Highly effective targeted tumor recognition via vectors is crucial for cancer detection. In contrast to antibodies and proteins, peptides are direct targeting ligands with a low molecular weight. In the present study, a peptide magnetic nanovector platform containing a lipid bilayer was designed using a peptide amphiphile (PA) as a skeleton material in a controlled manner without surface modification. Fluorescein isothiocyanate-labeled epidermal growth factor receptor (EGFR) peptide nanoparticles (NPs) could specifically bind to EGFR-positive liver tumor cells. EGFR peptide magnetic vesicles (EPMVs) could efficiently recognize and separate hepatoma carcinoma cells from cell solutions and treated blood samples (ratio of magnetic EPMVs versus anti-EpCAM NPs: 3.5 ± 0.29). Analysis of the circulating tumor cell (CTC) count in blood samples from 32 patients with liver cancer showed that EPMVs could be effectively applied for CTC capture. Thus, this nanoscale, targeted cargo-packaging technology may be useful for designing cancer diagnostic systems.

Magnetic poly (D,L-lactide-co-glycolide) (PLGA)/lipid nanoparticles (MPLs) were fabricated from PLGA, L-α-phosphatidylethanolamine (DOPE), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-amino (polyethylene glycol) (DSPE-PEG-NH2), and magnetic nanoparticles (NPs), and then conjugated to trans-activating transcriptor (TAT) peptide. The TAT-MPLs were designed to target the brain by magnetic guidance and TAT conjugation. The drugs hesperidin (HES), naringin (NAR), and glutathione (GSH) were encapsulated in MPLs with drug loading capacity (>10%) and drug encapsulation efficiency (>90%). The therapeutic efficacy of the drug-loaded TAT-MPLs in bEnd.3 cells was compared with that of drug-loaded MPLs. The cells accumulated higher levels of TAT-MPLs than MPLs. In addition, the accumulation of QD-loaded fluorescein isothiocyanate (FITC)-labeled TAT-MPLs in bEnd.3 cells was dose and time dependent. Our results show that TAT-conjugated MPLs may function as an effective drug delivery system that crosses the blood brain barrier to the brain.

In the clinic, numeration of circulating tumor cells (CTCs) plays a critical role in cancer diagnosis and treatment, but conventional CTC identification and counting that rely on specific antibodies to characterize a cell's surface antigens are costive and with limitations. Importantly, false positive or negative results may occur due to the high heterogeneity and epithelial-mesenchymal transition (EMT) of CTCs. Herein we demonstrate a novel and effective CTC detecting nanoprobe that could rapidly respond to the high level of endogenous HO of CTCs and report the signal through fluorescence emission. Briefly, a hydrophobic coumarin-benzene boronic acid pinacol ester (Cou-Bpin) was grafted onto hydrophilic glycol chitosan (GC) to form an amphiphilic molecule, which further assembled into micellar nanoparticles in aqueous solution. This new nanoprobe was highly sensitive to HO with a detection limit of 0.1 μM and could rapidly enter the cells within 30 min. Upon exposure to intracellular HO, the nanoprobe exhibited remarkable one-photon and two-photon luminescent characteristics, which were suitable for imaging of endogenous HO of various human colorectal cancer cells and assist the identification of CTCs. Compared to a conventional CTC counting assay, the nanoprobe-based CTC numeration could overcome the false-negative findings due to the low expression of cytokeratin 19 (CK19). In a clinic test, CTC counting results based on the new nanoprobe match better to the postoperative pathological results of four clinic patients who had colorectal cancer at different stages.

Immune modulation is one of the most effective approaches in the therapy of complex diseases, including public health emergency. However, most immune therapeutics such as drugs, vaccines, and cellular therapy suffer from the limitations of poor efficacy and adverse side effects. Fortunately, cell membrane-derived nanoparticles (CMDNs) have superior compatibility with other therapeutics and offer new opportunities to push the limits of current treatments in immune modulation. As the interface between cells and outer surroundings, cell membrane contains components which instruct intercellular communication and the plasticity of cytomembrane has significantly potentiated CMDNs to leverage our immune system. Therefore, cell membranes employed in immunomodulatory CMDNs have gradually shifted from natural to engineered. In this review, unique properties of immunomodulatory CMDNs and engineering strategies of emerging CMDNs for immune modulation, with an emphasis on the design logic are summarized. Further, this review points out some pressing problems to be solved during clinical translation and put forward some suggestions on the prospect of immunoregulatory CMDNs. It is anticipated that this review can provide new insights on the design of immunoregulatory CMDNs and expand their potentiation in the precise control of the dysregulated immune system.

Eucommia ulmoides Oliv., a native Chinese plant species, has been used as a traditional Chinese medicine formulation to treat rheumatoid arthritis (RA), strengthen bones and muscles, and lower blood pressure. Various parts of this plant such as the bark, leaves, and flowers have been found to have anti-inflammatory properties. E. ulmoides has potential applications as a therapeutic agent against bone disorders, which were investigated in this study. In vitro, RA joint fibroblast-like synoviocytes (RA-FLS) were treated with different concentrations (0, 25, 50, 100, 200, 400, 800, and 1000 μg/mL) of E. ulmoides bark, leaf, and male flower alcoholic extracts (EB, EL, and EF, respectively) to determine their potential cytotoxicity. Tumor necrosis factor- (TNF-) α and nitric oxide (NO) levels in RA-FLS were quantified using enzyme-linked immunosorbent assay (ELISA). Furthermore, collagen-induced arthritis (CIA) rats were treated with EB, EL, EF, Tripterygium wilfordii polyglycoside (TG) or the normal control (Nor), and then ankle joint pathology, bone morphology, and serum and spleen inflammatory cytokine levels were evaluated. The results showed that, in RA-FLS, EB, EL, and EF were not cytotoxic; EB and EF reduced TNF-α supernatant levels; and EB, EL, and EF reduced NO levels. The results of in vivo experiments showed that EB, EL, and EF alleviated ankle swelling and joint inflammation, while all extracts diminished inflammatory cell infiltration, pannus and bone destruction, and bone erosion. All tested extracts inhibited interleukin- (IL-) 6, IL-17, and TNF-α mRNA in the spleen of CIA rats, while EB most effectively reduced osteoclasts and inhibited bone erosion. EF showed the most obvious inhibition of inflammatory factors and pannus. Thus, EB, EL, and EF may alleviate bone destruction by inhibiting inflammation.

Accurately distinguishing tumors from noncancerous inflammation and normal tissues is hugely significent for tumor diagnosis and therapy. However, tumor and inflammatory tissues have similar pathologic characteristics in their microenvironment, making differentiation very difficult. Here, a fluorescent cocktail nanoparticle capable of simultaneously detecting intracellular mRNA and H2O2 was designed to differentiate tumors from nontumor cells. To detect targeted mRNA in living cells, a DNA probe was generated using the fluorescence resonance energy transfer (FRET) principle. A pH-responsive amphiphilic polymer was synthesized to realize the transportation of the DNA probe. In addition, the polymer was conjugated with a coumarin-boronic acid ester (Cou-BE) H2O2 probe. According to the change in the fluorescence of Cou-BE, tumor and inflammatory cells could be distinguished from normal cells owing to their high concentration of H2O2. Because of the different concentrations of tumor-related mRNA in tumor and nontumor cells, the fluorescence intensity of the DNA probe-loaded nanoparticles inside tumor cells was different from that inside inflammatory cells. Therefore, our fluorescent cocktail strategy could discriminate simultaneously tumor, inflammation, and normal cells through the cooperative detection of intracellular mRNA and H2O2, which demonstrated potential application value in biomedical research and clinical diagnosis.

In recent years, great interest has been focused on the use of photosensitizers (PS) for photodynamic therapy (PDT) as safe and effective anti-tumor drugs. As a good lysosomal-targeted drug, folic acid (FA) is highly interesting as well. [Formula: see text]-methylpyridylporphyrin tailed with folate conjugate (Me-Por-FA) was newly designed and synthesized and the structure was confirmed by UV-vis, IR, 1H NMR, MS and elemental analysis. The interaction of this porphyrin with calf thymus DNA was the intercalative binding mode, which was confirmed by ultraviolet and fluorescence spectra, and the binding constants [Formula: see text] was 6.24 × 104 L/mol. The singlet oxygen (1O[Formula: see text] generated by Me-Por-FA was determined by 1, 3-diphenylisobenzofuran (DPBF) method using tetrapyridylporphyrin (H[Formula: see text]TMPyP) as a comparison with the following order: H2TMPyP > Me-Por-FA. Stained with LysoTracker[Formula: see text] Green DND-26, Me-Por-FA was mainly distributed over the lysosomes during 4 h, but H[Formula: see text]TMPyP was not. This suggests that Me-Por-FA could be developed as a targeted photosensitizer for precise photodynamic therapy.

Bipartite graphs are naturally used to model relationships between two different types of entities, such as people-location, author-paper, and customer-product. When modeling real-world applications like disease outbreaks, edges are often enriched with temporal information, leading to temporal bipartite graphs. While reachability has been extensively studied on (temporal) unipartite graphs, it remains largely unexplored on temporal bipartite graphs. To fill this research gap, in this paper, we study the reachability problem on temporal bipartite graphs. Specifically, a vertex u reaches a vertex w in a temporal bipartite graph G if u and w axe connected through a series of consecutive wedges with time constraints. Towards efficiently answering if a vertex can reach the other vertex, we propose an index-based method by adapting the idea of 2-hop labeling. Effective optimization strategies and parallelization techniques are devised to accelerate the index construction process. To better support real-life scenarios, we further show how the index is leveraged to efficiently answer other types of queries, e.g., single-source reachability query and earliest-arrival path query. Extensive experiments on 16 real-world graphs demonstrate the effectiveness and efficiency of our proposed techniques.