Targeting Telomere Dynamics as an Effective Approach for the Development of Cancer Therapeutics.

Telomere is a protective structure located at the end of chromosomes of eukaryotes, involved in maintaining the integrity and stability of the genome. Telomeres play an essential role in cancer progression; accordingly, targeting telomere dynamics emerges as an effective approach for the development of cancer therapeutics. Targeting telomere dynamics may work through multifaceted molecular mechanisms; those include the activation of anti-telomerase immune responses, shortening of telomere lengths, induction of telomere dysfunction and constitution of telomerase-responsive drug release systems. In this review, we summarize a wide variety of telomere dynamics-targeted agents in preclinical studies and clinical trials, and reveal their promising therapeutic potential in cancer therapy. As shown, telomere dynamics-active agents are effective as anti-cancer chemotherapeutics and immunotherapeutics. Notably, these agents may display efficacy against cancer stem cells, reducing cancer stem levels. Furthermore, these agents can be integrated with the capability of tumor-specific drug delivery by the constitution of related nanoparticles, antibody drug conjugates and HSA-based drugs.

Upcycling textile sludge into magnesium oxychloride cement: Physical properties, microstructure, and leaching behavior.

Textile sludge is a by-product produced during the wastewater treatment process in the textile printing and dyeing industry. Textile sludge is rich in heavy metal elements, which makes it a potential risk to the surrounding environment. This study designs a magnesium oxychloride cement (MOC) components to solidify harmful substances in textile sludge and studies the influence of textile sludge ash (TSA) on the mechanical properties and microstructure of MOC samples. The results indicated that adding 5 %-20 % TSA is beneficial for increasing the compressive strength of air-cured MOC paste and improving its water resistance. Meanwhile, the MOC sample shows volume expansion in 168 h, which is related to the further hydration of residual MgO. Incorporating 10 %-20 % TSA substantially increased the volume expansion ratio of the mixture compared to plain MOC sample. In addition, the porosity of TSA-modified MOC after water curing did not change significantly compared to the sample before water curing, while the pore structure of plain MOC after water curing significantly coarsened. This is mainly because TSA reacts with MOC and generates Mg-Al-Cl-Si-H and Mg-Cl-Si-H gels, consequently improving the water stability of MOC sample. At the nanoscale, the 3/5-phase crystal and unreacted MgO content in the 15 % TSA-modified MOC sample is relatively reduced by 7.79 % and 25 %, respectively, compared to the plain sample, but the 13 % gel phase is detected. In addition, the MOC component can effectively solidify heavy metal elements in textile sludge. For the leachate of 20 % TSA-modified MOC paste, the Ni element is not detected, and its solidifying effect on heavy elements such as Zn and Mn exceeded 99 %.

Recycling drinking water treatment sludge in construction and building materials: A review.

Drinking water treatment sludge (DWTS) is a by-product of water treatment, and it is difficult to recycle to high value and poses potential environmental risks. Recycling DWTS into cement-based materials is an effective measure to achieve its high-volume utilization and reduce its environmental load. DWTS is rich in silica-alumina phases and has potential pozzolanic activity after drying, grinding and calcination, giving it similar properties to traditional supplementary cementitious materials. Adjusting the sludge production process and coagulant type will change its physical and chemical properties. Adding a small amount of DWTS can generate additional hydration products and refine the pore structure of the cement sample, thus improving the mechanical properties and durability of the sample. However, adding high-volume DWTS to concrete causes microstructural deterioration, but it is feasible to use high-volume DWTS to produce artificial aggregates, lightweight concrete, and sintered bricks. Meanwhile, calcined DWTS has similar compositions to clay, which makes it a potential raw material for cement clinker production. Cement-based materials can effectively solidify heavy metal ions in DWTS, and alkali-activated binders, magnesium-based cement, and carbon curing technology can further reduce the risk of heavy metal leaching. This review provides support for the high-value utilization of DWTS in cement-based materials and the reduction of its potential environmental risks.

Antitumor efficacy of a recombinant EGFR-targeted fusion protein conjugate that induces telomere shortening and telomerase downregulation.

OBJECTIVE: To prepare a recombinant EGFR-targeted fusion protein drug conjugate acting on telomere and telomerase; and evaluate its antitumor efficacy. METHODS: We prepared a recombinant fusion protein Fv-LDP-D3 which consists of the Fv fragment of an anti-EGFR monoclonal antibody (MAb), the apoprotein of lidamycin (LDP), and the third domain (D3) of human serum albumin (HSA); then generated the conjugate Fv-LDP-D3∼AE by integrating the active enediyne chomophore (AE) of lidamycin. Accordingly, in vitro and in vivo experiments were performed. RESULTS: As shown, Fv-LDP-D3 specifically bound to EGFR highly-expressing cancer cells and intensely entered K-Ras mutant cells via enhanced macropinocytosis. By in vivo imaging, Fv-LDP-D3 displayed intense accumulation and persistent retention in tumor-site. Furthermore, the conjugate Fv-LDP-D3∼AE displayed highly potent cytotoxicity to cancer cells with IC50 at 0.1 nM level. The conjugate induced telomere shortening and downregulation of telomerase and EGFR pathway related proteins. Fv-LDP-D3∼AE exhibited prominent antitumor efficacy against human colorectal cancer xenograft accompanying with significant increase of serum IFN-ß in athymic mice. CONCLUSION: The recombinant fusion protein conjugate that exhibits the capability of tumor-targeting drug delivery can induce telomere shortening and telomerase downregulation. The investigation may lay the foundation for the development of MAb-HSA domain-based fusion protein drug conjugates.

The development of human serum albumin-based drugs and relevant fusion proteins for cancer therapy.

Human serum albumin (HSA)-based therapeutics have attracted tremendous attention in the development of anticancer agents. The versatile properties of HSA make HSA-based therapeutics possess improved pharmacokinetics, extended circulation half-life, enhanced efficacy, reduced toxicity, etc. Generally, the HSA-based therapeutics systems can be divided into four categories, i.e. HSA-drug nanoparticles, HSA-drug conjugates, HSA-binding prodrugs, and HSA-based recombinant fusion proteins: the latter mainly include antibody (domain)- and cytokine- fusion proteins. Advances in this area revealed the advantages of HSA-based systems in the development of tumor site-oriented therapeutics, partly referring to the enhanced penetration and retention (EPR) effect and the intensive macropinocytosis. Accordingly, a variety of technical platforms for the design and preparation of HSA-based therapeutics have been reported. Major strategies and directions for the drug development were discussed; those include (1) Tumor-site oriented drug delivery and enhanced drug retention, (2) Tumor-site prodrug release and activation, (3) Cancer cell bound intensive drug internalization, and (4) Tumor microenvironment (TME) directed immunomodulation. Notably, the multimodal HSA-based approach is promising for the development of tumor-oriented therapeutics for cancer therapy.