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Limitation of Anion Exchange Chromatography and Potential Application of Hydrophobic Interaction Chromatography for Monitoring AAV9 Capsid Degradation Upon Thermal Stress. 阴离子交换色谱法的局限性和疏水相互作用色谱法在监测热应力下 AAV9 荚膜降解过程中的潜在应用
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-11-15 DOI: 10.1016/j.xphs.2024.11.005
Antonela Rodriguez, Ali Banazadeh, Amr Ali, Rajeeva Singh, Chen Zhou

Adeno-Associated Virus (AAV) is often selected as the vector of choice for gene therapy due to its superior clinical performance compared to other gene delivery systems. Currently the characterization of AAV degradation, especially the chemical degradation of capsid, has been limited due to lack of suitable methods. Our study using AAV9 as a model molecule shows that anion exchange chromatography (AEX) as a charge-based separation method has limitations in monitoring the chemical degradation of AAV9 capsid due to a confounding effect from DNA cargo ejection. We developed a hydrophobic interaction chromatography (HIC) method, free from DNA interference, that could serve as a quick and reliable alternative to resource-demanding peptide mapping method for monitoring AAV capsid chemical degradation. Compared with brief thermal stress at 75 °C, AAV9 capsid exhibited much higher levels of chemical degradation but slower capsid titer loss upon extended exposure for 4 weeks at 40 °C.

腺相关病毒(AAV)因其优于其他基因递送系统的临床表现,通常被选为基因治疗的首选载体。目前,由于缺乏合适的方法,AAV 的降解特性,尤其是囊膜的化学降解,一直受到限制。我们以 AAV9 为模型分子进行的研究表明,阴离子交换色谱法(AEX)作为一种基于电荷的分离方法,在监测 AAV9 荚膜的化学降解方面存在局限性,因为 DNA 货物喷射会产生混杂效应。我们开发了一种疏水相互作用色谱(HIC)方法,该方法不受DNA干扰,可快速可靠地替代对资源要求较高的肽图法来监测AAV囊壳的化学降解。与75 °C的短暂热应激相比,AAV9噬菌体在40 °C下暴露4周后表现出更高水平的化学降解,但噬菌体滴度的损失更慢。
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引用次数: 0
Controlled Self-Assembly of Macrocyclic Peptide into Multifunctional Photoluminescent Nanoparticles. 将大环肽受控自组装成多功能光致发光纳米粒子。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-11-15 DOI: 10.1016/j.xphs.2024.11.006
Ranga Dissanayake, Nauman Nazeer, Zeyaealdin Zarei, Adnan Murad Bhayo, Marya Ahmed

Self-assembled peptide nanoparticles are unique stimuli responsive biodegradable materials with applications in biomedicines as delivery carriers and imaging agents. This study investigates the controlled self-assembly of chicken Angiogenin 4 derived immunomodulatory macrocyclic peptide (mCA4-5) in the presence of an inert amphipathic stabilizing peptide and as a function of pH, temperature and presence of ions to yield optically active, physiologically stable and biodegradable peptide nanoparticles. The photoluminescent peptide nanoparticles (PLPNs) produced were characterized for the size, surface charge, optical properties and crystallinity. The carvacrol loaded nanoparticles prepared by facile encapsulation of the drug during the self-assembly process were evaluated for the drug release efficacies, as a function of pH and in the presence of reducing agent. Carvacrol loaded, physiologically stable PLPNs obtained with high conversion efficacy were highly effective against planktonic bacteria and bacterial biofilms and efficiently eradicated intracellular bacteria in infected macrophages and fibroblast. Furthermore, the drug-loaded nanoparticles exhibited significant antioxidant activities and immunomodulatory effects, highlighting their multifunctional therapeutic potential.

自组装肽纳米颗粒是一种独特的刺激响应型生物可降解材料,可作为输送载体和成像剂应用于生物医学领域。本研究探讨了鸡血管生成素 4 衍生的免疫调节大环肽(mCA4-5)在惰性两性稳定肽的存在下,随着 pH 值、温度和离子存在的变化进行受控自组装,从而产生具有光学活性、生理稳定和可生物降解的肽纳米颗粒。对所制备的光致发光肽纳米颗粒(PLPNs)的尺寸、表面电荷、光学特性和结晶度进行了表征。在自组装过程中,通过对药物的简单封装,制备出了负载香芹酚的纳米颗粒,并对其药物释放效果进行了评估,评估结果与 pH 值和还原剂的存在有关。所获得的香芹酚负载型生理稳定 PLPN 具有很高的转化效力,对浮游细菌和细菌生物膜非常有效,并能有效消灭受感染巨噬细胞和成纤维细胞中的细胞内细菌。此外,载药纳米粒子还具有显著的抗氧化活性和免疫调节作用,凸显了其多功能治疗潜力。
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引用次数: 0
Ultrasound/Magnetic Resonance Bimodal Imaging-Guided CD20-Targeted Multifunctional Nanoplatform for Photothermal/Chemo Synergistic Therapy of B-Cell Lymphoma. 超声/磁共振双模成像引导的 CD20 靶向多功能纳米平台用于 B 细胞淋巴瘤的光热/化疗协同治疗
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-11-15 DOI: 10.1016/j.xphs.2024.11.004
Zhengji Wang, Jian Huang, Weiyang Lv, Chunxin Huang, Ying Wang, Xing Li, Huilin Liu, Liguo Hao

B-cell lymphoma has a poor prognosis due to difficulties in early diagnosis and the negative effects of systemic chemotherapy. Therefore, there is an urgent need to develop highly accurate and effective theranostic strategies for B-cell lymphoma. In this study, we designed a poly (lactic-co-glycolic acid) (PLGA)-based theranostic nanoplatform (denoted as TscNPs) to achieve ultrasound (US)/magnetic resonance (MR) bimodal imaging-guided photothermal (PTT)/chemo synergistic therapy of B-cell lymphoma. The nanoplatform was conjugated with a CD20 monoclonal antibody specifically targeting B-cell lymphoma to promote tumor accumulation. Encapsulated superparamagnetic iron oxide nanoparticles (SPIONs) as photothermal and MR imaging agents enabled thermal ablation of tumors and imaging-guided tumor therapy. When exposed to near-infrared (NIR) laser, TscNPs generate heat that induces optical droplet vaporization (ODV) of perfluoropentane (PFP), which transforms into microbubbles. This process not only enhanced ultrasound imaging, but also facilitated the release of celastrol (CST) from the nanoplatform, ultimately achieving a PTT/chemo synergistic therapy effect. In the tumor-bearing nude mice model, TscNPs were effectively accumulated in the tumor region. Furthermore, the combined treatment mode of TscNPs and NIR laser irradiation demonstrated a tumor inhibition rate of approximately 96.57%, which was significantly superior to the rates observed with PTT or chemotherapy alone. These results suggest that the multifunctional theranostic nanoplatform represents a promising new strategy for the therapy of B-cell lymphoma.

由于早期诊断困难和全身化疗的负面影响,B 细胞淋巴瘤的预后较差。因此,针对 B 细胞淋巴瘤开发高精度、高效的治疗策略迫在眉睫。在这项研究中,我们设计了一种基于聚乳酸-聚乙二醇酸(PLGA)的治疗纳米平台(简称 TscNPs),以实现超声(US)/磁共振(MR)双模成像引导的光热(PTT)/化疗协同治疗 B 细胞淋巴瘤。该纳米平台与专门针对 B 细胞淋巴瘤的 CD20 单克隆抗体共轭,以促进肿瘤聚集。封装的超顺磁性氧化铁纳米粒子(SPIONs)作为光热和磁共振成像剂可实现肿瘤的热消融和成像引导的肿瘤治疗。当暴露于近红外(NIR)激光时,超顺磁性氧化铁纳米粒子产生热量,诱导全氟戊烷(PFP)的光学液滴汽化(ODV),并转化为微气泡。这一过程不仅增强了超声成像,还促进了赛拉司特醇(CST)从纳米平台的释放,最终实现了 PTT/化疗的协同治疗效果。在肿瘤裸鼠模型中,TscNPs 能有效地在肿瘤区域聚集。此外,TscNPs 和近红外激光照射联合治疗模式的肿瘤抑制率约为 96.57%,明显优于 PTT 或单独化疗的抑制率。这些结果表明,多功能治疗纳米平台是治疗 B 细胞淋巴瘤的一种前景广阔的新策略。
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引用次数: 0
A Workflow for Accurate and Consistent Quantitation of Host Cell Proteins by SWATH LC-MS/MS Analysis to Support Process Development. 通过 SWATH LC-MS/MS 分析对宿主细胞蛋白质进行准确一致定量的工作流程,以支持工艺开发。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-11-15 DOI: 10.1016/j.xphs.2024.11.007
Jia Guo, Regina Kufer, Midori Greenwood-Goodwin, Stefanie Wohlrab, Fem Woodruff, Delia Li, Katharina Reckermann, Jonghae Youn, Dilip Kumar Reddy Kandula, Lei Xiong, Feng Yang

Residual host cell proteins (HCPs) in drug products may impact product quality, stability, efficacy and safety. To support consistent and accurate quantitative analysis for low levels of HCPs (≥ 1 ppm), the data-independent sequential window acquisition of all theoretical fragment ion spectra (SWATH) MS/MS-based method provides unique advantages over data dependent acquisition (DDA) or targeted methods for HCP identification and quantification. However, SWATH MS/MS-based methods can generate biased quantitative results that are highly dependent on the selected reference protein. In this study, we enhanced the accuracy of SWATH-based HCP quantitation relative to a spiked-in reference protein by selecting appropriate reference proteins based on their ranking values. We developed a reliable SWATH-based method for quantifying specific HCPs by adding sodium deoxycholate (SDC) during digestion to enhance both protein detection and quantitation consistency. By combining SWATH-based quantitation with standard addition, we showed its use in measuring HCP levels with good accuracy and reproducibility, confirmed by both targeted MRM-MS/MS and ELISA. Additionally, we demonstrated an automated Spectronaut data analysis workflow can efficiently generate SWATH quantitative results for HCPs in different in-process pools. Using SWATH-based quantitation, we were able to measure specific HCPs (e.g. Peroxiredoxin-1) and support process development with good throughput and quantitation consistency.

药物产品中残留的宿主细胞蛋白(HCPs)可能会影响产品质量、稳定性、疗效和安全性。为了支持对低水平 HCP(≥ 1 ppm)进行一致而准确的定量分析,与数据依赖性采集(DDA)或 HCP 鉴定和定量的靶向方法相比,基于数据依赖性的所有理论碎片离子谱的顺序窗口采集(SWATH)MS/MS 方法具有独特的优势。然而,基于 SWATH MS/MS 的方法可能会产生有偏差的定量结果,而这些结果高度依赖于所选的参考蛋白。在本研究中,我们根据参考蛋白质的排序值选择了合适的参考蛋白质,从而提高了基于 SWATH 的 HCP 定量相对于加标参考蛋白质的准确性。我们开发了一种可靠的基于 SWATH 的方法,通过在消化过程中添加脱氧胆酸钠 (SDC) 来定量特定的 HCP,从而提高蛋白质检测和定量的一致性。通过将基于 SWATH 的定量法与标准添加法相结合,我们展示了该方法在测量 HCP 水平方面的良好准确性和可重复性,并得到了靶向 MRM-MS/MS 和 ELISA 的证实。此外,我们还展示了自动 Spectronaut 数据分析工作流程,该流程可高效生成不同过程池中 HCP 的 SWATH 定量结果。利用基于 SWATH 的定量方法,我们能够测量特定的 HCPs(如过氧化还原酶-1),并以良好的通量和定量一致性支持工艺开发。
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引用次数: 0
Synchrotron computed tomography combined with AI-based image analysis for the advanced characterization of spray dried amorphous solid dispersion particles. 同步辐射计算机断层扫描与基于人工智能的图像分析相结合,用于喷雾干燥无定形固体分散颗粒的高级表征。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-11-14 DOI: 10.1016/j.xphs.2024.10.033
Tatiana Marcozzi, Sruthika Baviriseaty, Phillip Yawman, Shawn Zhang, Chris Vervaet, Valérie Vanhoorne, Sune Andersen

Particle engineering aims to design particles with specific properties. A deeper understanding of how particle formation relates to material attributes and process conditions are critical to strengthen knowledge on powder properties and enhance modeling capabilities. New, alternative powder characterization techniques can offer novel and more accurate measures for particle properties, giving more advanced characterization information. In this context, a case study is presented in which spray dried amorphous solid dispersion powders produced by modifying process conditions were characterized by both well-established compendial methods (i.e., laser light diffraction, SEM image analysis, bulk and tapped density, and gas adsorption), as well as a new method combining synchrotron computed tomography (SyncCT) with AI-based image analysis. SyncCT was used to classify and quantify the spray dried particles as hollow spheres and solid particles, giving a more detailed quality measure of the particle shape, as they impact downstream processing differently. Moreover, hollow particle wall thicknesses, as well as internal and external particle surface areas were measured by SyncCT. Altogether, powder characterization data from SyncCT show similar trends to that obtained from compendial techniques and giving additional quality measure regarding particle shape, showing promise of this new and advanced characterization method.

颗粒工程旨在设计具有特定性能的颗粒。更深入地了解颗粒形成与材料属性和工艺条件的关系,对于加强粉末特性知识和提高建模能力至关重要。新的替代性粉末表征技术可以提供新颖、更准确的颗粒特性测量方法,从而提供更先进的表征信息。在此背景下,我们介绍了一个案例研究,通过改变工艺条件生产的喷雾干燥非晶固体分散粉末,采用了成熟的简易方法(即激光衍射、扫描电子显微镜图像分析、堆积密度和攻丝密度以及气体吸附)以及结合同步辐射计算机断层扫描(SyncCT)和基于人工智能的图像分析的新方法进行表征。SyncCT 用于将喷雾干燥颗粒分类和量化为空心球和实心颗粒,从而更详细地衡量颗粒形状的质量,因为它们对下游加工的影响不同。此外,SyncCT 还测量了空心颗粒的壁厚以及内外颗粒表面积。总之,SyncCT 的粉末表征数据显示出与通过药典技术获得的数据相似的趋势,并提供了有关颗粒形状的额外质量测量,显示出这种新型先进表征方法的前景。
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引用次数: 0
Highly Sensitive and Robust LC-MS/MS Method for Determination up to 15 Small Molecule Nitrosamine Impurities in Pharmaceutical Drug Substances. 高灵敏度和稳健的 LC-MS/MS 方法,用于测定药物中多达 15 种小分子亚硝胺杂质。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-11-14 DOI: 10.1016/j.xphs.2024.11.003
Swapna Daripelli, Nitin Ashok Jadhav, Anindita Sarkar, Vinit Yadav, Mayank Bhanti, Mrunal Jaywant

Nitrosamine impurities have been classified as probable human carcinogens for decades. These impurities were reported in water, food, tobacco, pesticides, and plastics but received attention in mid-2018 when N-nitrosodimethylamine (NDMA) was reported in valsartan drug products. Subsequently, it was revealed that several small molecule and complex nitrosamine impurities can form in any active pharmaceutical ingredient (API) or drug product in which secondary or tertiary amines are present (as API or as impurities) along with a nitrosating agent. Consequently, regulators have provided several guidelines for the risk assessment of nitrosamine formation during manufacturing, storage, or from contaminated supply chains. This has led to a demand for validated analytical methods that quantify N-nitrosamine impurities in pharmaceutical products. In this study, a highly sensitive and robust analytical method was developed and validated for quantitatively determining up to 15 small nitrosamines at low levels (0.01 ppm) in sartan drug substances. The study also suggests that this method can be extended not only to corresponding sartan drug products but could also be used as a generic screening method to test a variety of drug substances, and drug products with the minimum required optimization of method conditions.

几十年来,亚硝胺杂质一直被列为可能的人类致癌物。据报道,这些杂质存在于水、食品、烟草、杀虫剂和塑料中,但在2018年年中,缬沙坦药物产品中的N-亚硝基二甲胺(NDMA)受到了关注。随后,有研究表明,在任何含有仲胺或叔胺(作为原料药或杂质)以及亚硝基化剂的活性药物成分(API)或药物产品中,都可能形成多种小分子和复合亚硝胺杂质。因此,监管机构为亚硝胺在生产、储存过程中或受污染的供应链中形成的风险评估提供了多项指导原则。这就要求采用经过验证的分析方法来定量检测药品中的 N-亚硝胺杂质。本研究开发并验证了一种高灵敏度和稳健的分析方法,可定量测定沙坦类药物中低浓度(0.01 ppm)的多达 15 种小亚硝胺。研究还表明,该方法不仅可扩展到相应的沙坦类药物产品,还可用作通用筛选方法,以检测各种药物物质和药物产品,同时只需对方法条件进行最低限度的优化。
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引用次数: 0
Biowaiver Monographs for Immediate-Release Solid Oral Dosage Forms: Voriconazole. 速释口服固体制剂的生物豁免专论:伏立康唑。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-11-13 DOI: 10.1016/j.xphs.2024.10.055
Kristian Beran, Bertil Abrahamsson, Naseem Charoo, Rodrigo Cristofoletti, René Holm, Atsushi Kambayashi, Peter Langguth, Alan Parr, James E Polli, Vinod P Shah, Jennifer Dressman

According to the ICH M9 Guideline, the triazole antifungal voriconazole is a Biopharmaceutics Classification System (BCS) class II drug, being highly soluble at the highest dose strength but not at the highest single dose. Although the ICH M9 allows for consideration of BCS-based biowaivers in such cases, voriconazole does not meet the additional requirement of dose proportional pharmacokinetics (PK) over the therapeutic dose range. By contrast, if the classification were based on the FDA solubility criteria that were in place prior to ICH M9 (based on the highest dose strength), voriconazole would belong to BCS class I and thus qualify for the BCS-based biowaiver. Since the highest oral dose strength of voriconazole dissolves very rapidly under all BCS conditions, and comparative in vitro dissolution of different tablet formulations aligns with the demonstration of BE in clinical studies, it seems that the ICH Guideline may be unnecessarily restrictive in the case of voriconazole. Therefore, this review discusses potential revisions of eligibility criteria and the extension of biowaiver approvals to encompass a wider range of appropriate drugs. Specifically, a classification system that is more relevant to in vivo conditions, the refined Developability Classification System (rDCS), coupled with biorelevant dissolution testing, may be more applicable to compounds like voriconazole.

根据 ICH M9 准则,三唑类抗真菌药物伏立康唑属于生物制药分类系统(BCS)II 类药物,在最高剂量强度下具有高溶解性,但在最高单剂量下不具有高溶解性。虽然 ICH M9 允许在这种情况下考虑基于 BCS 的生物豁免,但伏立康唑不符合在治疗剂量范围内剂量与药代动力学(PK)成比例的额外要求。相比之下,如果根据 ICH M9 之前的 FDA 溶解度标准(基于最高剂量强度)进行分类,伏立康唑将属于 BCS I 类,从而符合基于 BCS 的生物豁免条件。由于伏立康唑的最高口服剂量强度在所有 BCS 条件下都能快速溶解,且不同片剂的体外溶解度比较与临床研究中的 BE 证明一致,因此 ICH 指南似乎对伏立康唑有不必要的限制。因此,本综述讨论了资格标准的可能修订以及生物豁免批准范围的扩大,以涵盖更广泛的适当药物。具体来说,一个与体内条件更相关的分类系统,即改良的可发展性分类系统(rDCS),再加上与生物相关的溶出度测试,可能更适用于伏立康唑等化合物。
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引用次数: 0
Impact of Citrate on Mitigating Iron Mediated Polysorbate 80 Degradation in Biotherapeutic Formulation Placebos. 柠檬酸盐对缓解生物治疗配方安慰剂中铁介导的聚山梨醇酯 80 降解的影响
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-11-13 DOI: 10.1016/j.xphs.2024.10.038
Rong-Sheng Yang, Chengbei Li, Liliana Henriquez, Hongxia Wang, Jainik Panchal, Wendy Zhong, Hillary Schuessler

Polysorbate 80 (PS80), a widely used polymeric surfactant in biotherapeutic formulation, possesses a unique structural composition that effectively prevents protein aggregation in highly concentrated protein drug formulations. However, PS80 is susceptible to hydrolysis, due to the presence of fatty acid esters that can be enzymatically hydrolyzed, The unsaturated bonds in the fatty acids are prone to oxidative degradation when exposed to air, especially in the presence of transition metals such as iron and copper, which may be introduced during production and purification processes or from contamination in raw materials used in drug formulation. The degradation of PS80, particularly through metal-mediated oxidative degradation, poses a significant challenge for the industry. Among the identified trace metals, iron plays a crucial role as the redox reaction between ferrous ion (Fe(II)) and ferric ion (Fe(III)) generates radicals that initiate the degradation process. In order to investigate the impact of iron on PS80 degradation and understand the mechanism of iron-catalyzed oxidation, we utilized charge-reduction mass spectrometry and two-dimensional ion density mapping technologies to characterize the degradation of PS80. This method has proven to be a convenient and effective tool for the quick and detailed profiling of PS80, allowing for visual monitoring and examination of the changes that reflect the difficult-to-identify and easy-to-miss oxidized species of PS80. Additionally, a high-performance liquid chromatography coupled to inductively coupled plasma mass spectrometry method was developed for the separation and measurement of Fe(II) and Fe(III). Through this investigation, we determined that the involvement of Fe(II)/Fe(III) in PS80 degradation is a temperature dependent process. Furthermore, we found citrate not only promotes the conversion of Fe(II) to Fe(III), but it also chelates Fe(III) and prevents its reduction to Fe(II), thus inhibiting the initiation of the PS80 degradation. Therefore, the addition of citrate can be a crucial ingredient for controlling the degradation of PS80 in biologic drug substances and products. Overall, this investigation has provided valuable insights to enhance product stability, optimize processes, and ensure the quality of formulations containing PS80.

聚山梨醇酯 80(PS80)是一种在生物治疗配方中广泛使用的聚合物表面活性剂,它具有独特的结构组成,可有效防止高浓度蛋白质药物配方中的蛋白质聚集。脂肪酸中的不饱和键在暴露于空气中时容易发生氧化降解,尤其是在有铁和铜等过渡金属存在的情况下。PS80 的降解,尤其是通过金属介导的氧化降解,给行业带来了巨大挑战。在已确定的痕量金属中,铁起着至关重要的作用,因为亚铁离子(Fe(II))和铁离子(Fe(III))之间的氧化还原反应会产生自由基,从而启动降解过程。为了研究铁对 PS80 降解的影响并了解铁催化氧化的机理,我们利用电荷还原质谱法和二维离子密度图谱技术来表征 PS80 的降解过程。事实证明,这种方法是快速、详细分析 PS80 的便捷、有效工具,可以直观地监测和检查反映 PS80 难识别、易遗漏的氧化物种的变化。此外,我们还开发了一种高效液相色谱耦合电感耦合等离子体质谱法,用于分离和测量铁(II)和铁(III)。通过这项研究,我们确定了铁(II)/铁(III)参与 PS80 降解的过程与温度有关。此外,我们还发现柠檬酸盐不仅能促进 Fe(II) 转化为 Fe(III),还能螯合 Fe(III)并阻止其还原为 Fe(II),从而抑制 PS80 降解的开始。因此,添加柠檬酸盐可以成为控制生物药物物质和产品中 PS80 降解的关键成分。总之,这项研究为提高产品稳定性、优化工艺和确保含 PS80 制剂的质量提供了宝贵的见解。
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引用次数: 0
Mechanistic characterization of iron-catalyzed oxidation of polysorbate 80: The role of ferrous iron, hydrogen peroxide, and superoxide. 铁催化聚山梨醇酯 80 氧化的机理特征:亚铁、过氧化氢和超氧化物的作用。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-11-12 DOI: 10.1016/j.xphs.2024.10.053
David S Richards, Yaqi Wu, Christian Schöneich

We investigated the role of individual radical species during Fe-catalyzed oxidation of PS80. Solutions containing 1 gL-1 PS80 (0.1 % w/v) in 10 mM acetate buffer (pH 6) were exposed to various amounts of either Fe(II) or Fe(III), hydrogen peroxide (H2O2), and various enzymes or antioxidants. PS80 oxidation was measured using a fluorescence micelle assay (FMA) alongside LC-MS. Hydrogen peroxide inhibited PS80 oxidation in the presence of Fe(II) but promoted oxidation in the presence of Fe(III). Furthermore, Ferrostatin-1 (Fer-1), an antioxidant which is known to preferentially react with alkoxy radicals, inhibited PS80 oxidation in the presence of Fe(II). Superoxide dismutase (SOD) partially inhibited PS80 oxidation in the presence of either Fe(II) or Fe(III), suggesting that superoxide plays a role in both cases. Ferryl species (FeIV=O) or hydroxyl radicals (HO•), produced by the Fenton reaction, do not play a major role in the oxidation of PS80. Rather, oxidation was initiated by the reaction of both Fe(II) and Fe(III) with pre-existing lipid hydroperoxides on PS80, as well as via superoxide.

我们研究了单个自由基物种在铁催化 PS80 氧化过程中的作用。将 10 mM 乙酸缓冲液(pH 6)中含有 1 gL-1 PS80(0.1% w/v)的溶液暴露于不同量的铁(II)或铁(III)、过氧化氢(H2O2)以及各种酶或抗氧化剂中。使用荧光胶束分析法(FMA)和 LC-MS 测定 PS80 的氧化情况。过氧化氢抑制了铁(II)存在下的 PS80 氧化,但促进了铁(III)存在下的氧化。此外,已知能优先与烷氧基自由基发生反应的抗氧化剂铁前列素-1(Fer-1)也能抑制铁(II)存在时的 PS80 氧化。超氧化物歧化酶(SOD)可部分抑制铁(II)或铁(III)存在下的 PS80 氧化,这表明超氧化物在这两种情况下都发挥了作用。Fenton 反应产生的 Ferryl 物种(FeIV=O)或羟基自由基(HO-)在 PS80 的氧化过程中并不起主要作用。相反,氧化是由 Fe(II) 和 Fe(III) 与 PS80 上预先存在的脂质氢过氧化物反应以及超氧化物引发的。
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引用次数: 0
In vitro Analysis of XLAsp-P2 Peptide Loaded Cellulose Acetate Nanofiber for Wound Healing. 用于伤口愈合的 XLAsp-P2 肽负载醋酸纤维素纳米纤维的体外分析
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-11-12 DOI: 10.1016/j.xphs.2024.10.050
Saranya Selvaraj, Monali Perera, Piumika Yapa, Imalka Munaweera, Inoka C Perera, Tharindu Senapathi, Laksiri Weerasinghe

Recently, nanofiber-based wound dressings are currently a viable strategy to expedite the healing of wounds by providing a suitable microenvironment for tissue growth with active ingredients. This research study subjects the development of electrospun cellulose acetate (CA) nanofibers loaded with the XLAsp-P2, an antimicrobial peptide (AMP) that holds great potential for enhanced wound healing as a therapeutic agent. The synthesized XLAsp-P2-loaded CA nanofibers were fabricated via three loading percentages, 0.1 %, 0.2 %, and 0.3 % w/w, and characterized and evaluated their antimicrobial potential with MTT assay and Agar overlay methods as an alternative strategy. FT-IR analysis confirmed the compatibility of the peptide loaded CA nanocomposite, showing distinct peaks corresponding to the constituent materials. Scanning electron microscopy (SEM) analysis was employed to characterize the morphology of electrospun peptide CA nanocomposites and illustrate the fiber's size at the nanoscale. The in vitro release study during the 24 hrs, 87 % of the peptide was released which was approximately 5.2 mg; which was closer matched to the square root model of Higuchi at room temperature. MTT assay presented sensitive results towards Gram-positive bacteria compared to Gram Negative bacteria; which corresponded to the inhibition zones of the Agar overlay method proving that Escherichia coli (ATCC 25922) 17.66 ± 0.38 mm and Pseudomonas aeruginosa (ATCC 27853) 17.44 ± 0.38 mm exhibited moderate susceptibility, while Staphylococcus aureus (ATCC 25923)19.89 ± 0.69 mm and Bacillus cereus (ATCC 11778) 23.00 ± 0.33 mm showed promising responses. Collectively, The study's findings indicate that the XLAsp-P2 incorporated CA mat possesses an opportunity to function as an efficient platform for delivering therapeutic peptides.

最近,以纳米纤维为基础的伤口敷料是一种可行的策略,它能为含有活性成分的组织生长提供合适的微环境,从而加快伤口愈合。本研究的主题是开发负载了 XLAsp-P2 的电纺醋酸纤维素(CA)纳米纤维,XLAsp-P2 是一种抗菌肽(AMP),作为一种治疗剂,它在促进伤口愈合方面具有巨大潜力。通过 0.1%、0.2% 和 0.3% w/w 三种负载百分比合成了负载 XLAsp-P2 的醋酸纤维,并采用 MTT 检测法和琼脂覆盖法作为一种替代策略对其抗菌潜力进行了表征和评估。傅立叶变换红外分析证实了多肽负载 CA 纳米复合材料的相容性,显示出与组成材料相对应的明显峰值。扫描电子显微镜(SEM)分析表明了电纺多肽 CA 纳米复合材料的形态特征,并显示了纤维的纳米级尺寸。在 24 小时的体外释放研究中,87% 的肽被释放出来,约为 5.2 毫克;这与室温下的樋口平方根模型比较接近。与革兰氏阴性菌相比,MTT 法对革兰氏阳性菌更敏感;这与琼脂覆盖法的抑菌区一致,证明大肠杆菌(ATCC 25922)17.66 ± 0.38 毫米和铜绿假单胞菌(ATCC 27853)17.44 ± 0.38 毫米表现出中等敏感性,而金黄色葡萄球菌(ATCC 25923)19.89 ± 0.69 毫米和蜡样芽孢杆菌(ATCC 11778)23.00 ± 0.33 毫米表现出良好的反应。总之,研究结果表明,含有 XLAsp-P2 的 CA 垫有机会成为递送治疗肽的有效平台。
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Journal of pharmaceutical sciences
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