Multifunctional Biomimetic Nanocarriers for Dual-Targeted Immuno-Gene Therapy Against Hepatocellular Carcinoma.

Growing evidences have proved that tumors evade recognition and attack by the immune system through immune escape mechanisms, and PDL1/Pbrm1 genes have a strong correlation with poor response or resistance to immune checkpoint blockade (ICB) therapy. Herein, a multifunctional biomimetic nanocarrier (siRNA-CaP@PD1-NVs) is developed, which can not only enhance the cytotoxic activity of immune cells by blocking PD1/PDL1 axis, but also reduce tumor immune escape via Pbrm1/PDL1 gene silencing, leading to a significant improvement in tumor immunosuppressive microenvironment. Consequently, the nanocarrier promotes DC cell maturation, enhances the infiltration and activity of CD8+ T cells, and forms long-term immune memory, which can effectively inhibit tumor growth or even eliminate tumors, and prevent tumor recurrence and metastasis.

Human serum albumin as the carrier to fabricate STING-activating peptide nanovaccine for antitumor immunotherapy.

Tumor vaccines are emerging as one of the most promising therapeutic strategies for cancer treatment. With the advantages of low toxicity, convenient production and stable quality control, peptide vaccines have been widely used in preclinical and clinical trials involving various malignancies. However, when used alone, they still suffer from significant challenges including poor stability and immunogenicity as well as the low delivery efficiency, leading to limited therapeutic success.

Simultaneous Determination of Rifamycin Antibiotics and Their Active Metabolites in Human Plasma Using UHPLC-MS/MS to Evaluate Their Impact on Target Peak Concentrations: A Short Communication.

Background: Standard and proper antituberculosis (anti-TB) treatment is essential for patients with TB, and rifamycin antibiotics are key components of anti-TB therapy. Therapeutic drug monitoring (TDM) of rifamycin antibiotics can shorten the time to response and complete treatment of TB. Notably, antimicrobial activities of the major active metabolites of rifamycin are similar to those of their parent compounds.

Biodegradable MnO-based gene-engineered nanocomposites for chemodynamic therapy and enhanced antitumor immunity.

Immune checkpoint blockade (ICB) is emerging as a promising therapeutic approach for clinical treatment against various cancers. However, ICB based monotherapies still suffer from low immune response rate due to the limited and exhausted tumor-infiltrating lymphocytes as well as tumor immunosuppressive microenvironment. In this work, the cell membrane with surface displaying PD-1 proteins (PD1-CM) was prepared for immune checkpoint blockade, which was further combined with multifunctional and biodegradable MnO for systematic and robust antitumor therapy.

Self-assembled traditional Chinese nanomedicine modulating tumor immunosuppressive microenvironment for colorectal cancer immunotherapy.

Colorectal cancer (CRC), mostly categorized as a low immunogenic microsatellite-stable phenotype bearing complex immunosuppressive tumor microenvironment (TME), is highly resistant to immunotherapy. Seeking safe and efficient alternatives aimed at modulating tumor immunosuppressive TME to improve outcome of CRC is highly anticipated yet remains challenging. Enlightened from the drug complementary art in traditional Chinese medicine, we designed a self-assembled nanomedicine (termed LNT-UA) by the natural active ingredients of ursolic acid (UA) and lentinan (LNT) through a simple nano-precipitation method, without any extra carriers, for CRC immunotherapy.

Development and evaluation of a new test kit for determination of immunosuppressants in blood by UHPLC-MS/MS.

In this study, we have developed and validated a new test kit that applied pure solvents instead of blood samples for determination of immunosuppressant drugs in blood by ultra high performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS). We have used commercially available quality control samples to verify this new test kit, and the results showed that the performance of our new kit was comparable with commercially available kits by immunoassays. The new test kit is pure solvent-based, which saves the cost and can be directly loaded without pre-treatment, thus shortening the detection time.

CD16/PD-L1 bi-specific aptamer for cancer immunotherapy through recruiting NK cells and acting as immunocheckpoint blockade.

It is well established that natural killer (NK) cells can be used as an alternative candidate of T cells for adoptive cell therapy (ACT) due to its high killing capacity, off-the-shelf utility, and low toxicity. Though NK cells provide rapid and potent immune effects, they still suffer from insufficient infiltration and tumor immunosuppression environment, which result in unsatisfactory therapeutic efficiency. Herein, a highly stable CD16/PD-L1 bi-specific aptamer (defined as CP-bi-apt) with high affinity and selectivity was introduced to overcome these obstacles.

A highly stable multifunctional aptamer for enhancing antitumor immunity against hepatocellular carcinoma by blocking dual immune checkpoints.

T-lymphocytes play a potent role in cancer immunotherapy; while, limited tumor infiltrating lymphocytes (TILs) combined with severe immunosuppression always significantly hinder their antitumor immune responses, especially in solid tumors such as hepatocellular carcinoma (HCC). Here, we prepared a highly stable multifunctional aptamer for strengthening antitumor immunity against HCC solid tumors through a dual immune checkpoint blockade of CTLA-4 and PD-L1. The engineered multifunctional aptamer (termed P1/C4-bi-apt) can block both CTLA-4/B7 and PD-1/PD-L1 signaling pathways and thus enhance the antitumor immune responses.

A novel long-wavelength off-on fluorescence probe for nitroreductase analysis and hypoxia imaging.

Hypoxia is one of the most important features of various diseases including solid tumors. It is of significant clinical importance for hypoxia analysis in tumors, and the analysis of hypoxia can be moved away to the indirect detection of nitroreductase. Various fluorescence methods have been developed for the analysis of nitroreductase and tumor hypoxia due to their simplicity, non-invasiveness and excellent spatial-temporal resolution.

Protein-assisted formation of gold clusters-MnO nanocomposite for fluorescence imaging of intracellular glutathione.

Herein, a bovine serum albumin-stabilized gold clusters-MnO nanocomposite (BSA@AuNCs-MnO) was constructed. Manganese dioxide (MnO) was generated in situ on the gold clusters (BSA@AuNCs) based on the redox reaction between bovine serum albumin (BSA) and potassium permanganate (KMnO). The fluorescence of BSA@AuNCs can be quenched by the in-situ grown MnO, which has strong light absorption ability.

Artificial Engineered Natural Killer Cells Combined with Antiheat Endurance as a Powerful Strategy for Enhancing Photothermal-Immunotherapy Efficiency of Solid Tumors.

Although photothermal therapy (PTT) is preclinically applied in solid tumor treatment, incomplete tumor removal of PTT and heat endurance of tumor cells induces significant tumor relapse after treatment, therefore lowering the therapeutic efficiency of PTT. Herein, a programmable therapeutic strategy that integrates photothermal therapeutic agents (PTAs), DNAzymes, and artificial engineered natural killer (A-NK) cells for immunotherapy of hepatocellular carcinoma (HCC) is designed. The novel PTAs, termed as Mn-CONASHs, with 2D structure are synthesized by the coordination of tetrahydroxyanthraquinone and Mn ions.

Water-soluble organic probe for pH sensing and imaging.

pH value is one of the most important parameters, which show significant application in environmental monitoring, chemistry and biology. Abnormal pH values always associate with some serious diseases, including cancer and Alzheimer's disease. Thus, development of highly sensitive and selective method for pH sensing and imaging is of great importance.

Sensitive fluorometric determination of glutathione using fluorescent polymer dots and the dopamine-melanin nanosystem.

A bioinspired fluorometric method has been developed for the detection of glutathione (GSH) in biological fluids. It is based on the use of near-infrared fluorescent semiconducting polymer dots (P-dots) and of the dopamine (DA)-melanin nanosystem. The P-dots were prepared from poly(styrene-co-maleic anhydride), the semiconducting polymer poly[(9,9'-dioctyl-2,7-divinylenefluorenylene)-alt-2-methoxy-5-(2-ethyl-hexyloxy)-1,4-phenylene] and the fluorescent dye tetraphenylporphyrin.

Dual sensing of glutathione and acidic pH values by using MnO nanosheets and 3-acetyl-7-hydroxy-2H-chromen-2-one as a fluorescent pH probe.

A multifunctional nanoprobe is described for dual sensing of acidic pH values and glutathione (GSH) by combining the pH-responsive fluorescent probe 3-acetyl-7-hydroxy-2H-chromen-2-one (AHC) and MnO nanosheets. The fluorescence of the MnO/AHC composite is weak due to an inner filter effect. If, however, the MnO nanosheets are reductively decomposed by GSH, the blue fluorescence of the pH probe AHC (with excitation/emission maximum at 417/456 nm) will be restored.

Highly efficient redox reaction between potassium permanganate and 3,3',5,5'-tetramethylbenzidine for application in hydrogen peroxide based colorimetric assays.

Potassium permanganate (KMnO) is one of the most important oxidants, which plays important roles in many fields. Here, we found that KMnO could directly induce the oxidation of 3,3',5,5'-tetramethylbenzidine (TMB) to generate an oxidized product with a color change. This redox reaction is highly efficient, and 1 μM KMnO is enough to cause detectable changes in the absorbance signal.

Photoresponsive Nanovehicle for Two Independent Wavelength Light-Triggered Sequential Release of P-gp shRNA and Doxorubicin To Optimize and Enhance Synergistic Therapy of Multidrug-Resistant Cancer.

Prerelease of RNA molecules than chemotherapeutic drugs with a sufficient interval is a vital prerequisite for RNA/drug co-delivery strategy to overcome multidrug resistance (MDR) of cancer cells, but how to precisely control their release at different time points is still a grand challenge up to now. This study aims to on-demand remotely manipulate RNA and drug release in real time through single delivery system to sequentially play their respective roles for optimizing and enhancing their synergistic antitumor effects. To this end, a photoresponsive mesoporous silica nanoparticle (PMSN) is fabricated as a co-delivery vehicle of P-glycoprotein (P-gp) short-hairpin RNA (shRNA) and photocaged prodrug of doxorubicin (DOX), by which the orthogonal and sequential release of shRNA and DOX can be achieved using an external light.

Polydopamine-assisted versatile modification of a nucleic acid probe for intracellular microRNA imaging and enhanced photothermal therapy.

MicroRNAs play an important role in various biological processes, and their aberrant expression is closely associated with various human diseases, especially cancer. Real-time monitoring of microRNAs in living cells may help us to understand their role in cellular processes, which can further provide a basis for diagnosis and treatment. In this study, polydopamine was used to assist the versatile modification of a nucleic acid probe for intracellular microRNA imaging and enhanced photothermal therapy.

A cancer cell specific targeting nanocomplex for combination of mRNA-responsive photodynamic and chemo-therapy.

We have developed a cancer cell specific targeting nanocomplex which combines photodynamic therapy with chemotherapy through precisely responding to the intracellular tumor-related mRNA. The combined treatment of these two modalities showed significantly enhanced therapeutic effects on cancer cells.

A fluorescent turn on nanoprobe for simultaneous visualization of dual-targets involved in cell apoptosis and drug screening in living cells.

Herein, a novel dual-responsive two-color fluorescent nanoprobe has been designed for the fluorescence activation imaging of cell apoptosis in living cells. The nanoprobe consists of a gold nanoparticle core functionalized with a dense layer of DNA aptamers and peptides, which shows high affinity and specific response to cytochrome c (Cyt c) and caspase-3, respectively. The formation of the aptamer-Cyt c complex and the cleavage of the specific peptide by caspase-3 can liberate the dye labelled aptamers and peptides from the surface of gold nanoparticles, and then recover their fluorescence.

Tumor Microenvironment Activable Self-Assembled DNA Hybrids for pH and Redox Dual-Responsive Chemotherapy/PDT Treatment of Hepatocellular Carcinoma.

are employed, which could respond to tumor microenvironment stimuli for cancer cell specific real-time fluorescence imaging, tumor-specific synergistic photodynamic therapy and chemotherapy in hepatocellular carcinoma.

Smart Cu(II)-aptamer complexes based gold nanoplatform for tumor micro-environment triggered programmable intracellular prodrug release, photodynamic treatment and aggregation induced photothermal therapy of hepatocellular carcinoma.

This study describes smart Cu(II)-aptamer complexes based gold nanoplatform for tumor micro-environment triggered programmable prodrug release, in demand photodynamic therapy and aggregation induced photothermal ablation of hepatocellular carcinoma. The nanoplatform is consist of monodispersed gold nanoparticle (GNP) that is binding to HCC cell specific targeting aptamers (TLS11a) through Au-S bond; the aptamer is labeled with Ce6 at the 5'end and coordinated with Cu(II) through (GA) repeating bases to load AQ4N at the 3' end. In normal physiological conditions, the fluorescence and ROS generation ability of Ce6 are quenched by GNPs via RET; but in cancerous cells, the fluorescence and the ROS generation of Ce6 could be recovered by cleavage of Au-S bond through high level of intracellular GSH for real-time imaging and in demand PDT.

Peroxidase-like catalytic activity of copper ions and its application for highly sensitive detection of glypican-3.

Glypican-3 (GPC3) might be used as new biomarker of liver cancer for the development of new diagnostic methods. The most commonly used methods for protein detection are based on natural enzymes, which are easily affected by environmental conditions and suffer from the rigorous preparation conditions. Thus, the development of new enzyme mimetics with high and stable catalytic activity is of great significance in diagnostic applications.

Horseradish peroxidase and aptamer dual-functionalized nanoprobe for the amplification detection of alpha-methylacyl-CoA racemase.

Alpha-methylacyl-CoA racemase (AMACR) is over-expressed in many cancer types and can serve as a novel diagnostic biomarker. Development of convenient and sensitive detection methods of AMACR is of particular importance for cancer diagnosis. Aptamers are a type of recognition elements, which possess many advantages over antibody, making them suitable for applications in biosensing and biotechnology.

Multifunctional PEG modified DOX loaded mesoporous silica nanoparticle@CuS nanohybrids as photo-thermal agent and thermal-triggered drug release vehicle for hepatocellular carcinoma treatment.

The combination of a multi-therapeutic mode with a controlled fashion is a key improvement in nanomedicine. Here, we synthesized polyethylene glycol (PEG)-modified doxorubicin (DOX)-loaded mesoporous silica nanoparticle (MSN) @CuS nanohybrids as efficient drug delivery carriers, combined with photothermal therapy and chemotherapy to enhance the therapeutic efficacy on hepatocellular carcinoma (HCC). The physical properties of the nanohybrids were characterized by transmission electron microscopy (TEM), N2 adsorption and desorption experiments and by the Vis-NIR absorption spectra.

One-pot synthesized DNA-templated Ag/Pt bimetallic nanoclusters as peroxidase mimics for colorimetric detection of thrombin.

We developed a facile one-step approach to synthesize DNA-templated Ag/Pt bimetallic nanoclusters (DNA-Ag/Pt NCs), which possess highly-efficient peroxidase-like catalytic activity. With this finding, an aptamer based sandwich-type strategy is employed to design a label-free colorimetric aptasensor for the protein detection with high sensitivity and selectivity.