations, challenges and future prospects of QDs in biomedical applications.