Anti-lymphangiogenesis for boosting drug accumulation in tumors.

The inadequate tumor accumulation of anti-cancer agents is a major shortcoming of current therapeutic drugs and remains an even more significant concern in the clinical prospects for nanomedicines. Various strategies aiming at regulating the intratumoral permeability of therapeutic drugs have been explored in preclinical studies, with a primary focus on vascular regulation and stromal reduction. However, these methods may trigger or facilitate tumor metastasis as a tradeoff. Therefore, there is an urgent need for innovative strategies that boost intratumoral drug accumulation without compromising treatment outcomes. As another important factor affecting drug tumor accumulation besides vasculature and stroma, the impact of tumor-associated lymphatic vessels (LVs) has not been widely considered. In the current research, we verified that anlotinib, a tyrosine kinase inhibitor with anti-lymphangiogenesis activity, and SAR131675, a selective VEGFR-3 inhibitor, effectively decreased the density of tumor lymphatic vessels in mouse cancer models, further enhancing drug accumulation in tumor tissue. By combining anlotinib with therapeutic drugs, including doxorubicin (Dox), liposomal doxorubicin (Lip-Dox), and anti-PD-L1 antibody, we observed improved anti-tumor efficacy in comparison with monotherapy regimens. Meanwhile, this strategy significantly reduced tumor metastasis and elicited stronger anti-tumor immune responses. Our work describes a new, clinically transferrable approach to augmenting intratumoral drug accumulation, which shows great potential to address the current, unsatisfactory efficacies of therapeutic drugs without introducing metastatic risk.

Self-Assembly Nanostructure Induced by Regulation of G-Quadruplex DNA Topology via a Reduction-Sensitive Azobenzene Ligand on Cells.

The control of DNA assembly systems on cells has increasingly shown great importance for precisely targeted therapies. Here, we report a controllable DNA self-assembly system based on the regulation of G-quadruplex DNA topology by a reduction-sensitive azobenzene ligand. Specifically, three azobenzene multiamines are developed, and AzoDiTren is identified as the best G4 binder, which displays high affinity and specificity for G4 DNA. Moreover, the reduction-sensitive nature of the azobenzene scaffold allows AzoDiTren to induce a complete change of the G4 topology in a tissue-specific manner, even at high metal cation concentrations. On this basis, the AzoDiTren-induced G4 conformational switch achieves control of the self-assembly of G4-functionalized DNAs on cells. This strategy enables the regulation of G4 and DNA self-assembly by the bioreductant-responsive ligand.

Emerging nanotechnological approaches to regulating tumor vasculature for cancer therapy.

Abnormal angiogenesis stands for one of the most striking manifestations of malignant tumor. The pathologically and structurally abnormal tumor vasculature facilitates a hostile tumor microenvironment, providing an ideal refuge exclusively for cancer cells. The emergence of vascular regulation drugs has introduced a distinctive class of therapeutics capable of influencing nutrition supply and drug delivery efficacy without the need to penetrate a series of physical barriers to reach tumor cells. Nanomedicines have been further developed for more precise regulation of tumor vasculature with the capacity of co-delivering multiple active pharmaceutical ingredients, which overall reduces the systemic toxicity and boosts the therapeutic efficacy of free drugs. Additionally, precise structure design enables the integration of specific functional motifs, such as surface-targeting ligands, droppable shells, degradable framework, or stimuli-responsive components into nanomedicines, which can improve tissue-specific accumulation, enhance tissue penetration, and realize the controlled and stimulus-triggered release of the loaded cargo. This review describes the morphological and functional characteristics of tumor blood vessels and summarizes the pivotal molecular targets commonly used in nanomedicine design, and then highlights the recent cutting-edge advancements utilizing nanotechnologies for precise regulation of tumor vasculature. Finally, the challenges and future directions of this field are discussed.

Molecular imaging-guided extracellular vesicle-based drug delivery for precise cancer management: Current status and future perspectives.

Extracellular vesicles (EVs), the mediators of intercellular communication, have attracted the attention of researchers for the important roles they play in cancer treatment. Compared with other inorganic nano-materials, EVs possess the advantages of higher biocompatibility, better physiochemical stability, easier surface modification, and excellent biosafety. They can be used as an advanced drug delivery system with an improved therapeutic index for various therapeutic agents. Engineered EV-based imaging and therapeutic agents (engineered EVs) have emerged as useful tools in targeted cancer diagnosis and therapy. Non-invasive tracing of engineered EVs contributes to a better evaluation of their functions in cancer progression, in vivo dynamic biodistribution, therapeutic response, and drug-loading efficiency. Recent advances in real-time molecular imaging (MI), and innovative EV labeling strategies have led to the development of novel tools that can evaluate the pharmacokinetics of engineered EVs in cancer management, which may accelerate further clinical translation of novel EV-based drug delivery platforms. Herein, we review the latest advances in EVs, their characteristics, and current examples of EV-based targeted drug delivery for cancer. Then, we discuss the prominent applications of MI for tracing both natural and engineered EVs. Finally, we discuss the current challenges and considerations of EVs in targeted cancer treatment and the limitations of different MI modalities. In the coming decades, EV-based therapeutic applications for cancer with improved drug loading and targeting abilities will be developed, and better anti-cancer effects of drug delivery nanoplatform will be achieved.

Automated Industrial Composite Fiber Orientation Inspection Using Attention-Based Normalized Deep Hough Network.

Fiber-reinforced composites (FRC) are widely used in various fields due to their excellent mechanical properties. The mechanical properties of FRC are significantly governed by the orientation of fibers in the composite. Automated visual inspection is the most promising method in measuring fiber orientation, which utilizes image processing algorithms to analyze the texture images of FRC. The deep Hough Transform (DHT) is a powerful image processing method for automated visual inspection, as the "line-like" structures of the fiber texture in FRC can be efficiently detected. However, the DHT still suffers from sensitivity to background anomalies and longline segments anomalies, which leads to degraded performance of fiber orientation measurement. To reduce the sensitivity to background anomalies and longline segments anomalies, we introduce the deep Hough normalization. It normalizes the accumulated votes in the deep Hough space by the length of the corresponding line segment, making it easier for DHT to detect short, true "line-like" structures. To reduce the sensitivity to background anomalies, we design an attention-based deep Hough network (DHN) that integrates attention network and Hough network. The network effectively eliminates background anomalies, identifies important fiber regions, and detects their orientations in FRC images. To better investigate the fiber orientation measurement methods of FRC in real-world scenarios with various types of anomalies, three datasets have been established and our proposed method has been evaluated extensively on them. The experimental results and analysis prove that the proposed methods achieve the competitive performance against the state-of-the-art in F-measure, Mean Absolute Error (MAE), Root Mean Squared Error (RMSE).

The clinical effects of two non-invasive ventilation modes on premature infants with respiratory distress syndrome: A randomized controlled trial.

BACKGROUND: To compare the safety and effectiveness of nasal noninvasive high- frequency oscillatory ventilation (NHFOV) and duo positive airway pressure (DuoPAP) applications in preterm babies with respiratory distress syndrome (RDS). METHODS: This was a randomized controlled trial. Forty-three premature infants with RDS treated in the neonatal intensive care unit of Huaibei Maternal and Child Health Hospital from January 2020 to November 2021 were selected as the research participants. They were randomly divided into the NHFOV group (n = 22) and DuoPAP group (n = 21). General conditions, including the arterial oxygen partial pressure (PaO2), carbon dioxide partial pressure (PaCO2), oxygenation index (OI), the incidence of apnea at 72 hours, duration of noninvasive respiratory support, maternal high-risk factors, total oxygen consumption time, total gastrointestinal feeding time, and the frequency of intraventricular hemorrhage (IVH), neonatal necrotizing enterocolitis (NEC), and bronchopulmonary dysplasia (BPD) and apnea were compared between the NHFOV group and DuoPAP group at 12 and 24 hours after noninvasive respiratory support. RESULTS: There was no noteworthy difference between the 2 groups with respect to PaO2, PaCO2, OI, IVH, and NEC and BPD at different nodes (all P > .05). CONCLUSION: The endpoints of PaO2, PaCO2 and OI and complications of IVH, NEC, BPD and Apnea, and did not reveal any statistical differences between NHFOV and DuoPAP during the respiratory support in preterm babies with RDS.

Platelet-Mimicking Nanosponges for Functional Reversal of Antiplatelet Agents.

BACKGROUND: During long-term antiplatelet agents (APAs) administration, patients with thrombotic diseases take a fairly high risk of life-threatening bleeding, especially when in need of urgent surgery. Rapid functional reversal of APAs remains an issue yet to be efficiently resolved by far due to the lack of any specific reversal agent in the clinic, which greatly restricts the use of APAs. METHODS: Flow cytometry analysis was first applied to assess the dose-dependent reversal activity of platelet-mimicking perfluorocarbon-based nanosponges (PLT-PFCs) toward ticagrelor. The tail bleeding time of mice treated with APAs followed by PLT-PFCs was recorded at different time points, along with corresponding pharmacokinetic analysis of ticagrelor and tirofiban. A hemorrhagic transformation model was established in experimental stroke mice with thrombolytic/antiplatelet therapy. Magnetic resonance imaging was subsequently applied to observe hemorrhage and thrombosis in vivo. Further evaluation of the spontaneous clot formation activity of PLT-PFCs was achieved by clot retraction assay in vitro. RESULTS: PLT-PFCs potently reversed the antiplatelet effect of APAs by competitively binding with APAs. PLT-PFCs showed high binding affinity comparable to fresh platelets in vitro with first-line APAs, ticagrelor and tirofiban, and efficiently reversed their function in both tail bleeding and postischemic-reperfusion models. Moreover, the deficiency of platelet intrinsic thrombotic activity diminished the risk of thrombogenesis. CONCLUSIONS: This study demonstrated the safety and effectiveness of platelet-mimicking nanosponges in ameliorating the bleeding risk of different APAs, which offers a promising strategy for the management of bleeding complications induced by antiplatelet therapy.

Probiotic-Inspired Nanomedicine Restores Intestinal Homeostasis in Colitis by Regulating Redox Balance, Immune Responses, and the Gut Microbiome.

Microbiota-based therapeutics offer innovative strategies to treat inflammatory bowel diseases (IBDs). However, the poor clinical outcome so far and the limited flexibility of the bacterial approach call for improvement. Inspired by the health benefits of probiotics in alleviating symptoms of bowel diseases, bioartificial probiotics are designed to restore the intestinal microenvironment in colitis by regulating redox balance, immune responses, and the gut microbiome. The bioartificial probiotic comprises two components: an E. coli Nissle 1917-derived membrane (EM) as the surface and the biodegradable diselenide-bridged mesoporous silica nanoparticles (SeM) as the core. When orally administered, the probiotic-inspired nanomedicine (SeM@EM) adheres strongly to the mucus layer and restored intestinal redox balance and immune regulation homeostasis in a murine model of acute colitis induced by dextran sodium sulfate. In addition, the respective properties of the EM and SeM synergistically alter the gut microbiome to a favorable state by increasing the bacterial diversity and shifting the microbiome profile to an anti-inflammatory phenotype. This work suggests a safe and effective nanomedicine that can restore intestinal homeostasis for IBDs therapy.

Design of Diselenide-Bridged Hyaluronic Acid Nano-antioxidant for Efficient ROS Scavenging to Relieve Colitis.

Overproduction of reactive oxygen species (ROS), a key characteristic of inflammatory bowel disease (IBD), is responsible for dysregulation of signal transduction, inflammatory response, and DNA damage, which ultimately leads to disease progression and deterioration. Thus, ROS scavenging has become a promising strategy to navigate IBD. Inspired by the targeting capability of hyaluronic acid (HA) to CD44-overexpressed inflammatory cells together with the redox regulation capacity of diselenide compounds, we developed an oral nanoformulation, i.e., diselenide-bridged hyaluronic acid nanogel (SeNG), with a view to treat colitis through a ROS scavenging mechanism. Our data demonstrated that SeNG specifically accumulated in colitis tissue that was mediated by highly efficient CD44-HA interaction. This has allowed us to demonstrate a significant anti-inflammatory effect in an acute colitis mouse model induced by dextran sulfate sodium and trinitrobenzenesulfonic acid. Mechanistically, we continued to show SeNG reduced the ROS level via both direct elimination and up-regulation of the Nrf2/HO-1 signal pathway. Collectively, our work provides proof-of-principle evidence for a SeNG-mediated nano-antioxidant strategy, by which colitis could be effectively managed.

CsPbBr3 microarrays with tunable periodicity, optoelectronic and field emission properties using self-assembled polystyrene template and co-evaporation method.

The booming growth of all inorganic cesium lead halide perovskites in optoelectronic applications has prompted extensive research interest in the fabrication of ordered nanostructures or microarrays for enhanced device performances. However, the high cost and complexity of commercial lithographic approaches impede the facile fabrication of perovskite microarrays. Herein, CsPbBr3 microarrays with tunable periodicities have been fabricated using a self-assembled polystyrene nanosphere template and a co-evaporation method. The periodicity of CsPbBr3 microarrays is precisely manipulated by simply modifying the size of polystyrene nanospheres. These microarrays are beneficial for light harvesting, leading to better light absorption ability and prolonged photoinduced carrier lifetime. The longest average carrier lifetime of 58.3 ns is obtained for CsPbBr3 microarrays with a periodicity of 1.0 µm. More importantly, the periodic structures of CsPbBr3 microarrays result in a tunable density of emitter tips in field emission devices. Compared to compact CsPbBr3 films, a 68.2% decrease of the turn-on field is observed for CsPbBr3 microarrays when the periodicity is 150 nm. The higher density of emitter tips leads to larger local field enhancement, and hence the largest field enhancement factor of 3346.6. Finally, a good emission current stability for CsPbBr3 microarray-based field emission devices has been demonstrated.

EFEMP1 in Direct Inguinal Hernia: correlation with TIMP3 and Regulation Toward Elastin Homoeostasis as Well as Fibroblast Mobility.

AIM: This basic research aimed to detect the inner-correlation of EGF containing fibulin extracellular matrix protein 1 (EFEMP1), TIMP metallopeptidase inhibitor 3 (TIMP3), matrix metalloprotease 9 (MMP9), elastin (ELN) in direct inguinal hernia (IH), and their effect on fibroblasts motility. METHODS: Transversalis fascia samples from 20 direct IH patients and 20 varicocele (served as controls) patients were collected for detecting EFEMP1, TIMP3, MMP9 and ELN expressions by immunohistochemistry assay. Fibroblasts L929 cells were transfected with EFEMP1 overexpression plasmid or knock-down plasmid to investigate the influence of EFEMP1 dysregulation on L929 cell migration, invasion, TIMP3, MMP9 and ELN expressions. Additionally, rescue experiments were performed by adding TIMP3 knockdown plasmid to the EFEMP1-overexpressed L929 cells. RESULTS: Transversalis fascia EFEMP1, TIMP3 and ELN expressions were decreased, but MMP9 expression was increased in IH patients compared with controls. In IH patients, EFEMP1 was not correlated with TIMP3, but positively correlated with ELN and negatively correlated with MMP9; TIMP3 negatively correlated with MMP9, but positively correlated with ELN. Overexpression of EFEMP1 did not affect TIMP3 expression but increased ELN expression and decreased MMP9 expression in L929 cells. In addition, EFEMP1 suppressed L929 cell migration and invasion. The following rescue experiments indicated that silencing TIMP3 attenuated the effect of EFEMP1 overexpression on MMP9 and ELN expressions as well as the effect of EFEMP1 overexpression on cell migration and invasion in L929 cells. CONCLUSIONS: EFEMP1 is downregulated in direct IH, and it regulates ELN homoeostasis as well as fibroblast mobility via interacting with TIMP3.

An Expectation Maximization Based Adaptive Group Testing Method for Improving Efficiency and Sensitivity of Large-Scale Screening of COVID-19.

The pathogen of the ongoing coronavirus disease 2019 (COVID-19) pandemic is a newly discovered virus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Testing individuals for SARS-CoV-2 plays a critical role in containing COVID-19. For saving medical personnel and consumables, many countries are implementing group testing against SARS-CoV-2. However, existing group testing methods have the following limitations: (1) The group size is determined without theoretical analysis, and hence is usually not optimal. This adversely impacts the screening efficiency. (2) These methods neglect the fact that mixing samples together usually leads to substantial dilution of the SARS-CoV-2 virus, which seriously impacts the sensitivity of tests. In this paper, we aim to screen individuals infected with COVID-19 with as few tests as possible, under the premise that the sensitivity of tests is high enough. We propose an eXpectation Maximization based Adaptive Group Testing (XMAGT) method. The basic idea is to adaptively adjust its testing strategy between a group testing strategy and an individual testing strategy such that the expected number of samples identified by a single test is larger. During the screening process, the XMAGT method can estimate the ratio of positive samples. With this ratio, the XMAGT method can determine a group size under which the group testing strategy can achieve a maximal expected number of negative samples and the sensitivity of tests is higher than a user-specified threshold. Experimental results show that the XMAGT method outperforms existing methods in terms of both efficiency and sensitivity.

Polyethylenimine-Poly(lactic-co-glycolic acid)2 Nanoparticles Show an Innate Targeting Ability to the Submandibular Salivary Gland via the Muscarinic 3 Receptor.

Polymeric nanoparticles have been extensively explored for biomedical applications, especially as framework materials for the construction of functional nanostructures. However, less attention has been paid to the inherent biological activities of those polymers. In this work, one of the commonly used polymers in gene and protein delivery, polyethylenimine-poly(lactic-co-glycolic acid)2 (PEI-PLGA), was discovered by accident to be able to mediate the nanoparticles to target the submandibular salivary glands of mice after intravenous injection. PEI-PLGA nanoparticles with an unmodified PEI surface selectively accumulated in submandibular salivary glands with ex vivo and in vitro study, suggesting that a ligand-receptor interaction between PEI and muscarinic acetylcholine receptor subtype 3 (M3 receptor) contributed to this affinity. Docking computation for the molecular binding mode between PEI segments and M3 receptor indicated the way they interacted was similar to that of the FDA-approved specific M3 receptor antagonist, tiotropium. The key amino acids mediated this specific interaction between PEI-PLGA nanoparticles and M3 receptor were identified via a simulated alanine mutation study. This work demonstrates the unique characteristic of PEI-PLGA nanoparticles, which may be useful for the development of muscarinic receptor targeted nanomedicines and should be taken into consideration when PEI-based nanoparticles are applied in gene delivery.

Penetration Cascade of Size Switchable Nanosystem in Desmoplastic Stroma for Improved Pancreatic Cancer Therapy.

Pancreatic ductal adenocarcinoma (PDAC) cells are surrounded by a dense extracellular matrix (ECM), which greatly restricts the access of therapeutic agents, resulting in poor clinical response to chemotherapy. Transforming growth factor-ß1 (TGF-ß1) signaling plays a crucial role in construction of the desmoplastic stroma and provides potential targets for PDAC therapy. To surmount the pathological obstacle, we developed a size switchable nanosystem based on PEG-PLGA nanospheres encapsulated within liposomes for the combined delivery of vactosertib (VAC), a TGF-ß1 receptor kinase inhibitor, and the cytotoxic drug paclitaxel (TAX). By surface modification of the liposomes with a peptide, APTEDB, the nanosystem can be anchored to abundant tumor-associated fibronectin in PDAC stroma and decreases its size by releasing encapsulated TAX-loaded nanospheres, as well as VAC after collapse of the liposomes. The inhibition of ECM hyperplasia by VAC allows TAX more ready access to the cancer cells in addition to its small size, thereby shrinking pancreatic tumor xenografts more effectively than a combination of the free drugs. This size switchable nanosystem enables sequential delivery of drugs at a fixed dose combination with simplified administration and provides an encouraging cascade approach of drug penetration for enhanced chemotherapy in cancers with a dense desmoplastic stroma.

Molecularly engineered truncated tissue factor with therapeutic aptamers for tumor-targeted delivery and vascular infarction.

Selective occlusion of tumor vasculature has proven to be an effective strategy for cancer therapy. Among vascular coagulation agents, the extracellular domain of coagulation-inducing protein tissue factor, truncated tissue factor (tTF), is the most widely used. Since the truncated protein exhibits no coagulation activity and is rapidly cleared in the circulation, free tTF cannot be used for cancer treatment on its own but must be combined with other moieties. We here developed a novel, tumor-specific tTF delivery system through coupling tTF with the DNA aptamer, AS1411, which selectively binds to nucleolin receptors overexpressing on the surface of tumor vascular endothelial cells and is specifically cytotoxic to target cells. Systemic administration of the tTF-AS1411 conjugates into tumor-bearing animals induced intravascular thrombosis solely in tumors, thus reducing tumor blood supply and inducing tumor necrosis without apparent side effects. This conjugate represents a uniquely attractive candidate for the clinical translation of vessel occlusion agent for cancer therapy.

Development of a Cancer Vaccine Using In Vivo Click-Chemistry-Mediated Active Lymph Node Accumulation for Improved Immunotherapy.

Due to their ability to elicit a potent immune reaction with low systemic toxicity, cancer vaccines represent a promising strategy for treating tumors. Considerable effort has been directed toward improving the in vivo efficacy of cancer vaccines, with direct lymph node (LN) targeting being the most promising approach. Here, a click-chemistry-based active LN accumulation system (ALAS) is developed by surface modification of lymphatic endothelial cells with an azide group, which provide targets for dibenzocyclooctyne (DBCO)-modified liposomes, to improve the delivery of encapsulated antigen and adjuvant to LNs. When loading with OVA257-264 peptide and poly(I:C), the formulation elicits an enhanced CD8+ T cell response in vivo, resulting in a much more efficient therapeutic effect and prolonged median survival of mice. Compared to treatment with DBCO-conjugated liposomes (DL)-Ag/Ad without the azide targeting, the percent survival of ALAS-vaccine-treated mice improves by 100% over 60 days. Altogether, the findings indicate that the novel ALAS approach is a powerful strategy to deliver vaccine components to LNs for enhanced antitumor immunity.

Bioengineered bacteria-derived outer membrane vesicles as a versatile antigen display platform for tumor vaccination via Plug-and-Display technology.

An effective tumor vaccine vector that can rapidly display neoantigens is urgently needed. Outer membrane vesicles (OMVs) can strongly activate the innate immune system and are qualified as immunoadjuvants. Here, we describe a versatile OMV-based vaccine platform to elicit a specific anti-tumor immune response via specifically presenting antigens onto OMV surface. We first display tumor antigens on the OMVs surface by fusing with ClyA protein, and then simplify the antigen display process by employing a Plug-and-Display system comprising the tag/catcher protein pairs. OMVs decorated with different protein catchers can simultaneously display multiple, distinct tumor antigens to elicit a synergistic antitumour immune response. In addition, the bioengineered OMVs loaded with different tumor antigens can abrogate lung melanoma metastasis and inhibit subcutaneous colorectal cancer growth. The ability of the bioengineered OMV-based platform to rapidly and simultaneously display antigens may facilitate the development of these agents for personalized tumour vaccines.

Platelet-Membrane-Coated Nanoparticles Enable Vascular Disrupting Agent Combining Anti-Angiogenic Drug for Improved Tumor Vessel Impairment.

Compared with traditional chemotherapeutics, vascular disruption agents (VDAs) have the advantages of rapidly blocking the supply of nutrients and starving tumors to death. Although the VDAs are effective under certain scenarios, this treatment triggers angiogenesis in the later stage of therapy that frequently leads to tumor recurrence and treatment failure. Additionally, the nonspecific tumor targeting and considerable side effects also impede the clinical applications of VDAs. Here we develop a customized strategy that combines a VDA with an anti-angiogenic drug (AAD) using mesoporous silica nanoparticles (MSNs) coated with platelet membrane for the self-assembled tumor targeting accumulation. The tailor-made nanoparticles accumulate in tumor tissues through the targeted adhesion of platelet membrane surface to damaged vessel sites, resulting in significant vascular disruption and efficient anti-angiogenesis in animal models. This study demonstrates the promising potential of combining VDA and AAD in a single nanoplatform for tumor eradication.