Designing novel Au(III) complexes based on the structure of diazepam: Achieving a multiaction mechanism against glioma.

Metal-based drugs have been used in the clinical treatment of tumors for over 30 years. However, no metal-based drugs have been clinically approved to treat glioma. Although metal complexes have excellent cytotoxicity, their most critical problem is crossing the blood-brain barrier.

Development of Anticancer Ferric Complex Based on Human Serum Albumin Nanoparticles That Generate Oxygen in Cells to Overcome Hypoxia-Induced Resistance in Metal Chemotherapy.

To achieve the remarkable therapeutic efficacy of a ferric (Fe) complex via a reactive oxygen species (ROS) mechanism in solid tumors, a therapeutic Fe-based Schiff-base complex () was synthesized and encapsulated in human serum albumin (HSA) nanoparticles (NPs), which generated oxygen (O) in cancer cells in situ. The NP () delivery system effectively overcame hypoxia-induced resistance in metal chemotherapy, alleviated the hypoxic condition of tumor tissues, and showed excellent tumor suppression by generating excess ROS and promoting the apoptosis of SK-N-MC tumor cells. The not only enhanced the ability of the complex to target tumor cells but also decreased adverse effects in vivo.

Role of Ubiquitin-specific Proteases in Hepatocellular Carcinoma Pathogenesis.

Signaling pathways in hepatocellular carcinoma are primarily mediated by the phosphorylation and ubiquitination of post-translational proteins. In mammalian cells, ubiquitin-specific proteases (USPs) account for the majority of protein deubiquitination activities. In addition to transcriptional and post-translational regulation, ubiquitination plays an important role in the regulation of key proteins.

Encapsulation of Au(III) Complex Using Lactoferrin Nanoparticles to Combat Glioma.

Metal-based drugs have been used for decades to treat solid cancers; however, these drugs have no significant therapeutic effect on glioma because they cannot effectively cross the blood-brain barrier (BBB). To develop a novel metal-based agent that can cross the BBB to target glioma, we synthesized an Au complex (C2) with remarkable glioma cytotoxicity and fabricated lactoferrin (LF)-C2 nanoparticles (LF-C2 NPs) as a novel therapy. We confirmed that C2 kills glioma cells by inducing apoptosis and autophagic death.

Developing an Anticancer Platinum(II) Compound Based on the Uniqueness of Human Serum Albumin.

To develop the next-generation Pt drug with remarkable activity and low toxicity to maximally inhibit tumor growth, we optimized a Pt(II) thiosemicarbazone compound (C4) with remarkable cytotoxicity to SK-N-MC cells and then constructed a new human serum albumin-C4 (HSA-C4) complex delivery system. The results showed that C4 and the HSA-C4 complex have remarkable therapeutic efficiency and almost no toxicity; they induced apoptosis and inhibited tumor angiogenesis. This system showed potential as a practical Pt drug.

Attitude-Orbit Coupled Control of Gravitational Wave Detection Spacecraft with Communication Delays.

In order to meet the position and attitude requirements of spacecrafts and test masses for gravitational-wave detection missions, the attitude-orbit coordination control of multiple spacecrafts and test masses is studied. A distributed coordination control law for spacecraft formation based on dual quaternion is proposed. By describing the relationship between spacecrafts and test masses in the desired states, the coordination control problem is converted into a consistent-tracking control problem in which each spacecraft or test mass tracks its desired states.

Continuous Low-Thrust Maneuver Planning for Space Gravitational Wave Formation Reconfiguration Based on Improved Particle Swarm Optimization Algorithm.

This study proposes a three-spacecraft formation reconfiguration strategy of minimum fuel for space gravitational wave detection missions in the high Earth orbit (10 km). For solving the limitations of measurement and communication in long baseline formations, a control strategy of a virtual formation is applied. The virtual reference spacecraft provides a desired relative state between the satellites, which is then used to control the motion of the physical spacecraft to maintain the desired formation.

Adaptive Control for Gravitational Wave Detection Formation Considering Time-Varying Communication Delays.

A distributed six-degree-of-freedom (6-DOF) cooperative control for multiple spacecraft formation is investigated considering parametric uncertainties, external disturbances, and time-varying communication delays. Unit dual quaternions are used to describe the kinematics and dynamics models of the 6-DOF relative motion of the spacecraft. A distributed coordinated controller based on dual quaternions with time-varying communication delays is proposed.

Robust Control Allocation for Space Inertial Sensor under Test Mass Release Phase with Overcritical Conditions.

This paper proposes a robust control allocation for the capture control of the space inertial sensor's test mass under overcritical conditions. Uncertainty factors of the test mass control system under the overcritical condition are analyzed first, and a 6-DOF test mass dynamics model with system uncertainty is established. Subsequently, a time-varying weight function is designed to coordinate the allocation of 6-DOF generalized forces.

Combined effects of vitamin D and neferine on the progression and metastasis of colorectal cancer.

Purpose: To investigate the synergistic effect of vitamin D and neferine on the growth and metastasis of colorectal cancer (CRC).

Methods: The synergistic effect of biologically active form of vitamin D, VD and neferine on the treatment of CRC was investigated by bliss analysis. Colony formation and wound healing ability, migration and invasion ability, and epithelial mesenchymal transition of HCT-116 cells, as a response to the combination treatment with VD and neferine were evaluated.

Developing a Gallium(III) Agent Based on the Properties of the Tumor Microenvironment and Lactoferrin: Achieving Two-Agent Co-delivery and Multi-targeted Combination Therapy of Cancer.

To develop a next-generation anticancer metal-based drug, realize the multi-targeted combination therapy of protein drug and metal-based drug for cancer, solve their co-delivery challenges, and improve their in vivo targeting ability, we proposed to develop a multi-targeted anticancer metal-based agent exploiting the properties of the tumor microenvironment (TME) and of lactoferrin (LF). To this end, we optimized a series of gallium (Ga, III) isopropyl-2-pyridyl-ketone thiosemicarbazone compounds to obtain a Ga compound (C4) with remarkable cytotoxicity and then constructed a new LF-C4 nanoparticle (LF-C4 NP) delivery system. In vivo studies showed that LF-C4 NPs not only had a greater capacity for inhibiting tumor growth than LF or C4 alone but also solved the co-delivery problems of LF and C4 and improved their targeting ability.

Designing a multitarget In(III) compound to overcome the resistance of lung cancer cells to cisplatin.

Designing novel anticancer non-platinum metal agents is fully challenging. Herein, a series of little-known indium (In) 2-acetylpyridine thiosemicarbazone compounds as potential anticancer agents were designed, synthesized, and characterized. The hydrogen atoms at the N-4 position with the alkyl of the In compounds significantly increased cellular uptake and cytotoxicity.

Organometallic gold(I) and gold(III) complexes for lung cancer treatment.

Metal compounds, especially gold complexes, have recently gained increasing attention as possible lung cancer therapeutics. Some gold complexes display not only excellent activity in cisplatin-sensitive lung cancer but also in cisplatin-resistant lung cancer, revealing promising prospects in the development of novel treatments for lung cancer. This review summarizes examples of anticancer gold(I) and gold (III) complexes for lung cancer treatment, including mechanisms of action and approaches adopted to improve their efficiency.

Synthesis and in vitro/in vivo anticancer evaluation of pentacyclic triterpenoid derivatives linked with l-phenylalanine or l-proline.

Extensive research effort has been put in pentacyclic triterpenoids due to their numerous biological activities. However, their poor water solubility and low oral bioavailability limit their antitumor effects in vivo. To address these issues, 37 triterpenoid acid derivatives linked to l-phenylalanine or l-proline were designed and synthesized in this study.

Developing a Novel Indium(III) Agent Based on Human Serum Albumin Nanoparticles: Integrating Bioimaging and Therapy.

To effectively integrate diagnosis and therapy for tumors, we proposed to develop an indium (In) agent based on the unique property of human serum albumin (HSA) nanoparticles (NPs). A novel In(III) quinoline-2-formaldehyde thiosemicarbazone compound (C5) was optimized with remarkable cytotoxicity and fluorescence to cancer cells . An HSA-C5 complex NP delivery system was then successfully constructed.

Developing a Novel Anticancer Gold(III) Agent to Integrate Chemotherapy and Immunotherapy.

To effectively treat gastric cancer, we innovatively attempted to develop a metal agent to integrate immunotherapy and chemotherapy by dual targeting the cellular components in the tumor microenvironment (TME) based on the specific residue of human serum albumin (HSA) nanoparticles (NPs). We synthesized a series of Au(III) α-N-heterocyclic thiosemicarbazone compounds and obtained a Au agent () with remarkable cytotoxicity to gastric cancer cells; moreover, we successfully constructed a novel complex NP delivery system. Importantly, the results showed that / NPs effectively inhibited gastric tumor growth and NPs enhanced the therapeutic efficiency, bioavailability, and targeting ability compared with those of alone.

Synthesis of a series of novel In(III) 2,6-diacetylpyridine bis(thiosemicarbazide) complexes: structure, anticancer function and mechanism.

The anticancer function and anticancer mechanism of indium (In) complexes still remain mysterious to date. Furthermore, it is greatly challenging to design a multi-functional metal agent that not only kills cancer cells but also inhibits their invasion and metastasis. Thus, to develop novel next-generation anticancer metal agents, we designed and synthesized a series of novel In(iii) 2,6-diacetylpyridine bis(thiosemicarbazide) complexes (C1-C4) for the first time and then investigated their structure-activity relationships with human urinary bladder cancer (T-24) cells.

Developing a Novel Gold(III) Agent to Treat Glioma Based on the Unique Properties of Apoferritin Nanoparticles: Inducing Lethal Autophagy and Apoptosis.

Effective delivery of anticancer agents across the blood-brain barrier (BBB) required innovative strategies to achieve glioma regression. To resolve this problem, we proposed to develop a metal agent that target and treat glioma based on the unique property of apoferritin (AFt) nanoparticles (NPs). Thus, we synthesized a series of Au(III) 3-(4-metyl piperidine)thiosemicarbazides compounds and analyzed their structure-activity relationships, obtaining a Au agent (C6) with remarkable cytotoxicity in glioma.

Human Serum Albumin-Based Dual-Agent Delivery Systems for Combination Therapy: Acting against Cancer Cells and Inhibiting Neovascularization in the Tumor Microenvironment.

To cause tumor regression by acting against cancer cells and inhibiting neovascularization in the tumor microenvironment, we constructed human serum albumin (HSA)-based delivery systems of 2-acetylpyridine-4,4-dimethyl-3-thiosemicarbazone-copper(II) [Cu(Ap44mT)]Cl and paclitaxel to improve both the therapeutic efficacy and the targeting ability . X-ray crystallography and matrix-assisted laser desorption/ionization time-of-flight mass spectra confirmed that [Cu(Ap44mT)]Cl complexed with HSA, whereas paclitaxel was tethered to the HSA complex by a linker sensitive to the active matrix metalloproteinase 2 (MMP2) protein. Up to 78% of paclitaxel was released from HSA within 2 h owing to MMP2 protein cleavage.

Novel Brain-Tumor-Inhibiting Copper(II) Compound Based on a Human Serum Albumin (HSA)-Cell Penetrating Peptide Conjugate.

It is a great challenge to design drugs that penetrate the blood-brain barrier to inhibit brain tumor growth by acting against multiple targets and also improve their delivery efficacy and targeting ability to cancer cells. To overcome the above problems, we designed a multitarget metal agent for treating brain tumors based on an human serum albumin (HSA)-cell penetrating peptide conjugate. Thus, we rationally screened copper (Cu) and 2-acetyl-3-ethylpyrazine thiosemicarbazones to synthesize six compounds, and we investigated their structure-activity relationships and confirmed multiple mechanisms for brain glioma cells.

Novel Pt(ii) complexes with modified aroyl-hydrazone Schiff-base ligands: synthesis, cytotoxicity and action mechanism.

To develop new anti-tumour Pt(ii) agents, we designed and synthesized five Pt(ii) complexes. These Pt(ii) complexes were modified benzene rings of 2-hydroxybenzylidene with a hydrocarbyl or halogen group. The five Pt(ii) complexes possessed remarkable cytotoxicity against tumour cells in vitro.

Developing a binuclear multi-target Bi(III) complex by optimizing 2-acetyl-3-ethylpyrazine thiosemicarbazides.

On the one hand, the multi-target agents have been promising for overcoming the deficiency of the single targeted anticancer metal agents, on the other hand, bismuth (Bi) complexes have shown significant antiproliferative activity and minimal side effects. Therefore, to develop the next-generation anticancer metal agents, we designed and synthesized four novel binuclear Bi(III) complexes by modifying the N-4 position of a series of 2-Acetyl-3-ethylpyrazine thiosemicarbazides, and then investigated their structure-activity relationships to human cancer cell lines, obtaining a lead Bi drug (C4) with significant antiproliferative activity to human bladder cancer cells (T24). C4 arrested the cell cycle in the S-phase by regulation of cyclin and cyclin-dependent kinases, and exerted a chemotherapeutic effect via multi-target mechanism including the activation of apoptotic and autophagic cell signaling pathways.

Anticancer and biological properties of a Zn-2,6-diacetylpyridine bis(thiosemicarbazone) complex.

Herein, to develop a multi-target anticancer metal agent and achieve a "1 + 1 > 2" pharmaceutical effect, we rationally designed and synthesized five complexes (C1-C5) by synergistically exploiting the properties of Zn(ii) and a series of modified 2,6-diacetylpyridine bis(thiosemicarbazone) ligands. By investigating the structure-activity relationships, we found that the binuclear Zn(ii) complex (C5) acts against human bladder cancer cells (T-24) with significant cytotoxicity. We subsequently determined the multiple anticancer mechanisms of C5 to T-24 cells, including inhibiting the activity of topoisomerase I (Topo I), blocking the cell cycle in the S phase, and inducing apoptosis and autophagy in T-24 cells.