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A double-edged sword: The complex interplay between engineered nanoparticles and platelets 双刃剑:工程纳米粒子与血小板之间复杂的相互作用
IF 6.1 2区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-04-06 DOI: 10.1002/btm2.10669
Yathreb Asaad, Danielle Nemcovsky-Amar, Josué Sznitman, Pierre H. Mangin, Netanel Korin

Nanoparticles (NP) play a crucial role in nanomedicine, serving as carriers for localized therapeutics to allow for precise drug delivery to specific disease sites and conditions. When injected systemically, NP can directly interact with various blood cell types, most critically with circulating platelets. Hence, the potential activation/inhibition of platelets following NP exposure must be evaluated a priori due to possible debilitating outcomes. In recent years, various studies have helped resolve the physicochemical parameters that influence platelet-NP interactions, and either emphasize nanoparticles' therapeutic role such as to augment hemostasis or to inhibit thrombus formation, or conversely map their potential undesired side effects upon injection. In the present review, we discuss some of the main effects of several key NP types including polymeric, ceramic, silica, dendrimers and metallic NPs on platelets, with a focus on the physicochemical parameters that can dictate these effects and modulate the therapeutic potential of the NP. Despite the scientific and clinical significance of understanding Platelet-NP interactions, there is a significant knowledge gap in the field and a critical need for further investigation. Moreover, improved guidelines and research methodologies need to be developed and implemented. Our outlook includes the use of biomimetic in vitro models to investigate these complex interactions under both healthy physiological and disease conditions.

纳米粒子(NP)在纳米医学中发挥着至关重要的作用,它是局部治疗药物的载体,可将药物精确输送到特定的疾病部位和病症。在全身注射时,纳米粒子可直接与各种血细胞相互作用,其中最重要的是与循环中的血小板相互作用。因此,必须事先评估接触 NP 后血小板的潜在激活/抑制作用,因为这可能会导致衰弱。近年来,各种研究帮助解决了影响血小板与 NP 相互作用的理化参数,并强调了纳米粒子的治疗作用,如增强止血或抑制血栓形成,或反过来描绘了其注射后的潜在不良副作用。在本综述中,我们讨论了几种主要 NP 类型(包括聚合物、陶瓷、二氧化硅、树枝状聚合物和金属 NP)对血小板的一些主要影响,重点是能决定这些影响并调节 NP 治疗潜力的理化参数。尽管了解血小板-NP 相互作用具有重要的科学和临床意义,但该领域仍存在巨大的知识差距,亟需进一步研究。此外,还需要制定和实施更好的指南和研究方法。我们的展望包括使用仿生体外模型来研究这些在健康生理和疾病条件下的复杂相互作用。
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引用次数: 0
Ultrasound inhibits tumor growth and selectively eliminates malignant brain tumor in vivo 超声波抑制肿瘤生长并选择性消除体内恶性脑肿瘤
IF 6.1 2区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-04-01 DOI: 10.1002/btm2.10660
Nitsa Buaron, Antonella Mangraviti, Yuan Wang, Ann Liu, Mariangela Pedone, Eric Sankey, Itay Adar, Abraham Nyska, Riki Goldbart, Tamar Traitel, Henry Brem, Betty Tyler, Joseph Kost

Glioma is one of the most common primary malignant brain tumors. Despite progress in therapeutic approaches, the median survival of patients with glioma remains less than 2 years, generating the need for new therapeutic approaches. Ultrasound (US) is widely used in medical fields and is used as a therapeutic tool mainly for improving the performance of therapeutic entities. In this study, we examined a novel approach using low frequency US (20 kHz) (LFUS) as an independent treatment tool for malignant glioma, since primary studies showed that cancer cells are more susceptible to LFUS than healthy cells. LFUS safety and efficacy were examined in a 9L gliosarcoma-bearing female Fischer 344 rats. Two LFUS protocols were examined: a one-time treatment (US1X), and two treatments 24 h apart (US2X). For safety evaluation, rats were monitored for weight change and pain measurements. For efficacy, tumor volume was measured as a function of time and the tumor structural chances were examined histopathologically. LFUS treatment showed rapid inhibition of tumor growth, seen as soon as 12 h after US application. In addition, LFUS was found to affect the tumor structure, which was more extensive (>60% of tumor area) in smaller tumors. In US2X, the tumor tissue was completely destroyed, and an extensive immune response was observed. Importantly, the treatment was highly selective, keeping the healthy tissue surrounding the tumor unharmed. We developed a highly efficient and selective therapeutic protocol for treating malignant glioma with minimal side effects based solely on LFUS.

胶质瘤是最常见的原发性恶性脑肿瘤之一。尽管治疗方法取得了进展,但胶质瘤患者的中位生存期仍不足 2 年,因此需要新的治疗方法。超声波(US)被广泛应用于医疗领域,作为一种治疗工具,主要用于改善治疗实体的性能。在本研究中,我们研究了一种使用低频 US(20 kHz)(LFUS)作为恶性胶质瘤独立治疗工具的新方法,因为初步研究显示癌细胞比健康细胞更容易受到 LFUS 的影响。研究人员以雌性费舍尔 344 大鼠为研究对象,对 9L 脑胶质瘤的安全性和有效性进行了研究。实验采用了两种 LFUS 方案:一次性治疗(US1X)和间隔 24 小时的两次治疗(US2X)。在安全性评估方面,对大鼠的体重变化和疼痛测量进行监测。疗效方面,测量肿瘤体积与时间的关系,并从组织病理学角度检查肿瘤的结构变化。LFUS 治疗可迅速抑制肿瘤生长,在使用 US 后 12 小时内就可看到。此外,LFUS 对肿瘤结构也有影响,在较小的肿瘤中,LFUS 对肿瘤结构的影响更为广泛(占肿瘤面积的 60%)。在 US2X 中,肿瘤组织被完全破坏,并观察到广泛的免疫反应。重要的是,治疗具有高度的选择性,肿瘤周围的健康组织没有受到伤害。我们开发出了一种高效、选择性强的治疗方案,仅靠 LFUS 就能治疗副作用极小的恶性胶质瘤。
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引用次数: 0
Development of a novel glucose-dendrimer based therapeutic targeting hyperexcitable neurons in neurological disorders 开发基于葡萄糖二聚体的新型疗法,靶向治疗神经系统疾病中的过度兴奋神经元
IF 6.1 2区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-03-26 DOI: 10.1002/btm2.10655
Anjali Sharma, Nirnath Sah, Rishi Sharma, Preeti Vyas, Wathsala Liyanage, Sujatha Kannan, Rangaramanujam M. Kannan

Neuronal hyperexcitability and excitotoxicity lies at the core of debilitating brain disorders such as epilepsy and traumatic brain injury, culminating in neuronal death and compromised brain function. Overcoming this challenge requires a unique approach that selectively restores normal neuronal activity and rescues neurons from impending damage. However, delivering drugs selectively to hyperexcitable neurons has been a challenge, even upon local administration. Here, we demonstrate the remarkable ability of a novel, scalable, generation-two glucose-dendrimer (GD2) made primarily of glucose and ethylene glycol building blocks, to specifically target hyperexcitable neurons in primary culture, ex vivo acute brain slices, and in vivo mouse models of acute seizures. Pharmacology experiments in ex vivo brain slices suggest GD2 uptake in neurons is mediated through glucose transporters (GLUT and SGLT). Inspired by these findings, we conjugated GD2 with a potent anti-epileptic drug, valproic acid (GD2–VPA), for efficacy studies in the pilocarpine-mouse model of seizure. When delivered intranasally, GD2–VPA significantly decreased the seizure-severity. In summary, our findings demonstrate the unique selectivity of glucose dendrimers in targeting hyperexcitable neurons, even upon intranasal delivery, laying the foundation for neuron-specific therapies for the precise protection and restoration of neuronal function, for targeted neuroprotection.

神经元过度兴奋和兴奋毒性是癫痫和创伤性脑损伤等令人衰弱的脑部疾病的核心,最终导致神经元死亡和脑功能受损。要克服这一挑战,需要一种独特的方法,选择性地恢复神经元的正常活动,并将神经元从即将发生的损伤中解救出来。然而,选择性地向过度兴奋的神经元输送药物一直是个难题,即使是局部给药也是如此。在这里,我们展示了一种新型、可扩展的二代葡萄糖二聚体(GD2)的非凡能力,这种二聚体主要由葡萄糖和乙二醇结构单元组成,能在原代培养、体外急性脑切片和体内急性癫痫小鼠模型中特异性地靶向兴奋过度的神经元。体外脑片的药理实验表明,神经元对 GD2 的吸收是通过葡萄糖转运体(GLUT 和 SGLT)介导的。受这些发现的启发,我们将 GD2 与一种强效抗癫痫药物丙戊酸(GD2-VPA)共轭,用于皮洛卡品小鼠癫痫模型的药效研究。经鼻给药后,GD2-VPA 能显著降低癫痫发作的严重程度。总之,我们的研究结果表明,葡萄糖树突状分子具有独特的选择性,即使在鼻内给药时也能靶向过度兴奋的神经元,这为神经元特异性疗法奠定了基础,可精确保护和恢复神经元功能,实现有针对性的神经保护。
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引用次数: 0
Vaccine adjuvants for infectious disease in the clinic 临床中的传染病疫苗佐剂
IF 6.1 2区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-03-22 DOI: 10.1002/btm2.10663
Morgan Goetz, Naaz Thotathil, Zongmin Zhao, Samir Mitragotri

Adjuvants, materials added to vaccines to enhance the resulting immune response, are important components of vaccination that are many times overlooked. While vaccines always include an antigen to tell the body what to vaccinate to, of equal importance the adjuvant provides the how, a significant factor in producing a complete response. The adjuvant space has been slow to develop with the first use of an adjuvant in a licensed vaccine occurring in the 1930s, and remaining the only adjuvant in licensed vaccines for the next 80 years. However, with vaccination at the forefront of protection against new and complex pathogens, it is important to consider all components when designing an effective vaccine. Here we summarize the adjuvant space in licensed vaccines as well as the novel adjuvant space in clinical trials with a specific focus on the materials utilized and their resulting impact on the immune response. We discuss five major categories of adjuvant materials: aluminum salts, nanoparticles, viral vectors, TLR agonists, and emulsions. For each category, we delve into the current clinical trials space, the impact of these materials on vaccination, as well as some of the ways in which they could be improved. Adjuvants present an exciting opportunity to improve vaccine responses and stability, this review will help inform about the current progress of this space.

Translational impact statement

In the aftermath of the COVID-19 pandemic, vaccines for infectious diseases have come into the spotlight. While antigens have always been an important focus of vaccine design, the adjuvant is a significant tool for enhancing the immune response to the vaccine that has been largely underdeveloped. This article provides a broad review of the history of adjuvants and, the current vaccine adjuvant space, and the progress seen in adjuvants in clinical trials. There is specific emphasis on the material landscape for adjuvants and their resulting mechanism of action. Looking ahead, while the novel vaccine adjuvant space features exciting new technologies and materials, there is still a need for more to meet the protective needs of new and complex pathogens.

佐剂是添加到疫苗中以增强免疫反应的材料,是疫苗接种的重要组成部分,但却常常被忽视。虽然疫苗总是包含抗原,告诉身体接种什么疫苗,但同样重要的是佐剂提供了如何接种的方法,这是产生完整反应的一个重要因素。佐剂领域的发展一直很缓慢,20 世纪 30 年代首次在许可疫苗中使用佐剂,此后的 80 年中,佐剂一直是许可疫苗中的唯一佐剂。然而,由于疫苗接种是抵御新型复杂病原体的最前沿,因此在设计有效疫苗时必须考虑到所有成分。在此,我们总结了许可疫苗中的佐剂领域以及临床试验中的新型佐剂领域,并特别关注所使用的材料及其对免疫反应的影响。我们将讨论五大类佐剂材料:铝盐、纳米颗粒、病毒载体、TLR 激动剂和乳剂。对于每一类佐剂,我们都会深入探讨当前的临床试验领域、这些材料对疫苗接种的影响以及一些可以改进的方法。佐剂为改善疫苗反应和稳定性提供了一个令人兴奋的机会,本综述将有助于了解该领域目前的进展情况。
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引用次数: 0
Human induced pluripotent stem cells-derived liver organoids grown on a Biomimesys® hyaluronic acid-based hydroscaffold as a new model for studying human lipoprotein metabolism 在基于透明质酸的 Biomimesys® hydroscaffold 上生长的人类诱导多能干细胞衍生肝脏器官组织是研究人类脂蛋白代谢的新模型
IF 6.1 2区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-03-16 DOI: 10.1002/btm2.10659
Meryl Roudaut, Amandine Caillaud, Zied Souguir, Lise Bray, Aurore Girardeau, Antoine Rimbert, Mikaël Croyal, Gilles Lambert, Murielle Patitucci, Gaspard Delpouve, Élodie Vandenhaute, Cédric Le May, Nathalie Maubon, Bertrand Cariou, Karim Si-Tayeb

The liver plays a key role in the metabolism of lipoproteins, controlling both production and catabolism. To accelerate the development of new lipid-lowering therapies in humans, it is essential to have a relevant in vitro study model available. The current hepatocyte-like cells (HLCs) models derived from hiPSC can be used to model many genetically driven diseases but require further improvement to better recapitulate the complexity of liver functions. Here, we aimed to improve the maturation of HLCs using a three-dimensional (3D) approach using Biomimesys®, a hyaluronic acid-based hydroscaffold in which hiPSCs may directly form aggregates and differentiate toward a functional liver organoid model. After a 28-day differentiation 3D protocol, we showed that many hepatic genes were upregulated in the 3D model (liver organoids) in comparison with the 2D model (HLCs). Liver organoids, grown on Biomimesys®, exhibited an autonomous cell organization, were composed of different cell types and displayed enhanced cytochromes P450 activities compared to HLCs. Regarding the functional capacities of these organoids, we showed that they were able to accumulate lipids (hepatic steatosis), internalize low-density lipoprotein and secrete apolipoprotein B. Interestingly, we showed for the first time that this model was also able to produce apolipoprotein (a), the apolipoprotein (a) specific of Lp(a). This innovative hiPSC-derived liver organoid model may serve as a relevant model for studying human lipopoprotein metabolism, including Lp(a).

肝脏在脂蛋白的代谢中起着关键作用,控制着脂蛋白的生成和分解。要加快开发新的人体降脂疗法,必须有相关的体外研究模型。目前由 hiPSC 衍生的肝细胞样细胞(HLCs)模型可用于模拟许多基因驱动的疾病,但需要进一步改进才能更好地再现肝脏功能的复杂性。在这里,我们的目标是使用一种三维(3D)方法来改善 HLCs 的成熟,该方法使用了一种基于透明质酸的水支架 Biomimesys®,hiPSC 可在其中直接形成聚集体并向功能性肝脏类器官模型分化。经过 28 天的三维分化后,我们发现与二维模型(HLCs)相比,三维模型(肝脏器官组织)中的许多肝脏基因上调。与 HLCs 相比,在 Biomimesys® 上生长的肝脏器官组织表现出自主的细胞组织,由不同类型的细胞组成,并显示出更强的细胞色素 P450 活性。关于这些器官组织的功能能力,我们发现它们能够积聚脂质(肝脏脂肪变性)、内化低密度脂蛋白并分泌脂蛋白B。有趣的是,我们首次发现这种模型还能产生脂蛋白(a),即脂蛋白(a)的特异性脂蛋白。这种创新的 hiPSC 衍生肝脏类器官模型可作为研究人类脂蛋白代谢(包括脂蛋白(a))的相关模型。
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引用次数: 0
Tolerability of a piezoelectric microneedle electroporator in human subjects 压电微针电穿孔器在人体中的耐受性
IF 6.1 2区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-03-14 DOI: 10.1002/btm2.10662
Chao-Yi Lu, Pankaj Rohilla, Eric I. Felner, Gaurav Byagathvalli, Erkan Azizoglu, M. Saad Bhamla, Mark R. Prausnitz

Electroporation, or the use of electric pulses to facilitate the intracellular delivery of DNA, RNA, and other molecules, is a well-established technique, that has been demonstrated to significantly augment the immunogenicity of DNA/mRNA vaccines and therapeutics. However, the clinical translation of traditional electroporators has been limited due to high costs, large size, complex user operation, and poor tolerability in humans due to nerve stimulation. In prior work, we introduced ePatch: an ultra-low-cost, handheld, battery-free electroporator employing a piezoelectric pulser coupled with a microneedle electrode array that showed enhanced immunogenic responses to an intradermal SARS-CoV-2 DNA vaccine in mice. The current study shifts focus from efficacy to tolerability, hypothesizing that ePatch's microneedle array, which localizes the electric field to the superficial skin strata, will minimize nerve stimulation and improve patient comfort. We tested this hypothesis in 14 healthy adults, monitoring pain and other potential adverse effects associated with electroporation. Compared to the insertion of a traditional hypodermic needle, the ePatch was less painful. Adverse effects such as pain, tenderness, erythema and swelling at the application sites were minimal, transient, and statistically indistinguishable between the experimental and placebo ePatch application, suggesting excellent tolerability towards electroporation. In summary, ePatch has a favorable tolerability profile in humans and offers the potential for the safe use of electroporation in a variety of clinical settings, including DNA and mRNA vaccination.

电穿孔,即使用电脉冲促进 DNA、RNA 和其他分子的细胞内输送,是一种成熟的技术,已被证明可显著增强 DNA/mRNA 疫苗和疗法的免疫原性。然而,由于成本高、体积大、用户操作复杂以及神经刺激对人体的耐受性差等原因,传统电穿孔器的临床应用一直受到限制。在之前的工作中,我们介绍了 ePatch:一种超低成本、手持式、无电池的电穿孔器,采用压电脉冲器与微针电极阵列相结合,在小鼠皮内注射 SARS-CoV-2 DNA 疫苗后显示出增强的免疫原性反应。目前的研究将重点从疗效转移到了耐受性上,假设 ePatch 的微针阵列能将电场定位到皮肤浅层,从而最大限度地减少对神经的刺激,提高患者的舒适度。我们在 14 名健康成年人身上测试了这一假设,并监测了电穿孔带来的疼痛和其他潜在不良反应。与传统的皮下注射针相比,ePatch 的疼痛感更小。施用 ePatch 时,施用部位的疼痛、触痛、红斑和肿胀等不良反应极小,而且是一过性的,施用实验用 ePatch 与施用安慰剂在统计学上没有区别,这表明电穿孔具有极佳的耐受性。总之,ePatch 在人体中具有良好的耐受性,有望在各种临床环境中安全使用电穿孔,包括 DNA 和 mRNA 疫苗接种。
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引用次数: 0
Evaluation of a novel vaginal cells self-sampling device for human papillomavirus testing in cervical cancer screening: A clinical trial assessing reliability and acceptability 评估用于宫颈癌筛查中人类乳头瘤病毒检测的新型阴道细胞自采样装置:评估可靠性和可接受性的临床试验
IF 6.1 2区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-03-13 DOI: 10.1002/btm2.10653
Chung-Yao Yang, Ting-Chang Chang, Hung-Hsueh Chou, Angel Chao, Shih-Tien Hsu, Yu-Hsiang Shih, Huei-Jean Huang, Cheng-Tao Lin, Min-Yu Chen, Lou Sun, Kuan-Gen Huang, Kai-Yun Wu, Wu-Chiao Hsieh, Yi-Ting Huang, Liang-Hsuan Chen, Chien-Hsing Lu, Hao Lin, Chao-Min Cheng

Cervical cancer is a significant public health concern, particularly in low- and middle-income countries where resources for prevention and treatment are limited. Routine screening, such as the Papanicolaou test (Pap smears) and human papillomavirus (HPV) testing, plays a crucial role in the early detection and prevention of cervical cancer. However, the participation rate in cervical cancer screening programs remains below optimal levels due to various factors. This study aimed to evaluate the reliability and acceptability of the HygeiaTouch Self Sampling Kit for Women in collecting vaginal samples for HPV typing, comparing the results with samples collected by physicians. The study included 1210 women aged 21–65 from three medical centers in Taiwan. The findings indicated that the self-sampling kit was as effective as physician-collected specimens in terms of obtaining valid samples and identifying HPV. The agreement between the two methods was 88%, with a κ value of 0.75. Furthermore, the study assessed the mechanical characteristics of the self-sampling applicator through tensile, bending, and torque tests, and determined that it was safe for intravaginal use. Additionally, the study evaluated the safety and satisfaction of self-sampling and found a low rate of adverse events (0.7%) and high levels of satisfaction (over 90%) among participants. Overall, we demonstrated that the HygeiaTouch Self Sampling Kit for Women is a reliable and acceptable device for HPV testing and cervical screening, providing a convenient, safe, and effective alternative for women.

宫颈癌是一个重大的公共卫生问题,尤其是在中低收入国家,因为这些国家用于预防和治疗的资源有限。常规筛查,如巴氏涂片检查(Papanicolaou test)和人类乳头瘤病毒(HPV)检测,在早期发现和预防宫颈癌方面发挥着至关重要的作用。然而,由于各种因素的影响,宫颈癌筛查项目的参与率仍未达到最佳水平。本研究旨在评估 HygeiaTouch 女性自我采样套件在采集阴道样本进行 HPV 分型时的可靠性和可接受性,并将结果与医生采集的样本进行比较。研究对象包括来自台湾三家医疗中心的 1210 名 21-65 岁女性。研究结果表明,在获取有效样本和鉴定 HPV 方面,自我采样工具包与医生采集的样本同样有效。两种方法的一致性为 88%,κ值为 0.75。此外,该研究还通过拉伸、弯曲和扭矩测试评估了自采样涂抹器的机械特性,并确定其在阴道内使用是安全的。此外,该研究还评估了自我采样的安全性和满意度,发现不良事件发生率低(0.7%),参与者满意度高(超过 90%)。总之,我们证明了 HygeiaTouch 女性自我采样套件是一种可靠、可接受的 HPV 检测和宫颈筛查设备,为女性提供了一种方便、安全、有效的选择。
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引用次数: 0
Synchronously in vivo real-time monitoring bacterial load and temperature with evaluating immune response to decipher bacterial infection 体内实时监测细菌负荷和温度,同时评估免疫反应,破解细菌感染难题
IF 6.1 2区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-03-12 DOI: 10.1002/btm2.10656
Huaixuan Sheng, Huizhu Li, Shunyao Li, Chengxuan Yu, Yueming Wang, Haichen Hu, Lu Fang, Fuchun Chen, Yanyan Lu, Xiaogang Xu, Xing Yang, Shiyi Chen, Yuefeng Hao, Yunxia Li, Sijia Feng, Jun Chen

Determining the precise course of bacterial infection requires abundant in vivo real-time data. Synchronous monitoring of the bacterial load, temperature, and immune response can satisfy the shortage of real-time in vivo data. Here, we conducted a study in the joint-infected mouse model to synchronously monitor the bacterial load, temperature, and immune response using the second near-infrared (NIR-II) fluorescence imaging, infrared thermography, and immune response analysis for 2 weeks. Staphylococcus aureus (S. aureus) was proved successfully labeled with glucose-conjugated quantum dots in vitro and in subcutaneous-infected model. The bacterial load indicated by NIR-II fluorescence imaging underwent a sharp drop at 1 day postinfection. At the same time, the temperature gap detected through infrared thermography synchronously brought by infection reached lowest value. Meanwhile, the flow cytometry analysis demonstrated that immune response including macrophage, neutrophil, B lymphocyte, and T lymphocyte increased to the peak at 1 day postinfection. Moreover, both M1 macrophage and M2 macrophage in the blood have an obvious change at ~ 1 day postinfection, and the change was opposite. In summary, this study not only obtained real-time and long-time in vivo data on the bacterial load, temperature gap, and immune response in the mice model of S. aureus infection, but also found that 1 day postinfection was the key time point during immune response against S. aureus infection. Our study will contribute to synchronously and precisely studying the complicated complex dynamic relationship after bacterial infection at the animal level.

确定细菌感染的精确过程需要丰富的体内实时数据。对细菌载量、温度和免疫反应进行同步监测可以满足实时活体数据不足的问题。在此,我们在关节感染小鼠模型中进行了一项研究,利用第二次近红外(NIR-II)荧光成像、红外热成像和免疫反应分析,对细菌负荷、温度和免疫反应进行了为期两周的同步监测。金黄色葡萄球菌(S. aureus)在体外和皮下感染模型中被证明成功标记了葡萄糖结合量子点。感染后 1 天,近红外-II 荧光成像显示的细菌量急剧下降。与此同时,通过红外热成像检测到的温度差也同步达到了感染后的最低值。同时,流式细胞术分析表明,巨噬细胞、中性粒细胞、B 淋巴细胞和 T 淋巴细胞的免疫反应在感染后 1 天达到高峰。此外,血液中的 M1 巨噬细胞和 M2 巨噬细胞在感染后约 1 天均有明显变化,且变化方向相反。综上所述,本研究不仅获得了金黄色葡萄球菌感染小鼠模型体内细菌负荷、温差和免疫反应的实时、长时间数据,而且发现感染后1天是金黄色葡萄球菌感染免疫反应的关键时间点。我们的研究将有助于在动物水平上同步、精确地研究细菌感染后复杂的动态关系。
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引用次数: 0
Siglec15/TGF-β bispecific antibody mediates synergistic anti-tumor response against 4T1 triple negative breast cancer in mice Siglec15/TGF-β 双特异性抗体介导小鼠对 4T1 三阴性乳腺癌的协同抗肿瘤反应
IF 6.1 2区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-03-11 DOI: 10.1002/btm2.10651
Limei Shen, Alison M. Schaefer, Karthik Tiruthani, Whitney Wolf, Samuel K. Lai

An ideal tumor-specific immunomodulatory therapy should both preferentially target the tumor, while simultaneously reduce the immunosuppressive environment within the tumor. This guiding principle led us to explore engineering Siglec-15 (S15) targeted bispecific antibody (bsAb) to enhance therapy against triple negative breast cancer (TNBC). S15 appears to be exclusively expressed on macrophages and diverse tumor cells, including human and mouse 4T1 TNBC. TGF-β is a growth hormone frequently associated with increased tumor invasiveness, including in TNBC. Here, to overcome the immune-suppressive environment within TNBC tumors to enable more effective cancer therapy, we engineered a bispecific antibody (bsAb) targeting both Siglec15 and TGF-β. In mice engrafted with orthotopic 4T1 tumors, S15/TGF-β bsAb treatment was highly effective in suppressing tumor growth, not only compared to control monoclonal antibody (mAb) but also markedly more effective than mAbs against S15 alone, against TGF-β alone, as well as a cocktail of both anti-S15 and anti-TGF-β mAbs. We did not detect liver and lung metastasis in mice treated with S15/TGF-β bsAb, unlike all other treatment groups at the end of the study. The enhanced anti-tumor response observed with S15/TGF-β bsAb correlated with a less immunosuppressive environment in the tumor. These results underscore S15-targeted bsAb as a promising therapeutic strategy for TNBC, and possibly other S15 positive solid tumors.

理想的肿瘤特异性免疫调节疗法应该既能优先靶向肿瘤,又能减少肿瘤内的免疫抑制环境。在这一指导原则的指引下,我们开始探索设计 Siglec-15(S15)靶向双特异性抗体(bsAb),以加强对三阴性乳腺癌(TNBC)的治疗。S15 似乎只在巨噬细胞和多种肿瘤细胞(包括人类和小鼠 4T1 TNBC)上表达。TGF-β 是一种生长激素,经常与肿瘤侵袭性增加有关,包括在 TNBC 中。在这里,为了克服 TNBC 肿瘤内的免疫抑制环境以实现更有效的癌症治疗,我们设计了一种同时靶向 Siglec15 和 TGF-β 的双特异性抗体(bsAb)。在移植了正位 4T1 肿瘤的小鼠中,S15/TGF-β bsAb 治疗在抑制肿瘤生长方面非常有效,不仅与对照组单克隆抗体(mAb)相比效果更好,而且明显优于单独针对 S15 的 mAb、单独针对 TGF-β 的 mAb 以及抗 S15 和抗 TGF-β mAb 的鸡尾酒。与所有其他治疗组不同的是,在研究结束时,我们没有在使用S15/TGF-β bsAb治疗的小鼠身上发现肝脏和肺部转移。观察到的 S15/TGF-β bsAb 抗肿瘤反应的增强与肿瘤中较少的免疫抑制环境有关。这些结果表明,S15 靶向 bsAb 是治疗 TNBC 以及其他可能的 S15 阳性实体瘤的一种很有前景的治疗策略。
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引用次数: 0
Correction to “Primary T-cell-based delivery platform for in vivo synthesis of engineered proteins” 对 "基于初级 T 细胞的体内合成工程蛋白质的输送平台 "的更正
IF 6.1 2区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-03-10 DOI: 10.1002/btm2.10658

Radhakrishnan H, Newmyer SL, Ssemadaali MA, Javitz HS, Bhatnagar P. Primary T-cell-based delivery platform for in vivo synthesis of engineered proteins. Bioeng Transl Med. 2024; 9(1):e10605. doi:10.1002/btm2.10605

4.10 In vivo validation of delivery function of the engineered T cells (engineered for delivery function with NFAT-RE delivery system). The in vivo validation of our T-cell based delivery system was performed in mice at SRI International in accordance with the guidelines from the Institutional Animal Care and Use Committee (Approval # 22001). Six- to 8-week-old female NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice were purchased from The Jackson Laboratory. After mandatory quarantine, the NSG mice were anesthetized and 2 × 106 FRα+Luc2-2A-E2Crimson+A2780cis cells in 100 μL 1× PBS were i.p. implanted. The tumor growth was monitored every 3–4 days for the next 12 days using i.p. injected 150 mg d-Luciferin per kg of mouse dissolved in 1× PBS. At 11 days after implantation, the mice were randomized into two groups (n = 5 each). The two groups were then treated with 2 × 106 primary CD4 T cells engineered for delivery function (i.e., FRα-CAR with NFAT-RE inducible Nluc reporter) or the control primary CD4 T cells (FRα-CAR only, i.e., without NFAT-RE inducible Nluc reporter) every day for 5 days. The bioluminescent reporter (Nluc) activity was determined by i.p. injection of the Nano-Glo® substrate (1:20 dilution of the substrate in 1× PBS, equivalent to 0.5 mg per kg of mouse) on Days 0, 1, 2, 3, 4, and 5 after treatment. Imaging was performed in a IVIS Lumina X5 imaging system. The data were quantified by analysis of the ROI using Living Image software. The tumor luminescence is plotted as the mean ± SEM of total flux (photons/s) against days after treatment.

Radhakrishnan H、Newmyer SL、Ssemadaali MA、Javitz HS、Bhatnagar P. 基于初级 T 细胞的体内合成工程蛋白输送平台。Bioeng Transl Med.2024; 9(1):e10605. doi:10.1002/btm2.10605与手稿其余部分使用泛CD3 T细胞得出的数据不同,图4d-f使用的是CD4 T细胞。我们对此错误表示歉意。我们在以下地方进行了更正:图 4d-f 标签,经编辑后表明使用的是 CD4 T 细胞图 4 标题,经编辑后表明使用的是 CD4 T 细胞图 4.基于初级 T 细胞的递送平台的功能验证。(a、b)体外验证了与疾病负担成比例的靶向特异性递送功能。与各自的非靶标(FRαneg)对照细胞相比,具有 NFAT-RE 诱导递送功能的 FRα 特异性原代 T 细胞在与靶标细胞(a)FRα+A2780cis 和(b)FRα+KPCY 共培养时,报告活性呈比例增加。(c)使用为基于 T 细胞的递送平台开发的工艺制造的 CAR T 细胞减轻了肿瘤负担。用 FRα 特异性 CAR T 细胞治疗 NSG 小鼠腹膜内(i.p.)KPCY 肿瘤时,观察到肿瘤消退,且呈剂量依赖性(n = 每组 5 只小鼠)。静脉注射肿瘤发出的生物荧光(Luc2 活性)用于评估体内肿瘤负荷。统计分析采用双向方差分析和 Tukey's 多重比较检验。天数和FRα特异性CAR T细胞剂量对肿瘤负荷有统计学意义的交互作用(F[18, 96] = 4.595, p &lt; 0.0001)。(d-f)采用相同工艺制造的基于原代 T 细胞的递送平台在体内以抗原特异性的方式发挥作用(n = 每组 5 只小鼠)。将为 NFAT-RE 诱导递送功能而设计的 FRα 特异性原代 CD4 T 细胞以 24 小时为间隔,连续 5 天静注于携带 FRα+A2780cis 肿瘤的 NSG 小鼠体内,测量包括注射当天在内的 6 天 NFAT-RE 诱导效应因子(Nluc)活性,作为评估递送功能的基线。还包括一个对照组,以评估使用含有 Luc2+ 肿瘤细胞的 Nluc 底物可能产生的背景信号,并注射 FRα 特异性原代 CD4 CAR T 细胞(不含 NFAT-RE 诱导效应因子 [Nluc]),以维持同等的肿瘤负荷。(d)剂量、治疗和成像时间表示意图;(e)生物发光图像;(f)量化。所有结果均以平均值 ± SEM 表示。(a)、(b)和(f)的统计分析和 p 值采用 Holm-Sidak 法进行多重 t 检验。*p &lt; 0.05,**p &lt; 0.01,***p &lt; 0.001。利用原代 CD4 T 细胞,我们接下来制造了具有递送功能的 FRα-CAR+ T 细胞,即在接触目标 FRα 抗原后,FRα-CAR 激活 NFAT-RE 信号通路,诱导所需蛋白质的表达。实验过程详见图 4d,实验结果见图 4e、f。然后,将 2 × 106 FRα+Luc2+A2780cis 细胞点滴植入 NSG 小鼠体内。在第 0、1、2、3 和 4 天,用 2 × 106 FRα-CAR+ 原始 CD4 T 细胞(带有 NFAT-RE 诱导型 Nluc 报告因子)点滴治疗 12 天大的异种移植肿瘤。对照组用于评估在 Luc2+ 肿瘤细胞上使用 Nluc 底物产生的背景信号。该组接受了不含 NFAT-RE 诱导 Nluc 报告基因的 FRα-CAR+ 原始 CD4 T 细胞(对照 FRα-CAR+T 细胞)的静脉注射治疗,以维持相同的肿瘤负荷。对基线(第 0 天)以及第 1、2、3、4 和 5 天的效应细胞(Nluc)活性(图 4e)进行了测量和量化(图 4f)。在使用具有递送功能(即具有 NFAT-RE 诱导的 Nluc 报告器)的 FRα-CAR+ T 细胞处理的组中,观察到工程效应细胞活性(即递送功能)明显增加,这证实了工程原代 T 细胞具有靶诱导的原位递送功能。在第 4.1 节的关键资源表中增加内容,以说明 CD4 T 细胞的来源--人类原代 CD4 T 细胞斯坦福血液中心A1015A 第 4.10 节中的方法,经编辑以说明 CD4 T 细胞的使用4.10 工程 T 细胞递送功能的活体验证(利用 NFAT-RE 递送系统工程实现递送功能)。我们基于 T 细胞的递送系统的体内验证是在 SRI 国际公司的小鼠体内进行的,符合机构动物护理和使用委员会的指导方针(批准号 22001)。6至8周大的雌性NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ(NSG)小鼠购自杰克逊实验室。经过强制隔离后,将 NSG 小鼠麻醉,然后将 2 × 106 FRα+Luc2-2A-E2Crimson+A2780cis 细胞置于 100 μL 1×PBS 中,静脉注射。在接下来的 12 天中,每隔 3-4 天就通过静脉注射监测肿瘤的生长情况。
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