Specific Tumor Cell Detection by a Metabolically Targeted Aggregation-Induced Emission-Based Gold Nanoprobe.

Detection of circulating tumor cells (CTCs) could be widely used for early diagnosis and real-time monitoring of tumor progression in liquid biopsy samples. Compared with normal cells, tumor cells exhibit relatively strong negative surface charges due to the high rate of glycolysis. In this study, a cationic fluorescence "turn-on" aggregation-induced emission (AIE) nanoprobe based on gold nanorods (GNRs) was designed and tested to detect tumor cells specifically. In brief, tetraphenylethene (TPE), an AIE dye, was conjugated to the cationic polymer polyethylenimine (PEI) yielding TPEI. TPEI-PEG-SH was obtained by further functionalizing TPEI with a thiol group. TPEI-PEG-SH was grafted to the surface of GNRs, yielding the cationic AIE nanoprobe, named as GNRs-PEG-TPEI. The nanoprobe was characterized to have a uniform particle size of 172 nm, a strong positive surface charge (+54.87 mV), and a surface modification load of ∼40%. The in vitro stability of GNRs-PEG-TPEI was verified. The cellular imaging results demonstrated that the nanoprobe could efficiently recognize several types of tumor cells including MCF-7, HepG2, and Caco-2 while exhibiting specific fluorescence signals only after interacting with tumor cells and minimal background interference. In addition, the study investigated the toxicity of the nanoprobe to the captured cells and proved the safety of the nanoprobe. In conclusion, a specific and efficient nanoprobe was developed for capture and detection of different types of tumor cells based on their unique metabolic characteristics. It holds great promise for achieving early diagnosis and monitoring the tumor progression by detecting the CTCs in clinical liquid biopsy samples.

Rapid simultaneous determination of gut microbial phenylalanine, tyrosine, and tryptophan metabolites in rat serum, urine, and faeces using LC-MS/MS and its application to a type 2 diabetes mellitus study.

Gut microbial phenylalanine, tyrosine, and tryptophan metabolites are closely linked to various diseases. Monitoring the alterations of the related metabolites is vital to facilitate the understanding of pathophysiology of diseases. Herein, a rapid and sensitive assay based on LC-tandem mass spectrometry has been developed to analyze 20 gut microbial metabolites derived from phenylalanine, tyrosine, and tryptophan in rat serum, urine, and faeces. These microbial-derived metabolites were separated on a phenyl-hexyl column and simultaneously determined in a single run of 8 min. The detection limit for analytes ranged between 1.08 and 32.4 ng/mL. All calibration curves exhibited good linear relationships (R2 ≥ 0.9982). Intra- and inter-assay precision values were below 15% and accuracies ranged from 85% to 115% for all analytes. The selectivity, matrix effect, and recovery of this method were all satisfactory. The validated method was successfully applied to characterize the alterations of these metabolites in type 2 diabetes mellitus rat. In general, the developed assay is suitable for high-throughput monitoring of gut microbial phenylalanine, tyrosine, and tryptophan metabolites and provides a useful approach for exploring the mechanisms of microbial-derived metabolites in diseases.

Ligand-Modified Erythrocyte Membrane-Cloaked Metal-Organic Framework Nanoparticles for Targeted Antitumor Therapy.

Systemic chemotherapy for treating tumors often leads to serious systemic side effects and affects patient compliance. Although the emerging technology of drug delivery systems (DDSs) can deliver the required cargo to tumor sites, DDSs are limited due to insufficient targeting ability or deficient pharmacokinetics. Herein, we assembled a novel targeting DDS for precision tumor therapy by applying a tumor-targeting polypeptide cyclic RGD (cRGD)-modified erythrocyte membrane (eM-cRGD) cloaked on zeolitic imidazolate framework-8 (ZIF-8) nanoparticles (NPs) with encapsulated doxorubicin (DOX). For a mass ratio of ZIF-8:DOX = 1:1, the loading capacity was up to 49%. The nanoscale-sized targeting DDS promoted NP accumulation in tumor tissues via enhanced permeability and retention (EPR) effects, and the NPs actively targeted ligands and were then transferred to endosomes. The pH-sensitive carriers released higher DOX levels under the low pH mimicking that of a tumor microenvironment and tumor intracellular organelles, allowing enhanced inhibition of cancer cell growth. The cumulative release rate of DOX from DOX@ZIF-8 NPs reached 82.8% at 48 h in acidic conditions of pH = 5.0, while the cumulative release rate of DOX from the DOX@ZIF-8 NPs reached only 24.92% at pH = 7.4. The internalization of the DDS was approximately 44.35% that of the unmodified DDS by immune cells, as confirmed by flow cytometry. In vivo studies verified that the RGD-modified DDS had the ability to prolong blood circulation (t1/2 = 6.81 h), enhancing the tumor-specific accumulation of NPs by means of the integrin αvß3 receptor-mediated pathway, which was further valuated in mice bearing human cervical cancer (HeLa) cells, and yielding a significant antitumor effect; the tumor inhibition rate was as high as 85.46%. Under the same conditions, the blood circulation half-life of the unmodified DDS was only 3.22 h, and the tumor inhibition rate of free DOX was 81.34%. Moreover, the RGD modified with a carrier could achieve a satisfactory chemotherapeutic effect while minimizing side effects. In summary, our novel targeting DDS could contribute to the development of intelligent DDSs for tumor precision therapy.

Untargeted metabolomics analysis on Cicer arietinium L.-Induced Amelioration in T2D rats by UPLC-Q-TOF-MS/MS.

ETHNOPHARMACOLOGICAL RELEVANCE: Cicer arietinium L., which belongs to Cicer genus, was not only a kind of traditional Chinese medicines (TCM) recorded in Pharmacopoeia of the People's Republic of China (version 2015), but also a kind of Uighur antidiabetic medicines. It has been used as an adjuvant drug or functional food for thousand years in Xinjiang province, China. However, the mechanisms of C. arietinium treatment in T2D have not been fully understood especially on the perspective of metabolomics. AIM OF THE STUDY: To clarify the potential mechanisms of C. arietinium treatment in T2D from the perspective of metabolomics since T2D is indeed a kind of metabolic syndromes. MATERIALS AND METHODS: T2D rat model was built by HFD for 4 weeks, combining with STZ administration. T2D rats were administrated C. arietinium extraction or metformin (positive control) for 4 weeks. UPLC-Q-TOF-MS was applied to screen and identify differential metabolites among groups. RESULTS: After 4 weeks of treatments, IR and inflammation were greatly ameliorated in C. arietinium group. And the therapeutic efficiency of C. arietinium treatment was comparable to metformin treatment. Differential metabolites related to C. arietinium treatment, including acylcarnitines, amino acid related metabolites and organic acids, were further used to indicate relevant pathways in T2D rats, including glyoxylate and dicarboxylate metabolism, tricarboxylic acid cycle, vitamin B6 metabolism and energy metabolism. CONCLUSIONS: In summary, C. arietinium treatment could effectively alleviate diabetic symptoms and regulate metabolic disorders in T2D rats.

Near-infrared light-triggered degradable hyaluronic acid hydrogel for on-demand drug release and combined chemo-photodynamic therapy.

In this study, an injectable and near-infrared (NIR) light-triggered ROS-degradable hyaluronic acid hydrogel platform was developed as localized delivery vehicle for photosensitizer protophorphyrin IX (PpIX) and anticancer drug doxorubicin (DOX), to achieve superior combined chemo-photodynamic therapy with light-tunable on-demand drug release. The in situ-forming hydrogel fabricated readily via the formation of dynamic covalent acylhydrazone bonds could efficiently prevent severe self-quenching effect of water-insoluble PpIX due to the covalent binding, leading to localized enhanced photodynamic therapy (PDT). Moreover, the extensive ROS generated by the hydrogel under NIR light irradiation could not only realize efficient PDT effect, but also cleave the ROS-cleavable small molecule crosslinker, inducing the desirable degradation of hydrogel and subsequent on-demand DOX release for cascaded chemotherapy. The developed versatile hyaluronic acid hydrogels have tunable properties, excellent biocompatibility, biodegradability and exhibit outstanding therapeutic effects in both in vitro cellular experiments and in vivo antitumor studies.