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Scandium (Sc) has great potential for use in aerospace and clean energy applications, but its supply is currently limited by a lack of commercially viable deposits and the environmental burden of its production. In this work, a biosorption-based flow-through process was developed for extraction of Sc from low-grade feedstocks. A microbe-encapsulated silica gel (MESG) biosorbent was synthesized through sol-gel encapsulation of Arthrobacter nicotianae, a bacterium that selectively adsorbs Sc. Microscopic imaging revealed a high cell loading and macroporous structure, which enabled rapid mass transport and adsorption/desorption of metal ions. The biosorbent displayed high Sc selectivity against lanthanides and major base metals, with the exception of Fe(III). Following pH adjustment to remove Fe(III) from an acid leachate prepared from lignite coal, a packed-bed column loaded with the MESG biosorbent exhibited near-complete Sc separation from lanthanides; the column eluate had a Sc enrichment factor of 10.9, with Sc constituting 96.4% of the total rare earth elements. The MESG biosorbent exhibited no significant degradation with regard to both adsorption capacity and physical structure after 10 adsorption/desorption cycles. Overall, our results suggest that the MESG biosorbent offers an effective and green alternative to conventional liquid-liquid extraction for Sc recovery.

Demanufacturing aims to recover value and conserve energy from end-of-life (EOL) products, contributing to sustainable manufacturing. To make the full use of EOL products, they are usually disassembled into components that have different values and embodied energy at different EOL options. This article studies a disassembly planning (DP) that integrates the decisions on disassembly sequence and EOL strategy to maximize the recovered value and energy conservation from EOL products. We propose a multiobjective DP based on the value recovery and energy conservation (MDPVE) model, which is different from the existing DP models by focusing on the embodied energy rather than the energy consumption during disassembly. An adapted multiobjective artificial bee colony (ABC) algorithm [multiobjective ABC (MOABC)] is developed to identify the Pareto solutions for the MDPVE and is compared with a well-known metaheuristic algorithm, Non-dominated Sorting Genetic Algorithm-II (NSGA-II). A real-world case study demonstrated the superior solution quality and computational efficiency of MOABC. Note to Practitioners —There is often more than one treatment option for EOL products or components, including reuse, remanufacturing, and recycling. However, the decision on which EOL option to select is not considered in most of the DP studies by assuming an EOL option given for each component. Hence, the disassembly plan with the EOL decision is focused in this article. As energy sustainability gains an increasing attention, it is essential to assess the profitability and energy conservation simultaneously for EOL products. Since there could be a tradeoff between recovered profit and conserved energy, a multiobjective evolutionary algorithm is developed for generating Pareto solutions which help decision-makers to find good solutions for both evaluation indicators.

Coal byproducts could be a promising feedstock to alleviate the supply risk of critical rare earth elements (REEs) due to their abundance and REE content. Herein, we investigated the economic and e...

Neodymium-iron-boron (NdFeB) magnets are the most powerful magnets per unit volume sold in the commercial market. Despite the increasing demand for clean energy applications such as electric vehicles and wind turbines, disruptive events including the COVID-19 pandemic have caused significant uncertainties in the supply and demand for NdFeB magnets. Therefore, this study aims to alleviate the risk of supply shortage for NdFeB magnets and the containing critical materials, rare-earth elements (REEs), through the development of a resilient reverse supply chain and logistics network design. We develop scenarios to model the unique impact of the COVID-19 pandemic on the proposed business, incorporating both disruption intensity and recovery rate. We formulate a chance-constrained two-stage stochastic programming model to maximize the profit while guaranteeing the network resiliency against disruption risks. To solve the problem in large-scale instances, we develop an efficient Benders decomposition algorithm that reduces the computational time by 98.5% on average compared to the default CPLEX algorithm. When applied to the United States, the model suggests the optimal facility locations, processing capacities, inventory levels, and material flows for NdFeB magnet recyclers that could meet 99.7% of the demand. To the best of our knowledge, this study is the first to incorporate the impacts of the COVID-19 pandemic to design a resilient NdFeB magnet recycling supply chain and logistics network, leveraging risk-averse stochastic programming.

This study applies design of experiments (DOE) methods in the conduct of a techno-economic assessment (TEA) on a newly developed rare-earth element (REE) recovery process. The goal of this effort is to identify main factors that affect the profitability of the process. We construct a factorial design with net profit as the response, where the experimental data are generated by simulation of different scenarios. The effects of different factors and their interactions are determined. Based on these results, a desirable recovery strategy is proposed. It is envisioned that the methods applied in the study can be utilized in other situations to promote the application of TEA in value recovery approaches.

There is an ever-increasing concern regarding electronic waste (e-waste), which is the fastest growing waste stream in the world. E-waste contains highly toxic materials such as halogenated flame retardants and heavy metals, as well as precious metals like gold, silver, and platinum. Its proper management and disposition are paramount. Incentivized by various legislations and the intrinsic value of critical metals inside, recycling of e-waste is becoming an attractive business opportunity that also benefits the environment. A novel electrochemical recovery (ER) process has been developed as a promising alternative to the existing pyrometallurgical and hydrometallurgical processes-based technologies to recover base metals, precious metals, and rare earth elements (REEs) from e-waste. Experimental results indicate that the ER process has lower chemical consumption, enhanced control, and reduced energy demand compared to the pyrometallurgical and the hydrometallurgical processes. To quantify and compare the environmental performances of the three technologies, life cycle analysis has been conducted. The baseline comparison used $1000 revenue from the e-waste recovery as a functional unit. Results show that the ER process outperforms the other two processes in almost all impact categories adopted in TRACI and ILCD while there is no clear winner between the hydrometallurgical and the pyrometallurgical processes. The life cycle analysis helped identify the significant inputs for different processes. The highest impactful input for the ER method is hydrochloric acid, and for the pyrometallurgical method is copper scrap, while for the hydrometallurgical method, it is hydrogen peroxide, an oxidizer that accelerates base metal extraction process that dominates the overall environmental footprint. Other than the baseline case, the environmental impacts of recovering REE from e-waste with different processes and from other method were studied. The results indicate REE recovered from e-waste has a lower environmental footprint than virgin extraction. Overall, the ER process has the lowest impacts on the environmental side among the three e-waste treatment processes. The environmental viability of the ER process warrants the further development of the ER process at industrial scale.

Agricultural waste was used as substrate for fermentation by Gluconobacter oxydans to produce lixiviant for rare earth element (REE) recovery from industrial waste materials, i.e., spent fluid cata...

A case study of hard disk drives (HDDs) and rare-earth magnets is presented to show the use of decision support tools to identify and assess the barriers and opportunities for circular business models. Pilot demonstration projects, which showcased HDD circular recovery strategies, were useful as a low-risk opportunity for business model experimentation and to build trust among key supply chain actors. A case study of hard disk drives and rare-earth magnets is presented to show the use of decision support tools (DSTs) to assess the complex interaction of variables that must be considered when demonstrating the viability of circular business models (CBMs). A mix of quantitative and qualitative DSTs such as life cycle assessment, techno-economic assessment, Ostrom's Framework for social-ecological systems, decision trees, and others were implemented by the iNEMI Value Recovery Project team to overcome many of the identified barriers to circular economy. The DSTs were used to guide stakeholder coordination, create and share environmental, logistical and financial data, and generate decision-making flowcharts which promote circular economic strategies. Demonstration projects were used as a low-risk opportunity for business model experimentation and to build trust among key supply chain actors. The tools highlighted by this case study could be useful for establishing or expanding CBMs for other electronic products or components, especially components containing critical materials.

Rare earth elements (REEs) such as neodymium (Nd) and dysprosium (Dy) are indispensable in modern society because they are vital for creating powerful neodymium-iron-boron (NdFeB) magnets used in many technological applications. These elements have been subject to a significant supply uncertainty. A promising strategy to alleviate supply risk is value recovery from end-of-life (EOL) products. This paper proposes a reverse supply network to optimize: 1) the locations and capacities of dismantling and recycling facilities, and 2) the transportation flows between collection centers, dismantling facilities, recycling facilities, and sales points. Two objectives are considered: maximizing profit and environmental benefits. A Pareto front is created that shows non-dominated optimal solutions. When the model was applied to the United States, California was found to be the most important state for EOL product collection, representing up to 22% of the total collection volume. Nevada, Tennessee, and Delaware were the key states for EOL product dismantling, and Nevada, Texas, and Delaware were the key states for NdFeB magnet recycling. A sensitivity analysis was performed to measure the impact of different NdFeB magnet price on the overall network design. While REE recovery is still at an early stage of the development, this research serves as a blueprint for constructing a profitable and environmentally friendly NdFeB magnet reverse supply chain.

Epithelial-mesenchymal transition (EMT) is closely associated with the development of drug resistance. Lipid metabolism plays an important role in EMT. This work was to study the cholesterol-lowering drug simvastatin for reversing EMT-associated resistance to chemotherapy via lipid metabolism. Methods: The combination of simvastatin and paclitaxel was used to overcome the EMT-associated drug resistance. For dual-action on both cancer cells and tumor-associated macrophages (TAM), the tumor microenvironment-activatable multifunctional liposomes were developed for drug codelivery. The liposomes were modified with a hairpin-structured, activatable cell-penetrating peptide that is specifically responsive to the tumor-associated protease legumain. Results: It was revealed simvastatin can disrupt lipid rafts (cholesterol-rich domains) and suppress integrin-β3 and focal adhesion formation, thus inhibiting FAK signaling pathway and re-sensitizing the drug-resistant cancer cells to paclitaxel. Furthermore, simvastatin was able to re-polarize tumor-associated macrophages (TAM), promoting M2-to-M1 phenotype switch via cholesterol-associated LXR/ABCA1 regulation. The repolarization increased TNF-α, but attenuated TGF-β, which, in turn, remodeled the tumor microenvironment and suppressed EMT. The liposomal formulation achieved enhanced treatment efficacy. Conclusion: This study provides a promising simvastatin-based nanomedicine strategy targeting cholesterol metabolism to reverse EMT and repolarize TAM to treat drug-resistant cancer. The elucidation of the molecular pathways (cholesterol/lipid raft/integrin β3/FAK and cholesterol-associated LXR/ABCA1 regulation) for anti-EMT and the new application of simvastatin should be of clinical significance.

Chemoresistance remains a formidable hurdle against cancer therapy. Seeking for novel therapy strategies is an urgent need for those who no longer benefit from chemotherapy. Chemoresistance is usually associated with the dysfunction of intrinsic apoptosis. Targeting extrinsic apoptosis via TRAIL signaling and the death receptors could be a potential solution to treat chemoresistant cancer. A highly biocompatible nano system for codelivery of the TRAIL DNA and the death receptor sensitizer monensin was developed, in which low-molecular-weight PEI (LMW-PEI) was crosslinked by the sulfhydryl cyclodextrin via disulfide bonds, and then bound with DNA, thus forming the bioreducible polyplex cores. In addition, the cyclodextrin also functioned as a carrier for the hydrophobic monensin via host-guest inclusion. Poly-γ-glutamic acid (γ-PGA) was used to modify the polyplex core via charge interaction. The γ-PGA corona can specifically bind with the tumor-associated gamma-glutamyl transpeptidase (GGT) overexpressed on the tumor cells, and achieve tumor-targeting delivery. Moreover, the tumor-homing peptide RGD-modified γ-PGA was also prepared as the surface coating materials for further improving gene delivery efficiency. This gene delivery system was characterized by the dual ligand-targeting, dual stimuli-responsive features. The ligands of RGD and γ-PGA can target the tumor-associated receptors (i.e., integrin and GGT). The conformation of γ-PGA is pH-sensitive, and the tumor acidic micro environments could trigger the detachment of surface-coating γ-PGA. The disulfide crosslinking LMW-PEI is redox-sensitive, and its fast disassembling in the tumor cells could favor the efficient gene delivery. The anti-tumor efficacy was demonstrated both in vitro and in vivo. Moreover, MYC-mediated synthetic lethality could be an important mechanism for overcoming the drug resistance. An important finding of our studies is the demonstration of the in vivo treatment efficacy of TRAIL/monensin, thus providing a potential novel therapeutic strategy for overcoming drug-resistant cancer.

Neodymium–iron–boron (NdFeB) magnets are widely used in clean energy applications such as wind turbines and electric vehicles whose demand is escalating. However, rare earth elements (REEs) for manufacturing NdFeB magnets are subject to significant supply uncertainty due to Chinese near-monopolistic supply. To mitigate the risk, companies are actively pursuing value recovery from end-of-life magnets. However, the questions of how to collect used magnets and smoothly transfer them through the reverse supply chain require further investigation. To address this challenge, this paper designs an efficient NdFeB magnet recovery infrastructure by identifying the optimal processing facility locations and defining the capacities and transportation flows that maximize the economic and environmental benefits and social support for the new business. Mathematical model and a multi-objective network design genetic algorithm (MONDGA) were designed to calculate solutions. When compared with the exact solutions implemente...

Rare earth permanent magnets (REPMs) play an essential role in various applications such as renewable energy production, and aerospace and defense related products. Rare earth elements (REEs) such as neodymium and dysprosium are used in REPMs, and the supply of these REEs has experienced volatility. To mitigate this risk, REEs may be recovered from end-of-life (EOL) products such as computer hard disk drives (HDDs). To facilitate REE/REPM recycling, this paper develops an operation and inventory management strategy to explore the profitability 1) under uncertain market supply and 2) with varying component/material values whose demand also faces significant uncertainties. The resulting strategy provides recommendations for the ordering and processing quantities associated with REPM containing products. An upper bound solution on the recovery profit was proposed to assess the performance of the developed strategy. We found that the proposed strategy helps increase the overall profit, and its performance is close to the upper bound. Finally, several scenarios were evaluated to examine how market conditions affect profit. To the best of authors’ knowledge, this research is the first study on REPM recycling that provides a promising strategy to the relevant industry.

Neodymium-iron-boron (NdFeB) magnets play a critical role in clean power products, e.g., electric vehicles and wind turbines. Since China has near monopolistic control of the supply of these magnets, many parties are interested in recovering end-of-life magnets for additional use cycles. Such a strategy requires a cost-effective approach to collect and process used magnets while maximizing the economic and environmental benefits. This paper employs fuzzy logic and non-dominated sorting genetic algorithm (NSGA-II) to solve a location-allocation problem for NdFeB magnet recovery under supply and demand uncertainties. A Pareto front is constructed to evaluate the performance of the proposed design.

Hard disk drives (HDDs) are prioritized by many stakeholders for implementation of circular economy initiatives due to their value and critical material content. Rare earth (RE) magnets are of particular interest for recovery and reuse (R&R), but the business model has not been demonstrated for feasibility at a large scale. This study assessed a pilot-scale R&R process for RE magnet assemblies and compared the environmental impacts with business as usual (BAU) (i.e. shredding whole HDDs at end-of-life), using life cycle assessment (LCA). The process was implemented by two major stakeholders in the HDD value chain – a large HDD user (i.e., data center) and a HDD manufacturer. Primary data on materials, transportation, and electricity inputs were collected from dismantling 6100 end-of-life HDDs in a data center, transporting the retrieved RE magnet assemblies to a HDD manufacturer, and placing them in new HDDs for reuse. LCA results indicated an 86% reduction in global warming potential: 3.70 kg CO2-eq per set of magnet assemblies from one HDD compared to the BAU system. The environmental benefit was predominantly due to foregoing the RE magnet production, which is the most energy and chemically intensive process within the magnet assembly. This pilot also highlighted the benefits of a collocated R&R process with data centers to address (1) data security concerns, (2) transboundary shipments of e-waste (whole HDDs vs. components), and (3) the need for a qualified manufacturing process for disassembly, which is required to reuse components in new HDDs.

A bioleaching process to extract rare-earth elements (REE) from fluidized catalytic cracking (FCC) catalysts was optimized using a heterotrophic bacterium Gluconobacter oxydans to produce organic acids from glucose. Parameters optimized included agitation intensity, oxygen levels, glucose concentrations, and nutrient additions. Biolixiviants from the optimized batch process demonstrated REE leaching efficiencies up to 56%. A continuous bioreactor system was subsequently developed to feed a leach process and demonstrated leaching efficiencies of 51%. A techno-economic analysis showed glucose to be the single largest expense for the bioleach process, constituting 44% of the total cost. The bioleaching plant described here was found profitable, although the margin was small. Lower cost carbon and energy sources for producing the biolixiviant, sourcing FCC catalysts with higher total REE content (>1.5% by mass), and improved leaching efficiencies would significantly increase the overall profit. A life cycle a...

Value recovery from end-of-life hard disk drives (HDDs) is a promising strategy to promote a circular economy due to the valuable material content, large availability, and regulated disposal for data security. However, current business practices are limited to reuse or shredding of HDDs for base metal recovery, which are not optimal for environmental sustainability. In particular, the neodymium-iron-boron (NdFeB) magnets, which contain rare earth elements (REEs) that have significant environmental impacts and supply chain risks, are not recovered. To address this challenge, technologies are emerging to enable REE recovery from HDDs. This work focuses on comparing novel technologies, including direct reuse of magnet assemblies, magnet-to-magnet recycling, and recovery of REEs. Life cycle assessment (LCA) was performed on each recovery pathway to quantify and compare the environmental impacts. Primary data were collected from Seagate and other key stakeholders in the HDD value chain. LCA results showed that reusing HDDs is the most environmentally friendly option in terms of global warming potential, reducing CO2 eq. emissions by 5∼18 kg per drive life cycle, when compared to the virgin production and shredding for aluminum recovery. Reuse of magnet assembly is the next best option (reducing ∼1.9 kg of CO2 eq. emissions), followed by magnet-to-magnet recycling (∼1.2 kg of CO2 eq. emissions), and metal recycling (∼0.02 kg of CO2 eq. emissions). Environmental hotspots were also identified, revealing the significant contribution of intercontinental transportation mode for the reverse logistics. Future research is suggested on optimizing the reverse supply chain to reduce the environmental footprint of HDD value recovery.

Precision medicine has made a significant breakthrough in the past decade. The most representative success is the molecular targeting therapy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) in non-small-cell lung cancer (NSCLC) with oncogenic drivers, approved by the US Food and Drug Administration (FDA) as first-line therapeutics for substituting chemotherapy. However, the rapidly developed TKI resistance invariably leads to unsustainable treatment. For example, gefitinib is the first choice for advanced NSCLC with EGFR mutation, but most patients would soon develop secondary EGFR

Neodymium-iron-boron (NdFeB) magnets offer the strongest magnetic field per unit volume, and thus, are widely used in clean energy applications such as electric vehicle motors. However, rare earth elements (REEs), which are the key materials for creating NdFeB magnets, have been subject to significant supply uncertainty in the past decade. NdFeB magnet-to-magnet recycling has recently emerged as a promising strategy to mitigate this supply risk. This paper assesses the environmental footprint of NdFeB magnet-to-magnet recycling by directly measuring the environmental inputs and outputs from relevant industries and compares the results with production from "virgin" materials, using life cycle assessments. It was found that magnet-to-magnet recycling lowers environmental impacts by 64-96%, depending on the specific impact categories under investigation. With magnet-to-magnet recycling, key processes that contribute 77-95% of the total impacts were identified to be (1) hydrogen mixing and milling (13-52%), (2) sintering and annealing (6-24%), and (3) electroplating (6-75%). The inputs from industrial sphere that play key roles in creating these impacts were electricity (24-93% of the total impact) and nickel (5-75%) for coating. Therefore, alternative energy sources such as wind and hydroelectric power are suggested to further reduce the overall environmental footprint of NdFeB magnet-to-magnet recycling.

Permanent magnets containing rare earth elements (REEs) such as Dysprosium and Neodymium offer an advantage over non-REE containing magnets (e.g. ferrite or AlNiCo) in terms of power relative to size. However, REE availability has varied significantly in recent years leading to volatility in the cost of rare earth permanent magnets (REPMs). The supply of REEs can be increased by recycling consumer products and industrial machinery that contain REPMs at product end-of-life (EOL). This paper discusses the REE recovery process for EOL products. The optimal dismantling of products is examined with an emphasis placed on obtaining used REPMs. The challenge of collecting, managing, transporting, and processing used products is addressed through the development of a cost model for REPM recovery. This model is used to investigate several EOL strategies for recovering REPMs. Sensitivity analysis is conducted to identify the key factors that influence value recovery economics. A hard disk drive serves as a case study for model demonstration.

Nanotechnology-based photothermal therapy has attracted great attention in the past decade. Nevertheless, photothermal therapy has some inherent drawbacks, such as the uneven heat production and limited laser penetration, often leading to insufficient treatment outcomes. Here, we developed a combination strategy to improve cancer therapy. The biomimetic albumin-modified gold nanorods (AuNRs) were prepared with incorporation of paclitaxel (PTX). This therapeutic system was characterized by several features. First, the albumin modification enhanced the biocompatibility and colloidal stability. Second, the surface-coated albumin promoted cellular uptake via the albumin-binding protein pathway. Third, PTX was incorporated via hydrophobic interaction between PTX and the albumin lipophilic domain. Fourth, the system can be used for combined photothermo-chemotherapy for yielding synergistic effects. The antitumor activity of the system was evaluated both in vitro and in vivo using the HCT116 colon cancer cell and tumor model. The combination therapy was found with an enhanced treatment efficiency and no obvious side effect. Most importantly, the thermal effect was also discovered with the ability to modulate the tumor microenvironments and suppress the macrophages polarization towards the M2 pro-tumor phenotype. It could be a mechanism for photothermal immunotherapy. The combination strategy and the system provide a potential method for cancer therapy., Graphical abstract The biomimetic albumin-modified gold nanorods (AuNRs) with incorporation of paclitaxel (PTX) were characterized by the improved biocompatibility and colloidal stability, and the enhanced cellular uptake, which were used for photothermo-chemotherapy with synergistic effects by efficiently killing the tumor cells and suppressing the macrophages polarization towards the M2 pro-tumor phenotype.fx1

Multidrug resistance (MDR) is a main obstacle in cancer chemotherapy. The MDR mechanisms involve P-glycoprotein (P-gp) overexpression, abnormality of apoptosis-related protein, and altered expression of drug-targeting proteins. Therapeutic proteins are emerging as candidates for overcoming cancer MDR because of not only their large molecular size that potentially circumvents the P-gp-mediated drug efflux but also their distinctive bioactivity distinguished from small-molecular drugs. Herein we report trichosanthin, a plant protein toxin, possesses synergistic effect with paclitaxel (PTX) in the PTX-resistance A549/T nonsmall cell lung cancer (NSCLC) cells, by reversing PTX-caused caspase 9 phosphorylation and inducing caspase 3-dependent apoptosis. Moreover, via intein-mediated site-specific protein ligation, a matrix metalloproteinase (MMP)-activatable cell-penetrating trichosanthin delivery system was constructed by modification of a cell-penetrating peptide and MMP-2-sensitive PEGylation to overcome the limitation of in vivo application of trichosanthin, by improving the short half-life and poor tumor targeting, as well as immunogenicity. In a mouse model bearing A549/T tumor, the MMP-activatable trichosanthin was further tested for its application for MDR reversal in combination with PTX liposomes. The delivery system showed synergy effect with PTX-loaded liposome in treating MDR cancer in vivo.

Nutrient transporters have been explored for biomimetic delivery targeting the brain. The albumin-binding proteins (e.g., SPARC and gp60) are overexpressed in many tumors for transport of albumin as an amino acid and an energy source for fast-growing cancer cells. However, their application in brain delivery has rarely been investigated. In this work, SPARC and gp60 overexpression was found on glioma and tumor vessel endothelium; therefore, such pathways were explored for use in brain-targeting biomimetic delivery. We developed a green method for blood-brain barrier (BBB)-penetrating albumin nanoparticle synthesis, with the capacity to coencapsulate different drugs and no need for cross-linkers. The hydrophobic drugs (i.e., paclitaxel and fenretinide) yield synergistic effects to induce albumin self-assembly, forming dual drug-loaded nanoparticles. The albumin nanoparticles can penetrate the BBB and target glioma cells via the mechanisms of SPARC- and gp60-mediated biomimetic transport. Importantly, by modification with the cell-penetrating peptide LMWP, the albumin nanoparticles display enhanced BBB penetration, intratumoral infiltration, and cellular uptake. The LMWP-modified nanoparticles exhibited improved treatment outcomes in both subcutaneous and intracranial glioma models, with reduced toxic side effects. The therapeutic mechanisms were associated with induction of apoptosis, antiangiogenesis, and tumor immune microenvironment regulation. It provides a facile method for dual drug-loaded albumin nanoparticle preparation and a promising avenue for biomimetic delivery targeting the brain tumor based on combination therapy.

Poor tumor-targeted and cytoplasmic delivery is a bottleneck for protein toxin-based cancer therapy. Ideally, a protein toxin drug should remain stealthy in circulation for prolonged half-life and reduced side toxicity, but turn activated at tumor. PEGylation is a solution to achieve the first goal, but creates a hurdle for the second because PEG rejects interaction between the drugs and tumor cells therein. Such PEG dilemma is an unsolved problem in protein delivery. Herein proposed is a concept of turning PEG dilemma into prodrug-like feature. A site-selectively PEGylated, gelatinase-triggered cell-penetrating trichosanthin protein delivery system is developed with three specific aims. The first is to develop an intein-based ligation method for achieving site-specific modification of protein toxins. The second is to develop a prodrug feature that renders protein toxins remaining stealthy in blood for reduced side toxicity and improved EPR effect. The third is to develop a gelatinase activatable cell-penetration strategy for enhanced tumor targeting and cytoplasmic delivery. Of note, site-specific modification is a big challenge in protein drug research, especially for such a complicated, multifunctional protein delivery system. We successfully develop a protocol for constructing a macromolecular prodrug system with intein-mediated ligation synthesis. With an on-column process of purification and intein-mediated cleavage, the site-specific PEGylation then can be readily achieved by conjugation with the activated C-terminus, thus constructing a PEG-capped, cell-penetrating trichosanthin system with a gelatinase-cleavable linker that enables tumor-specific activation of cytoplasmic delivery. It provides a promising method to address the PEG dilemma for enhanced protein drug delivery, and importantly, a facile protocol for site-specific modification of such a class of protein drugs for improving their druggability and industrial translation.

Chemotherapy is one of the most important strategies for glioma treatment. However, the "impermeability" of the blood-brain barrier (BBB) impedes most chemotherapeutics from entering the brain, thereby rendering very few drugs suitable for glioma therapy, letting alone application of a combination of chemotherapeutics. Thereby, there is a pressing need to overcome the obstacles. A dual-targeting strategy was developed by a combination of magnetic guidance and transferrin receptor-binding peptide T7-mediated active targeting delivery. The T7-modified magnetic PLGA nanoparticle (NP) system was prepared with co-encapsulation of the hydrophobic magnetic nanoparticles and a combination of drugs (i.e., paclitaxel and curcumin) based on a "one-pot" process. The combined drugs yielded synergistic effects on inhibition of tumor growth via the mechanisms of apoptosis induction and cell cycle arrest, displaying significantly increased efficacy relative to the single use of each drug. Dual-targeting effects yielded a10-fold increase in cellular uptake studies and a5-fold enhancement in brain delivery compared to the nontargeting NPs. For the in vivo studies with an orthotopic glioma model, efficient brain accumulation was observed by using fluorescence imaging, synchrotron radiation X-ray imaging, and MRI. Furthermore, the antiglioma treatment efficacy of the delivery system was evaluated. With application of a magnetic field, this system exhibited enhanced treatment efficiency and reduced adverse effects. All mice bearing orthotopic glioma survived, compared to a 62.5% survival rate for the combination group receiving free drugs. This dual-targeting, co-delivery strategy provides a potential method for improving brain drug delivery and antiglioma treatment efficacy.

Precision medicine has made a significant breakthrough in the past decade. The most representative success is the molecular targeting therapy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) in non-small-cell lung cancer (NSCLC) with oncogenic drivers, approved by the US Food and Drug Administration (FDA) as first-line therapeutics for substituting chemotherapy. However, the rapidly developed TKI resistance invariably leads to unsustainable treatment. For example, gefitinib is the first choice for advanced NSCLC with EGFR mutation, but most patients would soon develop secondary EGFRT790M mutation and acquire gefitinib resistance. TKI resistance is a severe emergency issue to be solved in NSCLC, but there are a few investigations of nanomedicine reported to address this pressing problem. To overcome EGFRT790M -associated drug resistance, a novel delivery and therapeutic strategy is developed. A PD-L1 nanobody is identified, and first used as a targeting ligand for liposomal codelivery. It is found that simvastatin/gefitinib combination nanomedicine can remodel the tumor microenvironment (e.g., neovascularization regulation, M2-macrophage repolarization, and innate immunity), and display the effectiveness of reversing the gefitinib resistance and enhancing the EGFRT790M -mutated NSCLC treatment outcomes. The novel simvastatin-based nanomedicine provides a clinically translatable strategy for tackling the major problem in NSCLC treatment and demonstrates the promise of an old drug for new application.

Tumor-associated proteases (TAPs) have been intensively studied because of their critical roles in cancer development. As a case in point, expression of matrix metalloproteases (MMP) is significantly up-regulated in tumorigenesis, invasion, and metastasis among a majority of cancers. Here we present a prodrug-type, MMP-2-responsive nanoprobe system with high efficiency and low toxicity for detecting MMP-2-overexpressed tumors. The nanoprobe system is featured by its self-assembled fabrication and FRET effect. This prodrug-type nanoprobe is selectively activated by MMP-2, and thus useful for detection of the MMP-2-overexpressed cells and tumors. The nanoprobe system works successfully in various animal tumor models, including human fibrosarcoma and subcutaneous glioma xenograft. Furthermore, in order to overcome the blood brain barrier (BBB) and achieve brain tumor targeting, a transferrin-receptor targeting peptide (T7 peptide) is strategically incorporated into the nanoprobe. The T7-functionalized nanoprobe is capable of detecting the orthotopic brain tumor, with clear, real-time in vivo imaging. This method is promising for in vivo detection of brain tumor, and real-time monitor of a TAP (i.e., MMP-2).

The wafer handling robot actions in cluster tools used for semiconductor manufacturing should serve to maximize throughput while maintaining good wafer quality. Since excessive delay in a process chamber may cause deterioration in wafer quality, wafer delays should be maintained in an acceptable range, or preferably, should be minimized. We focus on addressing these concerns for all wafers in a lot, including those in both the transient and possibly cyclic regime. As the general problem is computationally complex, we first assume that the robot sequence is given and develop a multistage linear programming (LP) model to minimize the total makespan, subject to wafer residency constraints, and subsequently the average delay. Forging into less tractable territory, we next develop a branch and bound algorithm to find an optimal robot sequence with minimum wafer delay. This approach enables us to solve problems that were not previously solvable. Simulation studies demonstrate that when the number of process modules grows to more than five, the branch and bound algorithm may fail to find an optimal solution due to computational complexity. In this case, we suggest a transient sequence based on cyclic policies together with the LP model; it is within 2% of optimal.