Development of targeted therapy therapeutics to sensitize triple-negative breast cancer chemosensitivity utilizing bacteriophage phi29 derived packaging RNA.

BACKGROUND: To date, triple-negative breast cancer (TNBC) treatment options are limited because of the loss of target receptors and, as a result, are only managed with chemotherapy. What is worse is that TNBC is frequently developing resistance to chemotherapy. By using small interfering RNA (siRNA)-based therapeutics, our recent work demonstrated X-box-binding protein 1 (XBP1) was linked to human epidermal growth factor receptor 2 positive (HER2+) breast cancer development and chemoresistance. Given the instability, off-target effects, net negative charge, and hydrophobicity of siRNA in vivo utilization and clinical transformation, its use in treatment is hampered. Thus, the development of a siRNA-based drug delivery system (DDS) with ultra-stability and specificity is necessary to address the predicament of siRNA delivery. RESULTS: Here, we assembled RNase resistant RNA nanoparticles (NPs) based on the 3WJ structure from Phi29 DNA packaging motor. To improved targeted therapy and sensitize TNBC to chemotherapy, the RNA NPs were equipped with an epidermal growth factor receptor (EGFR) targeting aptamer and XBP1 siRNA. We found our RNA NPs could deplete XBP1 expression and suppress tumor growth after intravenous administration. Meanwhile, RNA NPs treatment could promote sensitization to chemotherapy and impede angiogenesis in vivo. CONCLUSIONS: The results further demonstrate that our RNA NPs could serve as an effective and promising platform not only for siRNA delivery but also for chemotherapy-resistant TNBC therapy.

Activation of sirtuin 1 by catalpol-induced down-regulation of microRNA-132 attenuates endoplasmic reticulum stress in colitis.

Defective expression of NAD-dependent protein deacetylase sirtuin 1 (SIRT1) triggers endoplasmic reticulum (ER) stress and epithelial cell apoptosis in inflammatory bowel disease. MicroRNA-132 (miR-132) has been shown to regulate inflammatory processes through down-regulating SIRT1. Catalpol is a potential antioxidant and anti-apoptotic agent in inflammatory disease. This study aimed to investigate the signaling mechanisms underlying catalpol-induced SIRT1 activation and inhibition of ER stress in a rat colitis model. Colitis was established by intracolonic administration of 2, 4, 6-trinitrobenzene sulfonic acid. miR-132 expression was measured by quantitative real-time polymerase chain reaction and in situ hybridization, and the regulation of SIRT1 by miR-132 was examined by dual luciferase reporter assay. Protein expression related to ER stress and apoptosis was measured by western blotting. The ER stress marker proteins ATF6, CHOP, and caspase12, and acetylation of heat-shock factor-1 were increased in colitis and these increases were significantly reversed by catalpol, while the colitis-induced reduction in GRP78 was also reversed by catalpol. The inhibition of ER stress by catalpol was significantly inhibited by small interfering RNA targeting SIRT1 or miR-132. Moreover, other colitis symptoms including infiltration of inflammatory cells, cytokine profiles, oxidative responses, and epithelial cell apoptosis were also significantly decreased by catalpol. Mechanistically, the defective expression of SIRT1 in colitis was significantly counteracted by catalpol, while miR-132, which is a negative targeting regulator of SIRT1, was confirmed as the potential target of catalpol. These results support a link between ER stress and the miR-132/SIRT1/heat-shock factor-1 signaling pathway, and the modulation of this pathway by catalpol in colitis.

GE11-antigen-loaded hepatitis B virus core antigen virus-like particles efficiently bind to TNBC tumor.

Purpose: This study aimed to explore the possibility of utilizing hepatitis B core protein (HBc) virus-like particles (VLPs) encapsulate doxorubicin (Dox) to reduce the adverse effect caused by its off-target and toxic side effect. Methods: Here, a triple-negative breast cancer (TNBC) tumor-targeting GE11-HBc VLP was constructed through genetic engineering. The GE11 peptide, a 12-amino-acid peptide targeting epidermal growth factor receptor (EGFR), was inserted into the surface protein loops of VLPs. The Dox was loaded into HBc VLPs by a thermal-triggered encapsulation strategy. The in vitro release, cytotoxicity, and cellular uptake of TNBC tumor-targeting GE11-HBc VLPs was then evaluated. Results: These VLPs possessed excellent stability, DOX loading efficiency, and preferentially released drug payload at high GSH levels. The insertion of GE11 targeting peptide caused improved cellular uptake and enhanced cell viability inhibitory in EGFR high-expressed TNBC cells. Conclusion: Together, these results highlight DOX-loaded, EGFR-targeted VLPs as a potentially useful therapeutic choice for EGFR-overexpressing TNBC.

Lysozyme (Lys), Tannic Acid (TA), and Graphene Oxide (GO) Thin Coating for Antibacterial and Enhanced Osteogenesis.

Dental implants have great potential in the global market, around $3.7 billion in 2015, which will increase to $7 billion in 2023 with an annual increase rate of 8.2%. Incorporating antibacterial and osteogenic agents into implants is helpful to make the dental implants successful, which can be endowed by coatings. In recent years, graphene oxide (GO) and its composite materials have shown advances in the biomedical field. Lysozyme (Lys) and tannic acid (TA) are naturally derived, with promising antibacterial and osteogenic properties as well. In the present study, the strong antibacterial and enhanced osteogenic multilayer coating is fabricated using the facile and controllable layer by layer (LBL) technique to integrate GO, Lys, and TA. The thickness of coating exhibited a continuous growth with the deposited process as proved from UV-vis and ellipsometry data, and the physical properties of the coating, such as wettability, roughness, and stiffness are well characterized. The coatings exhibited the synergic effect on the killing bacteria, both Gram-negative bacteria and Gram-positive bacteria represented by E. coli and S. aureus, respectively, and enhancing osteogenesis of dental pulp stem cells (hDPSCs), showing the potential application on coatings of dental implants. Thus, the strategy applied here will inspire the design and development of dual functional surfaces for the success of implanted dental surface in future.

Myosin Light Chain Kinase: A Potential Target for Treatment of Inflammatory Diseases.

Myosin light chain kinase (MLCK) induces contraction of the perijunctional apical actomyosin ring in response to phosphorylation of the myosin light chain. Abnormal expression of MLCK has been observed in respiratory diseases, pancreatitis, cardiovascular diseases, cancer, and inflammatory bowel disease. The signaling pathways involved in MLCK activation and triggering of endothelial barrier dysfunction are discussed in this review. The pharmacological effects of regulating MLCK expression by inhibitors such as ML-9, ML-7, microbial products, naturally occurring products, and microRNAs are also discussed. The influence of MLCK in inflammatory diseases starts with endothelial barrier dysfunction. The effectiveness of anti-MLCK treatment may depend on alleviation of that primary pathological mechanism. This review summarizes evidence for the potential benefits of anti-MLCK agents in the treatment of inflammatory disease and the importance of avoiding treatment-related side effects, as MLCK is widely expressed in many different tissues.