The impact of deep-inspiration breath-hold total-body PET/CT imaging on thoracic 18F-FDG avid lesions compared with free-breathing.

OBJECTIVES: To investigate PET/CT registration and quantification accuracy of thoracic lesions of a single 30-second deep-inspiration breath-hold (DIBH) technique with a total-body PET (TB-PET) scanner, and compared with free-breathing (FB) PET/CT. METHODS: 137 of the 145 prospectively enrolled patients finished a routine FB-300 s PET/CT exam and a 30-second DIBH TB-PET with chest to pelvis low dose CT. The total-body FB-300 s, FB-30 s, and DIBH-30 s PET images were reconstructed. Quantitative assessment (SUVmax and SUVmean of lung and other organs), PET/CT registration assessment and lesion analysis (SUVmax, SUVpeak, SUVmean and tumor-background ratio) were compared with Wilcoxon signed-rank tests. RESULTS: The SUVmax and SUVmean of the lung with DIBH-30 s were significantly lower than those with FB. The distances of the liver dome between PET and CT were significantly smaller with DIBH-30 s than with FB. 195 assessable lesions in 106 patients were included, and the detection sensitivity was 97.9 % and 99.0 % in FB-300 s, and DIBH-30 s, respectively. For both small co-identified lesions (n = 86) and larger co-identified lesions with a diameter ≥ 1 cm (n = 91), the lesion SUVs were significantly greater with DIBH-30 s than with FB-300 s. Regarding lesion location, the differences of the SUVs for the lesions in the lower thorax area (n = 97, p < 0.001) were significant between DIBH-30 s and FB-300 s, while these differences were not statistically significant in the upper thorax (n = 80, p > 0.05). The lesion tumor-to-surrounding-background ratio (TsBR) was significantly increased, both in the upper and lower thorax. CONCLUSION: The TB DIBH PET/CT technique is feasible in clinical practice. It reduces the background lung uptake and achieves better registration and lesion quantification, especially in the lower thorax.

ATP-elicited Cation Fluxes Promote Volume-regulated Anion Channel LRRC8/VRAC Transport cGAMP for Antitumor Immunity.

The cyclic GMP-AMP synthase (cGAS)-stimulator of IFN genes (STING) pathway is instrumental to antitumor immunity, yet the underlying molecular and cellular mechanisms are complex and still unfolding. A new paradigm suggests that cancer cells' cGAS-synthesized cGAMP can be transferred to tumor-infiltrating immune cells, eliciting STING-dependent IFN-ß response for antitumor immunity. Nevertheless, how the tumor microenvironment may shape this process remains unclear. In this study, we found that extracellular ATP, an immune regulatory molecule widely present in the tumor microenvironment, can potentiate cGAMP transfer, thereby boosting the STING signaling and IFN-ß response in murine macrophages and fibroblasts. Notably, genetic ablation or chemical inhibition of murine volume-regulation anion channel LRRC8/volume-regulated anion channel (VRAC), a recently identified cGAMP transporter, abolished ATP-potentiated cGAMP transfer and STING-dependent IFN-ß response, revealing a crucial role of LRRC8/VRAC in the cross-talk of extracellular ATP and cGAMP. Mechanistically, ATP activation of the P2X family receptors triggered Ca2+ influx and K+ efflux, promoting reactive oxygen species production. Moreover, ATP-evoked K+ efflux alleviated the phosphorylation of VRAC's obligate subunit LRRC8A/SWELL1 on S174. Mutagenesis studies indicated that the phosphorylation of S174 on LRRC8A could act as a checkpoint for VRAC in the steady state and a rheostat of ATP responsiveness. In an MC38-transplanted tumor model, systemically blocking CD39 and ENPP1, hydroxylases of extracellular ATP and cGAMP, respectively, elevated antitumor NK, NKT, and CD8+ T cell responses and restrained tumor growth in mice. Altogether, this study establishes a crucial role of ATP in facilitating LRRC8/VRAC transport cGAMP in the tumor microenvironment and provides new insight into harnessing cGAMP transfer for antitumor immunity.

Development of an aptamer capable of multidrug resistance reversal for tumor combination chemotherapy.

Multidrug resistance (MDR) is a major factor in the failure of many forms of tumor chemotherapy. Development of a specific ligand for MDR-reversal would enhance the intracellular accumulation of therapeutic agents and effectively improve the tumor treatments. Here, an aptamer was screened against a doxorubicin (DOX)-resistant human hepatocellular carcinoma cell line (HepG2/DOX) via cell-based systematic evolution of ligands by exponential enrichment. A 50 nt truncated sequence termed d3 was obtained with high affinity and specificity for HepG2/DOX cells. Multidrug resistance protein 1 (MDR1) is determined to be a possible recognition target of the selected aptamer. Aptamer d3 binding was revealed to block the MDR of the tumor cells and increase the accumulation of intracellular anticancer drugs, including DOX, vincristine, and paclitaxel, which led to a boost to the cell killing of the anticancer drugs and lowering their survival of the tumor cells. The aptamer d3-mediated MDR-reversal for effective chemotherapy was further verified in an in vivo animal model, and combination of aptamer d3 with DOX significantly improved the suppression of tumor growth by treating a xenograft HepG2/DOX tumor in vivo. This work demonstrates the feasibility of a therapeutic DNA aptamer as a tumor MDR-reversal agent, and combination of the selected aptamer with chemotherapeutic drugs shows great potential for liver cancer treatments.

Analysis of the relationship between MYCN gene and serum NSE and urinary VMA levels and neuroblastoma pathological features and prognosis.

The purpose of this study was to explore the relationship between the MYCN gene, serum neuron-specific enolase (NSE), urinary vanillylmandelic acid (VMA) levels, and neuroblastoma pathological features and prognosis. Ninety-four children with neuroblastoma treated in the hospital were selected to compare the differences in MYCN gene amplification, serum NSE, and urinary VMA levels in children with different clinicopathological features and prognoses. The proportion of children with MYCN gene copy number ≥10 in INSS stage 3-4 was higher than that of children with INSS stage 1-2 (P < 0.05); the proportion of children with MYCN gene copy number ≥10 in high-risk children in the COG risk stratification was higher than that of children with intermediate and low risk (P < 0.05); the serum NSE of children aged >12 months higher than that of children aged ≤12 months (P < 0.05); serum NSE of children with tumors >500 cm3 higher than that of children with tumors ≤500 cm3 (P < 0.05); serum NSE and urinary VMA of children with INSS staging of stages 3-4 were higher than that of children with stages 1 to 2 (P < 0.05); serum NSE and urinary VMA in children with lymph node metastasis were higher than that of children without lymph node metastasis (P < 0.05); serum NSE of children with MYCN gene copy number ≥10 was higher than that of children without lymph node metastasis (P < 0.05); the proportion of children with MYCN gene copy number ≥10 who died, and the percentages of serum NSE and urinary VMA were higher than those of the surviving children (P < 0.05). MYCN gene amplification and serum NSE and urinary VMA levels were related to the age, tumor size, INSS stage, COG stage, lymph node metastasis, and prognosis of the children with neuroblastoma.

Ultrafast spectroscopy study of DNA photophysics after proflavine intercalation.

Proflavine (PF), an acridine DNA intercalating agent, has been widespread applied as an anti-microbial and topical antiseptic agent due to its ability to suppress DNA replication. On the other hand, various studies show that PF intercalation to DNA can increase photogenotoxicity and has potential chances to induce carcinomas of skin appendages. However, the effects of PF intercalation on the photophysical and photochemical properties of DNA have not been sufficiently explored. In this study, the excited state dynamics of the PF intercalated d(GC)9 • d(GC)9 and d(AT)9 • d(AT)9 DNA duplex are investigated in an aqueous buffer solution. Under 267 nm excitation, we observed ultrafast charge transfer (CT) between PF and d(GC)9 • d(GC)9 duplex, generating a CT state with an order of magnitude longer lifetime compared to that of the intrinsic excited state reported for the d(GC)9 • d(GC)9 duplex. In contrast, no excited state interaction was detected between PF and d(AT)9 • d(AT)9. Nevertheless, a localized triplet state with a lifetime over 5 µs was identified in the PF-d(AT)9 • d(AT)9 duplex.

PRMT5-mediated homologous recombination repair is essential to maintain genomic integrity of neural progenitor cells.

Maintaining genomic stability is a prerequisite for proliferating NPCs to ensure genetic fidelity. Though histone arginine methylation has been shown to play important roles in safeguarding genomic stability, the underlying mechanism during brain development is not fully understood. Protein arginine N-methyltransferase 5 (PRMT5) is a type II protein arginine methyltransferase that plays a role in transcriptional regulation. Here, we identify PRMT5 as a key regulator of DNA repair in response to double-strand breaks (DSBs) during NPC proliferation. Prmt5F/F; Emx1-Cre (cKO-Emx1) mice show a distinctive microcephaly phenotype, with partial loss of the dorsal medial cerebral cortex and complete loss of the corpus callosum and hippocampus. This phenotype is resulted from DSBs accumulation in the medial dorsal cortex followed by cell apoptosis. Both RNA sequencing and in vitro DNA repair analyses reveal that PRMT5 is required for DNA homologous recombination (HR) repair. PRMT5 specifically catalyzes H3R2me2s in proliferating NPCs in the developing mouse brain to enhance HR-related gene expression during DNA repair. Finally, overexpression of BRCA1 significantly rescues DSBs accumulation and cell apoptosis in PRMT5-deficient NSCs. Taken together, our results show that PRMT5 maintains genomic stability by regulating histone arginine methylation in proliferating NPCs.

Ultrafast and Multichannel Generation of the Triplet State in DNA-Intercalated Gilvocarcin V for an Enhanced Photoaddition Reaction.

Gilvocarcin V (GV) is a natural antibiotic exhibiting excellent antitumor activities and remarkably low toxicity in near-ultraviolet or visible light-dependent treatment. Notwithstanding, the [2 + 2] cycloaddition reaction between GV and thymine has been proven to be the key for its function in photodynamic therapy, and crucial mechanistic details about such a reaction are poorly understood. In this study, the electronic relaxation pathways and photoaddition reaction are characterized by femto- to nanosecond time-resolved spectroscopy combined with quantum chemical calculation. Our results reveal that ultrafast intersystem crossing (<3 ps) leads to the population of a local triplet excited state in DNA-intercalated GV. Such a state can further induce the formation of a biradical state, which is identified as the important reactive precursor for photoaddition between GV and thymine. The overall photoaddition quantum efficiency is determined to be 11.57 ± 1.0%. These results are essential to the elucidation of the DNA photoaddition mechanism of C-aryl glycoside-based artificial photocytotoxic agents and could help further development of those medicines.

FDG PET/CT Imaging of Liver and Spleen Histiocytic Sarcoma.

ABSTRACT: Histiocytic sarcoma is a tumor of the lymphohematopoietic system characterized by macrophage morphology and immunophenotype. Here, we report FDG PET/CT images of a 50-year-old man with coexisting histiocytic sarcoma of the liver and spleen. Images showed multiple enhanced uptake lesions of FDG in both the liver and spleen. Ultimately, histiocytic sarcoma was confirmed by the biopsy histopathology.

A hairpin-contained i-motif guided DNA nanoantenna for sensitive and specific sensing of tumor extracellular pH gradients.

Antenna, as a converter, could receive and convert signals from the outside world flexibly. Inspired by the behavior of antennas receiving external signals, we developed a pH-stimulated and aptamer-anchored Y-shaped DNA nanoantenna (termed pH-Apt-YNA) for sensitive and specific sensing of tumor extracellular pH gradients. The nanoantenna consisted of three functional nucleic acid sequences, an I-strand, Apt-Y-R and Y-L-G, where the I-strand endowed the DNA nanoantenna with the ability to receive and convert signals, the Apt-Y-R containing an aptamer fragment gave the DNA nanoantenna the ability to specifically anchor target tumor cells, and the complementarity of Y-L-G with the other two sequences ensured the stability of the DNA nanoantenna. Initially, the DNA nanoantenna was in a "silent" state, and rhodamine green was close to BHQ2, leading to suppressed signal emission. When the DNA nanoantenna anchored on the surface of target cancer cells through the aptamer recognition domain, the I-strand tended to fold into a hairpin-contained i-motif tetramer structure owing to the extracellular low pH stimuli, resulting in the DNA nanoantenna changing into an "active" state. In the meantime, rhodamine green moved far away from BHQ2, resulting in a strong signal output. The results demonstrate that the pH-Apt-YNA presents a sensitive pH sensing capacity within a narrow pH range of 6.2-7.4 and exhibits excellent specificity for the imaging of target cancer cell extracellular pH. Based on these advantages, we therefore anticipate that our facile design of the DNA nanoantenna with sensitive responsiveness provides a new way and great promise in the application of sensing pH-related physiological and pathological processes.

Mining multi-center heterogeneous medical data with distributed synthetic learning.

Overcoming barriers on the use of multi-center data for medical analytics is challenging due to privacy protection and data heterogeneity in the healthcare system. In this study, we propose the Distributed Synthetic Learning (DSL) architecture to learn across multiple medical centers and ensure the protection of sensitive personal information. DSL enables the building of a homogeneous dataset with entirely synthetic medical images via a form of GAN-based synthetic learning. The proposed DSL architecture has the following key functionalities: multi-modality learning, missing modality completion learning, and continual learning. We systematically evaluate the performance of DSL on different medical applications using cardiac computed tomography angiography (CTA), brain tumor MRI, and histopathology nuclei datasets. Extensive experiments demonstrate the superior performance of DSL as a high-quality synthetic medical image provider by the use of an ideal synthetic quality metric called Dist-FID. We show that DSL can be adapted to heterogeneous data and remarkably outperforms the real misaligned modalities segmentation model by 55% and the temporal datasets segmentation model by 8%.

Excited State Kinetics of Benzo[a]pyrene Is Affected by Oxygen and DNA.

Benzo[a]pyrene is a widespread environmental pollutant and a strong carcinogen. It is important to understand its bio-toxicity and degradation mechanism. Herein, we studied the excited state dynamics of benzo[a]pyrene by using time-resolved fluorescence and transient absorption spectroscopic techniques. For the first time, it is identified that benzo[a]pyrene in its singlet excited state could react with oxygen, resulting in fluorescence quenching. Additionally, effective intersystem crossing can occur from its singlet state to the triplet state. Furthermore, the interaction between the excited benzo[a]pyrene and ct-DNA can be observed directly and charge transfer between benzo[a]pyrene and ct-DNA may be the reason. These results lay a foundation for further understanding of the carcinogenic mechanism of benzo[a]pyrene and provide insight into the photo-degradation mechanism of this molecule.

Discrimination of Liver Metastases of Digestive System Neuroendocrine Tumors From Neuroendocrine Carcinoma by Computed Tomography-Based Radiomics Analysis.

OBJECTIVE: The aim of the study is to investigate the value of computed tomography (CT) radiomics features to discriminate the liver metastases (LMs) of digestive system neuroendocrine tumors (NETs) from neuroendocrine carcinoma (NECs). METHODS: Ninety-nine patients with LMs of digestive system neuroendocrine neoplasms from 2 institutions were included. Radiomics features were extracted from the portal venous phase CT images by the Pyradiomics and then selected by using the t test, Pearson correlation analysis, and least absolute shrinkage and selection operator method. The radiomics score (Rad score) for each patient was constructed by linear combination of the selected radiomics features. The radiological model was constructed by radiological features using the multivariable logistic regression. Then, the combined model was constructed by combining Rad score and the radiological model into logistic regression. The performance of all models was evaluated by the receiver operating characteristic curves with the area under curve (AUC). RESULTS: In the radiological model, only the enhancement degree (odds ratio, 8.299; 95% confidence interval, 2.070-32.703; P = 0.003) was an independent predictor for discriminating the LMs of digestive system NETs from those of NECs. The combined model constructed by the Rad score in combination with the enhancement degree showed good discrimination performance, with AUCs of 0.893, 0.841, and 0.740 in the training, testing, and external validation groups, respectively. In addition, it performed better than radiological model in the training and testing groups (AUC, 0.893 vs 0.726; AUC, 0.841 vs 0.621). CONCLUSIONS: The CT radiomics might be useful for discrimination LMs of digestive system NECs from NETs.

Clinical characteristics of anti-AChR-MuSK-LRP4 antibody-negative myasthenia gravis in China.

INTRODUCTION/AIMS: Descriptions of the clinical characteristics of anti-AChR-MuSK-LRP4 antibody-negative myasthenia gravis (triple-negative myasthenia gravis, TNMG) are lacking in the current literature. Therefore, we investigated the clinical characteristics of TNMG in Chinese patients. METHODS: We retrospectively analyzed 925 patients with MG registered in the Department of Neuroimmunology, Henan Institute of Medical and Pharmaceutical Sciences from January 2015 to March 2021. RESULTS: One hundred six patients diagnosed with TNMG were included in the study. The average age of onset was 32.4 y, with a male-to-female ratio of 1:1. The age of onset showed a bimodal distribution: 0-9 y and 40-49 y. Adult patients were more likely to have weakness of limb and bulbar muscles (p < .05). Thymic hyperplasia was found in 20.2% of the patients. Younger patients were more likely to relapse. The rate of adult early-onset myasthenia gravis reaching complete stable remission and pharmacological remission was 47.6%, and the prognosis was better than that in juvenile-onset myasthenia gravis (p = .019). Older age of onset was the only risk factor for the development of generalized TNMG from ocular TNMG (R = 1.046, p = .002, 95% confidence interval 1.017-1.077). DISCUSSION: This study showed that the clinical characteristics of patients with TNMG varied among the different age groups. Significant findings included a bimodal distribution of onset age, coexisting thymic hyperplasia, and a generally favorable prognosis.

Logic Nanodevice-Mediated Receptor Assembly for Nongenetic Regulation of Cell Behavior in Tumor-like Microenvironment.

The reprogramming of cell signaling and behavior through the artificial control of cell surface receptor oligomerization shows great promise in biomedical research and cell-based therapy. However, it remains challenging to achieve combinatorial recognition in a complicated environment and logical regulation of receptors for desirable cellular behavior. Herein, we develop a logic-gated DNA nanodevice with responsiveness to multiple environmental inputs for logically controlled assembly of heterogeneous receptors to modulate signaling. The "AND" gate nanodevice uses an i-motif and an ATP-binding aptamer as environmental cue-responsive units, which can successfully implement a logic operation to manipulate receptors on the cell surface. In the presence of both protons and ATP, the DNA nanodevice is activated to selectively assemble MET and CD71, which modulate the HGF/MET signaling, resulting in cytoskeletal reorganization to inhibit cancer cell motility in a tumor-like microenvironment. Our strategy would be highly promising for precision therapeutics, including controlled drug release and cancer treatment.

P2X1 enhances leukemogenesis through PBX3-BCAT1 pathways.

How bone marrow niches regulate leukemogenic activities of leukemia-initiating cells (LICs) is unclear. The present study revealed that the metabolic niche component, ATP, efficiently induced ion influx in LICs through its ligand-gated ion channel, P2X1. P2X1 deletion impaired LIC self-renewal capacities and resulted in an approximately 8-fold decrease in functional LIC numbers in a murine acute myeloid leukemia (AML) model without affecting normal hematopoiesis. P2X1 phosphorylation at specific sites of S387 and T389 was essential for sustaining its promoting effects on leukemia development. ATP-P2X1-mediated signaling upregulated the PBX3 level to transactivate BCAT1 to maintain LIC fates. P2X1 knockdown inhibited the proliferation of both human AML cell lines and primary cells. The P2X1 antagonist sufficiently suppressed AML cell proliferation. These results provided a unique perspective on how metabolic niche factor ATP fine-tunes LIC activities, which may benefit the development of strategies for targeting LICs or other cancer stem cells.

Metal Cluster Triggered-Assembling Heterogeneous Au-Ag Nanoclusters with Highly Loading Performance and Biocompatible Capability.

In this work, we firstly report the preparation of heterogeneously assembled structures Au-Ag nanoclusters (NCs) as good drug carriers with high loading performance and biocompatible capability. As glutathione-protected Au and Ag clusters self-assembled into porous Au-Ag NCs, the size value is about 1.358 (±0.05) nm. The morphology characterization revealed that the diameter of Au-Ag NCs is approximately 120 nm, as well as the corresponding potential ability in loading performance of the metal cluster triggered-assembling process. Compared with individual components, the stability and loading performance of heterogeneous Au-Ag NCs were improved and exhibit that the relative biocompatibility was enhanced. The exact information about this is that cell viability was approximately to 98% when cells were incubated with 100 µg mL-1 particle solution for 3 days. The drug release of Adriamycin from Au-Ag NCs was carried out in PBS at pH = 7.4 and 5.8, respectively. By simulating in vivo and tumor microenvironment, the release efficiency could reach over 65% at pH = 5.8 but less than 30% at pH = 7.2. Using an ultrasound field as external environment can accelerate the assembling process while metal clusters triggered assembling Au-Ag NCs. The size and morphology of the assembled Au-Ag NCs can be controlled by using different power parameters (8 W, 13 W, 18 W) under ambient atmosphere. Overall, a novel approach is exhibited, which conveys assembling work for metal clusters triggers into heterogeneous structures with porous characteristic. Its existing properties such as water-solubility, stability, low toxicity and capsulation can be considered as dependable agents in various biomedical applications and drug carriers in immunotherapies.

Effect of skeletal muscle loss during neoadjuvant imatinib therapy on clinical outcomes in patients with locally advanced GIST.

BACKGROUND: Currently, the effect of skeletal muscle loss during neoadjuvant imatinib therapy on clinical outcomes in patients with locally advanced gastrointestinal stromal tumors (LA-GIST) remains unclear. This study aims to investigate the relationship between changes in skeletal muscle and postoperative complications, survival and tumor response in patients with LA-GIST during neoadjuvant therapy with imatinib. METHODS: We retrospectively analyzed pre- and post-treatment computed tomography images of 57 GIST patients who underwent radical surgery after neoadjuvant therapy with imatinib from January 2013 to March 2019. Skeletal muscle index (SMI) was measured at the L3 vertebral level in all patients. A cut-off value (SMI < 52.3 cm2/m2 and < 38.6 cm2/m2 for men and women, respectively) published in a previous study was used to define sarcopenia. Based on gender, we defined ΔSMI (%)/250 days above 9.69% for men and ΔSMI (%)/250 days above 7.63% for women as significant muscle loss (SML). Factors associated with postoperative complications and tumor response were analyzed using logistic regression, and predictors affecting patient prognosis were analyzed using Cox regression. RESULTS: Of the 57 patients, sarcopenia was present before and after neoadjuvant therapy in 20 (35.09%) and 28 (49.12%) patients, respectively. It was not associated with immediate or long-term clinical outcomes. However, patients with SML during neoadjuvant therapy had a higher incidence of postoperative complications (60.00% vs. 25.00%, p = 0.008), worse pathological regression (44.00% vs. 75.00%, p = 0.017) and worse 3-year survival (Male, 68.75% vs. 95.45%, p = 0.027; Female, 66.67% vs. 100.00%, p = 0.046) than patients without SML. CONCLUSION: The development of SML during neoadjuvant therapy in LA-GIST patients, rather than pre- and post-treatment sarcopenia, is a major prognostic factor for the long-term prognosis and is also associated with recent postoperative complication rates and pathological regression.

A stable DNA Tetrahedra-AuNCs nanohybrid: On-site programmed disassembly for tumor imaging and combination therapy.

Despite DNA nanotechnology has spawned a broad variety and taken a giant leap toward cancer theranostic applications over the last decade, the homogeneous DNA nanostructures often suffer from fatal degradation due to their limited stability and specificity. Herein, for the first time, we report a stable DNA tetrahedra-gold nanoclusters (DT/AuNCs) nanohybrid with a self-assembly/programmed disassembly manner for stimuli-responsive tumor imaging and gene-chemo therapy. By utilizing the multifunctional peptides with positive and legumain-specific domains as bioligands, AuNCs were synthesized as signal generators and gate guard attached on the dual-responsive DT, forming the DT/AuNCs with sequential response to legumain-TK1 mRNA & glutathione. The tumorous biomarker of legumain initiated the signal generation relying on the nanosurface energy transfer effect of AuNCs and denudation of DT-Dox (preliminary disassembly). Successively, the dual-responsive DT-Dox administrated a sequential fragmentation along with Dox release in response to the up-regulated glutathione and TK1 mRNA (secondary disassembly), thereby leading to combined gene silencing and chemo-therapy. The results revealed that the DT/AuNCs nanohybrids significantly improved the stability and enhanced the therapeutic efficiency compared to naked DT. Endowing with remarkable stability against biological milieu and site specificity for drug release, our work exhibits a new prospect of fabricating DNA-based nanohybrids for precise tumor theranostics.

Acidic microenvironment triggered in situ assembly of activatable three-arm aptamer nanoclaw for contrast-enhanced imaging and tumor growth inhibition in vivo.

RATIONALE: Static assembled multivalent DNA nanotheranostics system have encountered some bottleneck problems in cancer imaging and therapy, such as poor penetration and high immunogenicity. Herein, we proposed an acidic tumor microenvironment triggered assembly of activatable multivalent nanodevice, called "three-arm aptamer nanoclaw" (TA-aptNC), assembled from three pH-responsive aptamer-decorated DNA monomers (pH-aptDMs) to facilitate their functions of imaging and therapy. METHODS: The activated TA-aptNC was constructed by acidic microenvironment triggered in situ assembly of three pH-aptDMs. Designer pH-aptDM was established based on the combination of a pH-responsive i-motif switch and an assembly module with a cell membrane anchoring aptamer ligand. Acidic microenvironment-triggered the assembly of the TA-aptNC was characterized by electrophoresis and atomic force microscopic (AFM). The binding affinity and stability of the TA-aptNC, comparing the monovalent pH-aptDM, were studied via the flow cytometry and nuclease resistance assays. Acidic microenvironment-activated contrast-enhanced tumor imaging and significantly antitumor efficiency were evaluated in vitro and in vivo. Results: At physiological pH environment, the pH-aptDMs with excellent tissue permeability exited as inactivated and monodispersed small monomer. When encountering acidic microenvironment at the tumor site, pH-responsive i-motif switch liberated from the pH-aptDMs, and the three unconstrained DNA modules (DM1, DM2 and DM3) subsequently assembled in situ into the TA-aptNC. Compared with monovalent pH-aptDMs, the spontaneously formed activatable TA-aptNC afforded 2-fold enhanced binding ability via the multivalent effect, which further facilitated the selective tumor cell uptake capability, thus enabling a contrast-enhanced tumor imaging and significantly antitumor efficiency in vivo without systemic toxicity. Conclusions: The proposed strategy offers valuable insight into excavating an endogenous stimuli-triggered assembly of multivalent nanodevice for accurate diagnosis and efficient tumor therapy.

Utilization of metal or non-metal-based functional materials as efficient composites in cancer therapies.

There has been great progress in cancer treatment through traditional approaches, even though some of them are still trapped in relative complications such as certain side effects and prospective chances of full recovery. As a conventional method, the immunotherapy approach is regarded as an effective approach to cure cancer. It is mainly promoted by immune checkpoint blocking and adoptive cell therapy, which can utilize the human immune system to attack tumor cells and make them necrose completely or stop proliferating cancer cells. Currently however, immunotherapy shows limited success due to the limitation of real applicable cases of targeted tumor environments and immune systems. Considering the urgent need to construct suitable strategies towards cancer therapy, metallic materials can be used as delivery systems for immunotherapeutic agents in the human body. Metallic materials exhibit a high degree of specificity, effectiveness, diagnostic ability, imaging ability and therapeutic effects with different biomolecules or polymers, which is an effective option for cancer treatment. In addition, these modified metallic materials contain immune-modulators, which can activate immune cells to regulate tumor microenvironments and enhance anti-cancer immunity. Additionally, they can be used as adjuvants with immunomodulatory activities, or as carriers for molecular transport to specific targets, which results in the loading of specific ligands to facilitate specific uptake. Here, we provide an overview of the different types of metallic materials used as efficient composites in cancer immunotherapy. We elaborate on the advancements using metallic materials with functional agents as effective composites in synergistic cancer treatment. Some nonmetallic functional composites also appear as a common phenomenon. Ascribed to the design of the composites themselves, the materials' surface structural characteristics are introduced as the drug-loading substrate. The physical and chemical properties of the functional materials emphasize that further research is required to fully characterize their mechanism, showing appropriate relevance for material toxicology and biomedical applications.