Safety Windows Research Articles

Flame-retardant reinforced halloysite nanotubes as multi-functional fillers for PEO-based polymer electrolytes

High ionic conductivity, fire safety, and broad electrochemical windows are crucial considerations for the next generation of solid polymer electrolytes (SPEs) employed in solid-state lithium-ion batteries. Based on these factors, we design a novel nanohybrid filler by loading a phosphazene-based flame retardant into halloysite nanotubes (HNT@FPPN). A 36 % reduction in the peak heat release rate (pHRR) confirms the enhanced fire safety of poly(ethylene oxide) (PEO)-based PEO-5HNT@FPPN SPE. Besides, the PEO-5HNT@FPPN electrolyte exhibits an enhanced ionic conductivity of 1.82 × 10-4 S cm−1 at 45 °C. The improved ionic conductivity is attributed to the plasticization effect of nanohybrids, which reduces the crystallinity and aids the motion of PEO chains. After 100 cycles, the as-fabricated Li/PEO-5HNT@FPPN/LiFePO4 cell shows stable cycling at 0.1C with a specific discharge capacity of 145 mAh/g. These findings demonstrate the unique properties of modified PEO SPEs, which may open new pathways for designing safer electrolytes.

Abstract LB428: Discovery of KY-001:A Direct Inhibitor of TEAD-YAP Protein-Protein Interaction for the Treatment of Advanced Solid Tumors with Abnormal Hippo Signaling Pathway

Abstract Background:The Hippo signaling is an important pathway that plays a crucial role in the regulation of numerous biological processes. The binding of YAP/TAZ transcriptional coactivators to TEAD proteins is the core of Hippo signaling in regulating the expression of a variety of genes that mediate many cellular functions. Abnormalities of Hippo signaling including mutation deficiency, fusion and YAP/TAZ overexpression are often found in solid tumors associated with excessive proliferation, drug resistance, or tumor immune evasion. Blocking the Hippo transcription activation, particularly the TAP/TAZ and TEAD interaction, therefore is an attractive therapeutic strategy for the treatment of advanced solid tumors associated with Hippo dysregulation. Results:We have developed a small molecule inhibitor, KY-001, that can bind to TEAD protein and directly disrupt its interaction with YAP/TAZ, thereby blocking Hippo signaling pathway. KY-001 can bind to TEAD (1-4) proteins with strong YAP/TAZ competitive activities in biochemical assays and can inhibit TEAD-YAP mediated transcriptional signals in cell. KY-001 selectively and potently inhibits the proliferation of cancer cells harboring Hippo deficient mutations, such as mesothelioma, lung cancer and other cell lines. Importantly, KY-001 directly affects the expression of some target genes downstream of YAP/TAZ-TEAD transcription activation in cell. KY-001 can strongly inhibit tumor growth in a dose dependent manner against Hippo mutation mesothelioma cancers in two different xenograft mouse tumor models. In addition, KY-001 shows remarkable synergistic effects with EGFR or KRAS G12C inhibitors in mouse non-small lung cancer models, suggesting it may be a promise therapy for treating targeted therapy induced resistant tumors with Hippo dysregulation. Pre-clinical studies shows that KY-001 has good overall druggable profiles with good safety windows in several animal species. Collectively, KY-001 shows high potency and selectivity in vitro and strong anti-tumor activities against Hippo mutation deficient cancers in pre-clinical models. Conclusions:KY-001 is a small molecule drug candidate which directly inhibits the interactions between TEAD and YAP1/TAZ proteins, thereby blocking the transcriptional activation of downstream Hippo signaling. In various tumor models, KY-001 monotherapy shows good efficacy for Hippo mutation deficient tumors. KY-001 also synergizes with other targeted therapy such as EGFR or KRAS G12C inhibitors for treating non-small lung cancers. KY-001 is expected to enter clinical studies in H2, 2024 for the treatment of Hippo dysregulated solid tumors. Citation Format: Kehao Zhao, Yong Zhag, Yufang Shi, Jian Chen. Discovery of KY-001:A Direct Inhibitor of TEAD-YAP Protein-Protein Interaction for the Treatment of Advanced Solid Tumors with Abnormal Hippo Signaling Pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB428.

Abstract 4702: MediLink’s TMALIN ADC linker technology: Tumor microenvironment specific extracellular and intracellular double cleavage mechanism for better efficacy and expanded target space

Abstract Antibody-drug conjugates (ADC) are a type of the fastest growing anticancer drug modalities. However, the traditional ADC technologies constrain on therapeutic development, requiring overexpressed targets, high internalizing antigens and efficient intracellular processing. To this end, MediLink’s TMALIN platform was developed, with an irreversible pyrimidine coupling anchor and a valyl dipropyl-lysyl glycinamide-methylene (-VK*G-NHCH2-O-) cleavable sequence. The TMALIN platform is featured as a high hydrophilicity linker-payload, remarkable stability in circulation, coupled with an efficient payload release mechanism which is achieved through the cleavage both extracellularly in the tumor microenvironment and intracellularly within lysosomes. A site-specific and homogeneous conjugation using TMALIN platform provides highly stable ADC in circulation. It is evidenced by less than 2% payload drop-off after a 21-day incubation in plasma under physiological conditions in vitro. This feature is observed in over 7 ADCs developed using the TMALIN platform. Additionally, the high stability was also illustrated by the pharmacokinetic profiles in NHP studies and clinical trials, with the overlapped curves of ADC and TAb in all TMALIN platform-based ADCs. Apart from the stability, a battery of in vitro and in vivo studies showed the linker-payload efficiently releases the payload in both tumor cells and the tumor microenvironment. Due to the high stability in circulation and efficient cleavage within tumors, the TMALIN platform ADCs have shown promising efficacy and good safety windows in preclinical studies. In xenograft mouse models, including those with low antigen expression, these ADCs have demonstrated tumor regressions and good tolerability. This highlights the potential of the TMALIN platform in improving the efficacy of ADCs and expanding their therapeutic applications. Furthermore, favorable safety profiles have been observed in clinical trials and/or pivotal non-human primate (NHP) studies for ADCs developed using the TMALIN platform. No drug-related adverse effects in organs were identified including the lungs, liver, or kidneys for those ADCs. In summary, the TMALIN platform addresses the unmet need of ADCs by releasing the payload extracellularly in tumors and tumor microenvironments on top of the known intracellular lysosomal cleavage mechanisms. This enables the advancement of ADC development, and has the potential to expand the field of ADC therapy and improve patient outcomes. Citation Format: Tongtong Xue, Liang Xiao, Qigang Liu, Shuai Song, Ailin Shan, Xiaozhou Zhang, Sasha Stann, Jiaqiang Cai. MediLink’s TMALIN ADC linker technology: Tumor microenvironment specific extracellular and intracellular double cleavage mechanism for better efficacy and expanded target space [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4702.

Experimental study of a multimechanism formation pressure prediction model influenced by shale content

The precise prediction of abnormally high-pressure formations has always been a hot topic in oil and gas exploration and development. In the Yingqiong Basin of the South China Sea, abnormally high-pressure formations are widespread, with narrow drilling safety windows and frequent accidents caused by the limited accuracy of formation pressure prediction. To improve the prediction accuracy of formation pressure, based on the characterization and classification method of the pressure forming mechanism of sediment and mechanics and considering the influence of shale content on pore pressure, in this study, soil consolidation acoustic experiments were carried out using real rock debris soil in a block of strata in this area. We obtained the response laws of parameters such as acoustic velocity and density under different pressure-forming mechanisms and established an acoustic density intersection chart exhibiting the influence of shale content. The experimental results show that under the same loading mechanism and conditions, the higher the shale content in the core is, the smaller the density, the smaller the acoustic velocity, and the smoother the trend line of the acoustic density intersection chart. When the shale content ≥0.5, under the unloading mechanism, the higher the shale content of the rock is, the further away the unloading trend line is from the loading trend line, and the greater the difference in the changes in the acoustic properties of the rock compared to the density properties. Moreover, the experimental conclusion also verified why the pressure formation mechanism in non-shale formations is difficult to determine. Based on the experimental results, the traditional Bowers model was improved, and a multimechanism formation pressure prediction model for the influence of shale content was established. The established model was validated and compared. The evaluation results showed that compared to the traditional model, the maximum prediction error of the multimechanism prediction model was reduced by approximately 20%, and the average prediction error was approximately 3%. This model effectively improved the prediction accuracy of the formation pore pressure.

Plasma Pharmacokinetics of N-Acetylgalactosamine-Conjugated Small-Interfering Ribonucleic Acids (GalNAc-Conjugated siRNAs).

Small-interfering ribonucleic acids (siRNAs) with N-acetylgalactosamine (GalNAc) conjugation for improved liver uptake represent an emerging class of drugs that modulate liver-expressed therapeutic targets. The pharmacokinetics of GalNAc-siRNAs are characterized by a rapid distribution from plasma to tissue (hours) and a long terminal plasma half-life, analyzed in the form of the antisense strand, driven by redistribution from tissue (weeks). Understanding how clinical pharmacokinetics relate to the dose and type of siRNA chemical stabilizing method used is critical, e.g., to design studies, to investigate safety windows, and to predict the pharmacokinetics of new preclinical assets. To this end, we collected and analyzed pharmacokinetic data from the literature regarding nine GalNAc-siRNAs. Based on this analysis, we showed that the clinical plasma pharmacokinetics ofGalNAc-siRNAs areapproximately dose proportional and similar between chemical stabilizing methods. This holds for both the area under the concentration-time curve (AUC) and the maximum plasma concentration (Cmax). Corresponding rat and monkey pharmacokinetic data for a subset of the nine GalNAc-siRNAs show dose-proportional Cmax, supra-dose-proportional AUC, and similar pharmacokinetics between chemical stabilizing methods​. Together, the animal and human pharmacokinetic data indicate that plasma clearance divided by bioavailability follows allometric principles and scales between species with an exponent of 0.75. Finally, the clinical plasma concentration-time profiles can be empirically described by standard one-compartment kinetics with first-order absorption up to 24h after subcutaneous dosing, and by three-compartment kinetics with first-order absorption in general. To describe the system more mechanistically, we report a corrected and unambiguously defined version of a previously published physiologically based pharmacokinetic model.

Multifunctional, bicontinuous, flexible comb copolymer electrolyte for solid-state supercapacitors

Solid electrolytes with high safety, good flexibility, and wide potential windows have attracted significant interest as alternatives to conventional liquid electrolytes, which have the disadvantages of flammability and leakage. Herein, we report a high-performance polymer electrolyte comprising a poly(isobornyl methacrylate)-co-poly(ethylene glycol) methyl ether methacrylate (PIBMA-co-PEGMA) (PIBEG) amphiphilic comb copolymer for solid-state supercapacitors (SCs). The PIBEG comb copolymer was synthesized via facile, inexpensive, and scalable free radical polymerization, followed by the incorporation of an ionic liquid (IL) to fabricate an ion-conducting flexible polymer electrolyte. Owing to the microphase-separated structure, the PIBEG films showed homogeneity and good flexibility up to 85 wt% of IL loading. The PIBEG/IL electrolytes had a bicontinuous, worm-like nanostructure with an ionic conductivity of 4.35 mS cm−1. The solid SC with PIBEG/IL electrolytes exhibited a specific capacitance of 48.6 F/g and an energy density of 37.12 Wh kg−1 at a power density of 1174 W kg−1, which are among the highest values reported for flexible solid SCs with conventional activated carbon electrodes. Furthermore, SCs could be fabricated without the use of separators or adhesives due to the multifunctional properties of PIBEG/IL electrolytes, including strong adhesion, high conductivity, and good mechanical strength.

Repurposing Metformin for Cancer Treatment: A Great Challenge of a Promising Drug.

The safety windows and toxicity of clinically available known drugs allow drug repurposing to be a popular treatment strategy for several diseases, including cancers. Several common drugs, e.g., metformin, statin, and aspirin are on clinical trials for repurposing in oncology treatment. Most of repurposed drugs, however, cannot be used as single agents and some do not exert any clinically significant effects. The limitations and possible biases from observational studies and preclinical models to repurpose these drugs are debatable. In this article, the limitations and probability of using metformin, one of the most repurposed drugs for cancer treatment and in oncological practice, are discussed.

Nonlinear analytical study of structural laminated glass under hard body impact in the pre-crack stage

Emerging glass structures, which frequently use laminated glass (LG) as load bearing elements, see a significant rise in recent decade. Existing analytical solutions for LG under impact present limitation when introduced into structural LG products, as structural LG having more glass plies and soft polymeric interlayers requires more accurate nonlinear analytical model. In this study, a nonlinear analytical model was proposed for the simply supported square structural LG subjected to hard body impact. The motion equations were established based on a third order shear deformation theory and von Kármán nonlinear strain–displacement relationship. Based on a two-step perturbation method, the solutions of the motion equations were obtained. The fourth-order Runge–Kutta method was used to capture the impact force variation. Drop weight impact tests with increasing impact velocity, were conducted to record the impact force of LG panels before breakage. Eighteen LG panels with PVB or SG interlayers were tested. Through analysing the fracture initiation from high speed photos as well as the impact force variation in the impact attempt causing fracture, certain feature of the experimental impact force response was determined to be validated with analytical prediction. The validation results show that the proposed model can well reproduce the examined feature and achieve satisfactory impact force response. Case study was then designed to investigate the influence due to the safety windows film on reducing the pre-crack impact response. The effective thickness of LG based on the equivalence of indentation was also proposed for the hard body impact.

Fine-Tuning the Biological Profile of Multitarget Mitochondriotropic Antioxidants for Neurodegenerative Diseases.

Neurotransmitter depletion and mitochondrial dysfunction are among the multiple pathological events that lead to neurodegeneration. Following our previous studies related with the development of multitarget mitochondriotropic antioxidants, this study aims to evaluate whether the π-system extension on the chemical scaffolds of AntiOXCIN2 and AntiOXCIN3 affects their bioactivity and safety profiles. After the synthesis of four triphenylphosphonium (TPP+) conjugates (compounds 2–5), we evaluated their antioxidant properties and their effect on neurotransmitter-metabolizing enzymes. All compounds were potent equine butyrylcholinesterase (eqBChE) and moderate electric eel acetylcholinesterase (eeAChE) inhibitors, with catechols 4 and 5 presenting lower IC50 values than AntiOXCIN2 and AntiOXCIN3, respectively. However, differences in the inhibition potency and selectivity of compounds 2–5 towards non-human and human cholinesterases (ChEs) were observed. Co-crystallization studies with compounds 2–5 in complex with human ChEs (hChEs) showed that these compounds exhibit different binging modes to hAChE and hBChE. Unlike AntiOXCINs, compounds 2–5 displayed moderate human monoamine oxidase (hMAO) inhibitory activity. Moreover, compounds 4 and 5 presented higher ORAC-FL indexes and lower oxidation potential values than the corresponding AntiOXCINs. Catechols 4 and 5 exhibited broader safety windows in differentiated neuroblastoma cells than benzodioxole derivatives 2 and 3. Compound 4 is highlighted as a safe mitochondria-targeted antioxidant with dual ChE/MAO inhibitory activity. Overall, this work is a contribution for the development of dual therapeutic agents addressing both mitochondrial oxidative stress and neurotransmitter depletion.

(Invited) Greener Supercapacitors: Aqueous Binders and Moisture Tolerant Electrolytes

Supercapacitors possess higher power densities than batteries and can therefore fill important gaps in applications extending from electric cars to grid stabilization. Accordingly, the market for the industrially most relevant type, electrical double layer capacitors (EDLCs), is estimated to grow to 3 billion US$ by 2025. With the widespreading of such technology, concerns about the environmental impact of EDLCs are unavoidably rising. Besides the use of greener materials, sustainable and low cost production processes, as well as easy end-of-life disposal need to be implemented. In this contribution, research on two highly relevant aspects will be presented: aqueous binders and electrolytes.[1]Binders hold together the active materials in EDLC electrodes, allowing high mass loadings while staying flexible. Suitable candidates are preferentially processable in water, cheap, and electrochemically stable, and show good rheological properties for the optimal coating of the current collectors. Within the ULTIMATE project, a national collaboration coordinated by a leading European manufacturer of EDLCs, it could be demonstrated that mixtures of natural polysaccharides such as starch and guar gum enable increased mass loadings with respect to conventional binder formulations.[2,3] Key to this improvement is the reduced shrinkage of the electrode coating upon drying, which causes severe cracking of thick coatings. Higher loading results in higher areal capacitance because the weight fraction of the active materials is larger compared to the inactive ones, e.g., the current collectors. Finally, the new binders were demonstrated inert towards several conventional and novel electrolytes and not affecting the device’s cycle life in long-term, voltage hold tests.The electrolyte choice has also a determining role with regards of environmental sustainability of the device, both with respect to processing and disposal. As traces of moisture can severely limit the electrochemical stability, electrolytes and assembled cells have to be thoroughly dried with energy intensive procedures. This is especially demanding in the case of ionic liquids. On the other hand, ionic liquids (IL) are often soluble in water and can therefore be recovered from end-of-life EDLCs with environmentally friendly and facile aqueous treatments, while volatile organic solvents need to be removed by more energy intensive heating. Regarding requirements for applications, electrolytes must also provide a wide electrochemical stability window in order to maximize energy density. They should ideally be non-flammable, non-toxic, and cheap. These approaches were then used to verify recent studies on the electrochemical stability of hydrophilic ionic liquids, in this case OTf- and BF4 - based ones. Interestingly, they suggested that hydrophilic ionic liquids with significant water content do not show increased decomposition reactions at elevated voltages, based on simulations and experiments on model carbon surfaces.[4] In more realistic setups closer to application, these results could be tentatively confirmed, suggesting cost and energy savings from a much-reduced need for drying of ionic liquids, while retaining the benefits of fire safety and large voltage windows.

SCC evaluation of composite materials for natural gas absorber based on experimental and numerical methods

Pressure vessel is a primary barrier to gathering system and an important guarantee for normal production in the oilfield. Composite materials for pressure vessels are widely used to adapt to acidic media and temperature and pressure environment. Therefore, the stress corrosion cracking (SCC) is easily caused considering harsh working condition and multi-material structure. Pressure vessel defect due to SCC can cause material strength degradation, medium leakage and even explosion. In order to analyze the stress distribution of the whole equipment and verify the crack detection results in the field, a detailed finite elements model (FEM) of the absorber considering the composite material is established based on mechanical experiments and field data. On the other hand, a WOL specimen FEM is established according to the industry standard. Finally, twelve SCC evaluation experiments of composite materials are carried out based on the results of two established FEM, and the safety windows of 316L and SA516-70 are obtained in specific stress corrosion environments. The work presented in this paper can offer a technological basis and theoretical foundation for strength design of composite materials for pressure vessels in sour environment.

Structure-Activity Relationship Studies on Diversified Salicylamide Derivatives as Potent Inhibitors of Human Adenovirus Infection.

The effective treatment of adenovirus (HAdV) infections in immunocompromised patients still poses great challenges. Herein, we reported our continued efforts to optimize a series of salicylamide derivatives as potent inhibitors of HAdV infection. Of these, nine compounds (11, 13, 14, 17, 20, 58, 60, 62, and 70) showed significantly improved anti-HAdV activities with nanomolar to submicromolar IC50 values and high selectivity indexes (SI > 100), indicating better safety windows, compared to those of the lead compound niclosamide. Our mechanistic assays suggest that compounds 13, 62, and 70 exert their activities in the HAdV entry pathway, while compounds 14 and 60 likely target the HAdV DNA replication, and 11, 17, 20, and 58 inhibit later steps after DNA replication. Given the broad anti-viral activity profile of niclosamide, these derivatives may also offer therapeutic potential for other viral infections.

Light-controllable dithienylethene-modified cyclic peptides: photoswitching the in vivo toxicity in zebrafish embryos.

This study evaluates the embryotoxicity of dithienylethene-modified peptides upon photoswitching, using 19 analogues based on the β-hairpin scaffold of the natural membranolytic peptide gramicidin S. We established an in vivo assay in two variations (with ex vivo and in situ photoisomerization), using larvae of the model organism Danio rerio, and determined the toxicities of the peptides in terms of 50% lethal doses (LD50). This study allowed us to: (i) demonstrate the feasibility of evaluating peptide toxicity with D. rerio larvae at 3–4 days post fertilization, (ii) determine the phototherapeutic safety windows for all peptides, (iii) demonstrate photoswitching of the whole-body toxicity for the dithienylethene-modified peptides in vivo, (iv) re-analyze previous structure–toxicity relationship data, and (v) select promising candidates for potential clinical development.

Simple Hamiltonian approach to describe large-amplitude and higher-order parametric resonances.

Parametric resonance is a complex phenomenon that touches many aspects of scientific and technical society, but is still not well understood because of the intensive calculations required to describe the behavior. Thus the importance of developing simple mathematical approaches to describe parametric resonance cannot be overstated. Here a consistent theory of the parametric resonance of a harmonic oscillator under any periodic frequency modulation is constructed. Using a Hamiltonian approach and resonance approximation, simple equations were derived and critical amplitudes for all parametric resonance orders were obtained for any periodic modulation function. The theory agrees with the well-known result for the main resonance and gives correct power dependence on damping. In addition, the theory qualitatively predicts behavior at large modulations. This simplified approach revealed unique features-"safety windows" at large modulation amplitudes where parametric resonance does not occur which were then qualitatively confirmed with numerical simulations. The Hamiltonian approach should serve as a framework that a greater understanding of parametric resonance at large amplitudes and higher orders can be built upon.

Intracellular Delivery of siRNAs Targeting AKT and ERBB2 Genes Enhances Chemosensitization of Breast Cancer Cells in a Culture and Animal Model.

Pharmacotherapy as the mainstay in the management of breast cancer suffers from various drawbacks, including non-targeted biodistribution, narrow therapeutic and safety windows, and also resistance to treatment. Thus, alleviation of the constraints from the pharmacodynamic and pharmacokinetic profile of classical anti-cancer drugs could lead to improvements in efficacy and patient survival in malignancies. Moreover, modifications in the genetic pathophysiology of cancer via administration of small nucleic acids might pave the way towards higher response rates to chemotherapeutics. Inorganic pH-dependent carbonate apatite (CA) nanoparticles were utilized in this study to efficiently deliver various classes of therapeutics into cancer cells. Co-delivery of drugs and genetic materials was successfully attained through a carbonate apatite delivery device. On 4T1 cells, siRNAs against AKT and ERBB2 plus paclitaxel or docetaxel resulted in the largest increase in anti-cancer effects compared to CA/paclitaxel or CA/docetaxel. Therefore, these ingredients were selected for further in vivo investigations. Animals receiving injections of CA/paclitaxel or CA/docetaxel loaded with siRNAs against AKT and ERBB2 possessed significantly smaller tumors compared to CA/drug-treated mice. Interestingly, synergistic interactions in target protein knock down with combinations of CA/AKT/paclitaxel, CA/ERBB2/docetaxel were documented via western blotting.

Abstract 3202: A probody drug conjugate targeting CD166 (ALCAM) enhances preclinical antitumor activity of a probody therapeutic targeting PD-1

Abstract Immune checkpoint blockade therapies have been shown to induce potent and durable anti-tumor immunity in many cancer types. Nevertheless, not all patients benefit from immunotherapy, and immune-related adverse events remain a problem. Recently, it has been demonstrated that Antibody Drug Conjugates (ADCs) are not only capable of killing cancer cells but also can act to induce the immunogenic cell death of tumor cells as well as directly activate dendritic cells. These results provided a rationale to combine ADCs with immunotherapy to enhance the potential of immune checkpoint blockade therapies in a broader population of patients. CytomX Therapeutics has developed a new class of antibodies called Probody™ therapeutics, designed to widen the therapeutic window by minimizing binding to target in healthy tissue while being specifically activated in the tumor microenvironment (TME) by tumor-associated proteases. Probody technology has been evaluated in preclinical studies in several antibody formats, with efficacy and increased safety windows observed for Probody therapeutics targeting the PD-1 pathway, Probody drug conjugates (PDCs) targeting highly expressed tumor antigens, and T-cell engaging bispecific Probody therapeutics. Here we extend our evaluation of the Probody platform to the combination of CX-2009, an investigational PDC targeting human CD166, with an investigational Probody therapeutic targeting PD-1. To evaluate the anti-tumor activity of PDC CX-2009 in a syngeneic mouse model, human CD166 was overexpressed on the surface of the CT-26 murine colon carcinoma cell line. The combination treatment of CX-2009 with a surrogate mouse anti-PD-1 Probody molecule significantly inhibited tumor growth in human CD166 positive CT-26 tumor-bearing mice as compared to CX-2009 or anti-PD-1 Probody molecule alone. Tumor rejection is partially dependent on CD8+ T cells as illustrated by the evidence of a CD8+ memory T cell response in a re-challenge assay, and a reduced activity of CX-2009 alone or in combination with a mouse anti-PD-1 Probody molecule after CD8+ T cell depletion. The immunogenic potential of CX-2009 was further evaluated in multiple in vitro assays using human cancer cells and human PBMCs. In contrast to its cytotoxic activity towards CD166+ tumor cells, CX-2009 spares T cells and may enhance T cell priming. These preclinical data demonstrate the potential utility of a combination of PDC CX-2009 with a Probody therapeutic targeting the PD-1 pathway. Generally, these data highlight the potential to combine ADCs or PDCs with immune checkpoint blockade therapies. PROBODY is a trademark of CytomX Therapeutics, Inc. Citation Format: Erwan Le Scolan, Tiffany Tse, Michael Krimm, Will Garner, Hikmat Assi, Jennifer Razo, Laurie Wong, Kenneth Wong, Victoria Singson, Jennifer Leong, Linnea Diep, Jennifer Richardson, Siew Schleyer, Dylan Daniel, Marcia Belvin, Michael Kavanaugh. A probody drug conjugate targeting CD166 (ALCAM) enhances preclinical antitumor activity of a probody therapeutic targeting PD-1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3202.

Cytotoxicity Enhancement in Breast Cancer Cells with Carbonate Apatite-Facilitated Intracellular Delivery of Anti-Cancer Drugs.

Pharmacotherapy as the mainstay in the management of breast cancer has demonstrated various drawbacks, including non-targeted bio distribution and narrow therapeutic and safety windows. Thus, enhancements in pharmacodynamic and pharmacokinetic profiles of the classical anti-cancer drugs could lead to improved efficacy against cancer cells. Therefore, inorganic pH-dependent carbonate apatite (CA) nanoparticles were utilized to efficiently deliver various drugs into cancer cells. Following characterization and various modifications in the structure of CA complexes with different drugs, lifted outcomes were achieved. Markedly, complexing paclitaxel with CA resulted in 20.71 ± 4.34% loading efficiency together with 24.14 ± 2.21% enhancement in cytotoxicity on MCF-7 cells plus superior in vivo anti-tumour efficacy compared to free paclitaxel.

Discovery and development of pyrotinib: A novel irreversible EGFR/HER2 dual tyrosine kinase inhibitor with favorable safety profiles for the treatment of breast cancer

The discovery and development of a novel irreversible EGFR/HER2 dual tyrosine kinase inhibitor SHR1258 (pyrotinib) for the treatment of HER2-postive breast cancer is presented. The structure-activity relationship of lead series and their pharmacokinetic properties were evaluated to identify the potential candidates for further in vivo efficacy studies and preclinical safety assessments. Metabolic pathway and drug-drug interaction were also investigated in preclinical settings. In particular, major metabolites in human and animal species were assessed with regard to potential toxicity or off-target side effects. Overall, the potent and selective EGFR/HER2 dual inhibitor, pyrotinib, displayed robust anti-tumor effects on HER2-overexpressing xenograft models and sufficiently safety windows in animals as well as favorable pharmacokinetic properties in human, which substantially ensures current clinical development. Finally, recent advances of pyrotinib in clinical studies are highlighted with very encouraging outcomes in patients with HER2-postive advanced breast cancer.

Ionic liquid hybrids: Progress toward non-corrosive electrolytes with high-voltage oxidation stability for magnesium-ion based batteries

Magnesium – ion batteries have the potential for high energy density but require new types of electrolytes for practical application. Ionic liquid (IL) electrolytes offer the opportunity for increased safety and broader voltage windows relative to traditional electrolytes. We present here a systematic study of both the conductivity and oxidative stability of hybrid electrolytes consisting of eleven ILs mixed with dipropylene glycol dimethylether (DPGDME) or acetonitrile (ACN) cosolvents and magnesium bis(trifluoromethylsulfonyl)imide (Mg(TFSI)2). Our study finds a correlation of higher conductivity of ILs with unsaturated rings and short carbon chain lengths, but by contrast, these ILs also exhibited lower oxidation voltage limits. For the cosolvent additive, although glymes have a demonstrated capability of coordination with Mg2+ ions, a decrease in conductivity compared to acetonitrile hybrid electrolytes was observed. When cycled within the appropriate voltage range, the IL-hybrid electrolytes that show the highest conductivity provide the best cathode magnesiation current densities and lowest polarization as demonstrated with a Mg0.15MnO2 and Mg0.07V2O5 cathodes.

5-Hydroxy-7-azaindolin-2-one, a novel hybrid of pyridinol and sunitinib: design, synthesis and cytotoxicity against cancer cells.

Angiogenesis plays important roles in tumor growth and metastasis. Sunitinib (Sutent®) is an antitumor agent targeting receptor tyrosine kinases which are involved in angiogenesis as well as cancer cell growth and survival. Using the pyridin-3-ol scaffold, which was previously reported as an excellent antioxidant and antiangiogenic platform, we have synthesized sunitinib mimics 6 by hybridizing bicyclic pyridinol 4 as a key scaffold and pyrrole-2-carbaldehydes 7 as side chains. Cytotoxicity assays showed that compounds 6 have comparable to better anticancer activity than sunitinib against five different cancer cell lines. In addition, compounds 6 showed even lower levels of cytotoxicity against normal cells, resulting in up to 26-fold better safety windows, than sunitinib. Signaling pathway-associated transcription factor reporter assay and western blot analyses revealed that apoptosis induction in MDA-MB-231 human breast cancer cells by 6F is mainly mediated through the p53 increase and down-regulation of phospho-signal transducer and activator of transcription 3 (STAT3) and its target gene products, cyclin D, Bcl-2, and survivin. The data strongly suggest that our hybrid compounds can provide a novel anticancer scaffold with improved and safer cytotoxicity profiles than sunitinib.