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 (5b) with remarkable cytotoxicity to gastric cancer cells; moreover, we successfully constructed a novel HSA-5b complex NP delivery system. Importantly, the in vivo results showed that 5b/HSA-5b NPs effectively inhibited gastric tumor growth and HSA-5b NPs enhanced the therapeutic efficiency, bioavailability, and targeting ability compared with those of 5b alone. Furthermore, the in vitro/in vivo results revealed that 5b/HSA-5b NPs could integrate chemotherapy and immunotherapy by synergistically attacking two different cellular components in TME at the same time, namely, polarizing the tumor-associated macrophages and inducing apoptosis of gastric cancer cells.

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. Moreover, we confirmed that C6 kills glioma cells by inducing lethal autophagy and apoptosis. Importantly, our results revealed that the successfully constructed apoferritin-C6 NPs (AFt-C6 NPs) can effectively cross the BBB, inhibit glioma growth, and selectively accumulate in tumors.

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. The HSA–6b complex structure indicated that 6b binds to the IIA subdomain of HSA and His242 replaces the Br ligand in 6b in coordination with Cu2+. In vivo data suggested that both 6b and the HSA–6b–peptide conjugate penetrate the blood–brain barrier and inhibit brain tumor growth with few side effects. Furthermore, the HSA–peptide conjugate also improved the delivery efficacy and targeting ability of 6b in vivo.

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 in vivo. 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. In addition, a large amount of Cu­(Ap44mT) was released from HSA in a pH 4.7 buffer. In vivo results revealed the following: (1) the tumor inhibitory rates of the HSA conjugate and the two-agent combination were 72.1 and 50.7%, respectively; (2) the inhibition rate of tumor angiogenesis of the HSA conjugate (73.3%) was higher than that of the two-agent combination (52.4%); (3) the increased amount of Cu in the tumor treated with the HSA conjugate was about 2-fold that in the tumor treated with the two-agent combination. Obviously, the HSA conjugate not only possessed a stronger capacity to inhibit neovascularization and the growth of liver tumors but also improved the targeting ability compared to the combination of the two agents alone.

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 in vitro. An HSA−C5 complex NP delivery system was then successfully constructed. Importantly, the HSA−C5 complex NPs have stronger bioimaging and therapeutic efficiency relative to C5 alone in vivo. Besides, the results of gene chip analysis revealed that C5/HSA−C5 complex NPs act on cancer cells through multiple mechanisms: inducing autophagy, apoptosis, and inhibiting the PI3K−Akt signaling pathway.

The Zn(ii) complexes kill cells by p53-mediated mitochondrial pathway, inhibiting topoisomerase and inducing autophagy.

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. Furthermore, free C4 and LF-C4 NPs inhibited tumor growth through multiple synergistic actions on the TME: killing cancer cell, inhibiting tumor angiogenesis, and activating immune system.

Integrated Gasification Combined Cycle with embedded membrane reactor modules (IGCC-MR) represents a new technology option for the coproduction of electricity and pure hydrogen endowed with enhanced environmental performance capacity. It is viewed as an alternative to conventional coal-and gasfired power generation technologies. An IGCC-MR power plant needs to be techno-economically evaluated in the presence of irreducible regulatory and fuel market uncertainties for the potential deployment of an initial fleet of demonstration plants at the commercial scale. This paper applies a systematic methodological framework to assess the economic value of flexible alternatives in the design and operation of an IGCC-MR plant under the aforementioned sources of uncertainty. The main objective is to demonstrate the potential value enhancements associated with the long-term economic performance of flexible IGCC-MR project investments, by managing the uncertainty associated with future environmental regulations and fuel costs. The paper provides an overview of promising design flexibility concepts for IGCC-MR power plants and focuses on operational and constructional systems flexibility. Operational flexibility is realized through temporary plant shutdown with considerations of regulatory and market uncertainties. Constructional flexibility is realized by considering the installation of a Carbon Capture and Storage (CCS) unit at three strategic periods: (1) installation at the initial construction phase, (2) retrofitting at a later stage, and (3) retrofitting at a later stage with preinvestment. Monte Carlo simulations and financial analysis demonstrate that, in the presence of irreducible uncertainty, the most economically advantageous flexibility option is to install CCS in the initial IGCC-MR construction phase. C⃝ 2015 Wiley Periodicals, Inc. Syst Eng 18: 208-227, 2015