Preclinical monotherapeutic and anti-PD-1 synergistic anti-tumor efficacy of MNC-168, a novel human-derived live biotherapeutic product.

e14581 Background: Human gut microbiome has been extensively demonstrated as a critical causative factor in determining the efficacy of cancer immunotherapy. Cumulative clinical evidences indicate the prevalent presence of Enterococcus species in the responder of anti-PD-1 treated patients. We here demonstrated the preclinical anti-tumor efficacy of a novel human derived Enterococcus strain MNC-168. Methods: Using multiple murine syngeneic cold tumor models and in vivo pharmacokinetics mouse model, we characterized the anti-tumor activity and pharmacokinetics of MNC-168 via oral-delivered route in monotherapy and immune checkpoint inhibitor (ICI) anti-mPD-1 combination. Systematic multi-omics analyses and in vitro mechanistic study were conducted to reveal the biomarkers and mode of action of MNC-168. Results: We found MNC-168 significantly and mono-therapeutically counteract tumor development in diverse tumor models, including colorectal cancer (with tumor inhibition ratio of 65.5%), hepatocellular carcinoma (27.4%), fibrosarcoma (33.5%) and renal carcinoma (56.4%). Notably, MNC-168 in combination with anti-mPD-1 synergistically exerted the tumor inhibition ratio up to 68.3-89.2% and significantly reverse anti-mPD-1 non-responsiveness. Integrated multi-omics analyses and in vitro validation study revealed the mechanism by which MNC-168 reinvigorates the immune system through targeting multiple routes, including activating systemic and tumor-resident innate and adaptive immunity, removal of tumor physical barrier, reinforced recruitment of tumor-infiltrating lymphocytes, and maintenance of immuno-stimulant activity via production of immune-simulating metabolites. Activation and boosting of interferon-γ production of CD8 T cells and CD4 T cells are the vital mediators for the anti-tumor ability of MNC-168. In vivo pharmacokinetics study shows that the anti-tumor efficacy of MNC-168 is positively correlated with gut-restricted abundance of MNC-168. Conclusions: MNC-168 is highly potently used as a first-in-class live biotherapeutic product for cancer monotherapy and promoting efficacy of ICI-mediated cancer immunotherapy.

Au-siRNA@ aptamer nanocages as a high-efficiency drug and gene delivery system for targeted lung cancer therapy

Background Gene and chemical therapy has become one of the rising stars in the field of molecular medicine during the last two decades. However, there are still numerous challenges in the development of efficient, targeted, and safe delivery systems that can avoid siRNA degradation and reduce the toxicity and adverse effects of chemotherapy medicine. Results In this paper, a highly efficient AS1411 aptamer modified, dsDNA and MMP-2 cleavable peptide-fabricated gold nanocage vehicle, which could load doxorubicin hydrochloride (DOX) and siRNAs to achieve a combination of tumor responsive genetic therapy, chemotherapy, and photothermal treatment is presented. Our results show that this combined treatment achieved targeted gene silencing and tumor inhibition. After nearly one month of treatment with DOX-loaded Au-siRNA-PAA-AS1411 nanoparticles with one dose every three days in mice, a synergistic effect promoting the eradication of long-lived tumors was observed along with an increased survival rate of mice. The combined genetic, chemotherapeutic, and photothermal treatment group exhibited more than 90% tumor inhibition ratio (tumor signal) and a ~ 67% survival rate compared with a 30% tumor inhibition ratio and a 0% survival rate in the passive genetic treatment group. Conclusions The development of nanocarriers with double-stranded DNA and MMP-2 cleavable peptides provides a new strategy for the combined delivery of gene and chemotherapy medicine. Au-siRNA-PAA-AS1411 exerts high anticancer activities on lung cancer, indicating immense potentials for clinical application.

Chemical Constituent of β-Glucuronidase Inhibitors from the Root of Neolitsea acuminatissima

Neolitsea acuminatissima (Lauraceae) is an endemic plant in Taiwan. One new carboline alkaloid, demethoxydaibucarboline A (1), two new eudesmanolide-type sesquiterpenes, methyl-neolitacumone A (2), neolitacumone E (3), and twelve known compounds (4–15) were isolated from the root of Neolitsea acuminatissima. Their structures were elucidated by spectroscopic analysis. Glucuronidation represents a major metabolism process of detoxification for carcinogens in the liver. However, intestinal bacterial β-Glucuronidase (βG) has been considered pivotal to colorectal carcinogenesis. To develop specific bacterial-βG inhibitors with no effect on human βG, methanolic extract of roots of N. acuminatissima was selected to evaluate their anti-βG activity. Among the isolates, demethoxydaibucarboline A (1) and quercetin (8) showed a strong bacterial βG inhibitory effect with an inhibition ratio of about 80%. Methylneolitacumone A (2) and epicatechin (10) exhibited a moderate or weak inhibitory effect and the enzyme activity was less than 45% and 74%, respectively. These four compounds specifically inhibit bacterial βG but not human βG. Thus, they are expected to be used for the purpose of reducing chemotherapy-induced diarrhea (CID). The results suggest that the constituents of N. acuminatissima have the potential to be used as CID relief candidates. However, further investigation is required to determine their mechanisms of action.

A Portable, Single-Use, Paper-Based Microbial Fuel Cell Sensor for Rapid, On-Site Water Quality Monitoring

Human access to safe water has become a major problem in many parts of the world as increasing human activities continue to spill contaminants into our water systems. To guarantee the protection of the public as well as the environment, a rapid and sensitive way to detect contaminants is required. In this work, a paper-based microbial fuel cell was developed to act as a portable, single-use, on-site water quality sensor. The sensor was fabricated by combining two layers of paper for a simple, low-cost, and disposable design. To facilitate the use of the sensor for on-site applications, the bacterial cells were pre-inoculated onto the device by air-drying. To eliminate any variations, the voltage generated by the microorganism before and after the air-drying process was measured and calculated as an inhibition ratio. Upon the addition of different formaldehyde concentrations (0%, 0.001%, 0.005%, and 0.02%), the inhibition ratios obtained were 5.9 ± 0.7%, 6.9 ± 0.7%, 8.2 ± 0.6%, and 10.6 ± 0.2%, respectively. The inhibition ratio showed a good linearity with the formaldehyde concentrations at R2 = 0.931. Our new sensor holds great promise in monitoring water quality as a portable, low-cost, and on-site sensor.