European Journal of Pharmaceutics and Biopharmaceutics最新文献_第9页

Simple ROS-responsive micelles loaded Shikonin for efficient ovarian cancer targeting therapy by disrupting intracellular redox homeostasis 简单的 ROS 响应胶束负载 Shikonin，通过破坏细胞内氧化还原平衡实现高效的卵巢癌靶向治疗。

IF 4.4 2区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutics and Biopharmaceutics

Pub Date : 2024-10-05 DOI: 10.1016/j.ejpb.2024.114525

Kangyuan Hu , Xiuhua Li , Zhaodan Tan , Yan Shi

Ovarian cancer is the most common malignant tumor in women. Shikonin (SHK), an herbal extract from Chinese medicine, shows promise in treating ovarian cancer by inducing reactive oxygen species (ROS). However, its clinical use is limited by poor tumor targeting and low bioavailability, and its therapeutic potential is further compromised by the elevated levels of antioxidants such as glutathione (GSH) within tumor cells. In this study, a novel formulation of ROS-responsive micelles loaded with SHK was developed using hyaluronic acid-phenylboronic acid pinacol ester conjugation (HA-PBAP) for targeted therapy of ovarian cancer through disruption of intracellular redox homeostasis. The SHK@HA-PBAP exhibits targeted delivery to ovarian cancer cells through the interaction between HA and CD44 receptors. Upon internalization by cancer cells, the high levels of intracellular ROS triggered the degradation of SHK@HA-PBAP and simultaneously released SHK and generated GSH scavenger quinone methide (QM). The SHK and QM released from the SHK@HA-PBAP effectively induce the production of ROS and deplete intracellular GSH, leading to the disruption of intracellular redox homeostasis and subsequent induction of cell death. These characteristics collectively inhibit the growth of ovarian cancer. In vitro and in vivo studies have demonstrated that SHK@HA-PBAP micelles exhibit superior antitumor efficacy compared to free SHK in both A2780 cells and A2780 tumor-bearing mice. The ROS-responsive SHK@HA-PBA presents a promising therapeutic approach for the treatment of ovarian cancer.

卵巢癌是女性最常见的恶性肿瘤。石杉碱甲是一种中药提取物，可通过诱导活性氧（ROS）治疗卵巢癌。然而，其临床应用受到肿瘤靶向性差和生物利用度低的限制，而且肿瘤细胞内谷胱甘肽（GSH）等抗氧化剂水平的升高进一步削弱了其治疗潜力。本研究利用透明质酸-苯硼酸频哪醇酯共轭（HA-PBAP）技术开发了一种负载有 SHK 的 ROS 响应胶束新配方，通过破坏细胞内的氧化还原平衡对卵巢癌进行靶向治疗。SHK@HA-PBAP通过HA和CD44受体之间的相互作用对卵巢癌细胞进行靶向递送。癌细胞内化后，高水平的细胞内氧化还原反应会引发 SHK@HA-PBAP 的降解，同时释放 SHK 并生成 GSH 清除剂醌甲醚（QM）。SHK@HA-PBAP 释放的 SHK 和 QM 能有效诱导 ROS 的产生并消耗细胞内的 GSH，从而破坏细胞内的氧化还原平衡，进而诱导细胞死亡。这些特性共同抑制了卵巢癌的生长。体外和体内研究表明，与游离 SHK 相比，SHK@HA-PBAP 胶束在 A2780 细胞和 A2780 肿瘤小鼠中均表现出卓越的抗肿瘤功效。ROS反应型SHK@HA-PBA为卵巢癌的治疗提供了一种前景广阔的治疗方法。

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引用次数: 0

Development of puerarin-loaded poly(lactic acid) microspheres for sustained ocular delivery: In vitro/vivo evaluation 开发用于持续眼部给药的葛根素负载聚（乳酸）微球：体外/体内评估。

IF 4.4 2区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutics and Biopharmaceutics

Pub Date : 2024-10-05 DOI: 10.1016/j.ejpb.2024.114524

Yanqiu Long , Jie Hu , Yan Liu , Danqing Wu , Zhiyun Zheng , Shuangying Gui , Ning He

Diabetic retinopathy, an ocular complication of diabetes, is an important cause of blindness in adults. Puerarin is considered to have promising potential for clinical use in treating diabetic retinopathy. In this study, we designed a novel puerarin-loaded poly(lactic acid) sustained-release microspheres suitable for ocular administration, and we assessed its in vitro and in vivo properties. The preparation of puerarin-loaded microspheres was optimized by Box-Behnken response surface design. The encapsulation efficiency and drug loading of microspheres were 35.71% and 3.85%, respectively. The microspheres exhibited good dispersion and high safety, making it suitable for ocular drug delivery. In vitro release demonstrated that microspheres had a well-sustained release effectiveness, and its release behavior complied with the zero-order kinetic characteristics. The results of ocular tissue distribution revealed that the C_max and AUC_0-∞ of the microspheres group in the retina and choroid were considerably higher than those of the solution group and the intravenous injection group. This research revealed that intravitreal injection of microspheres can significantly prolong the half-life of puerarin in eye tissues and achieve sustained drug release. Therefore, intravitreal injection of microspheres has positive implications for the treatment of diabetic retinopathy.

糖尿病视网膜病变是糖尿病的眼部并发症，是导致成人失明的重要原因。葛根素被认为具有治疗糖尿病视网膜病变的临床应用潜力。在这项研究中，我们设计了一种适合眼部给药的新型葛根素负载型聚乳酸缓释微球，并对其体外和体内特性进行了评估。通过盒-贝肯响应面设计优化了葛根素载药微球的制备。微球的包封效率和载药量分别为 35.71% 和 3.85%。微球具有良好的分散性和较高的安全性，适用于眼部给药。体外释放表明，微球具有良好的持续释放效果，其释放行为符合零阶动力学特征。眼组织分布结果显示，微球组在视网膜和脉络膜中的Cmax和AUC0-∞明显高于溶液组和静脉注射组。该研究表明，微球玻璃体内注射能显著延长葛根素在眼组织中的半衰期，实现药物的持续释放。因此，微球玻璃体内注射对糖尿病视网膜病变的治疗具有积极意义。

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引用次数: 0

Acoustic resonance technology and quality by design approach facilitate the development of the robust tetrandrine nano-delivery system 声共振技术和质量设计方法促进了坚固耐用的四氢化萘纳米给药系统的开发。

IF 4.4 2区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutics and Biopharmaceutics

Pub Date : 2024-10-04 DOI: 10.1016/j.ejpb.2024.114522

Xiaoyang Zhang , Xi Wang , Jianlu Qu , Yao Zhang , Cunhao Li , Wei Wu , Wenlong Li

The aim of this study was to develop a sufficiently robust tetrandrine (Tet) nano-delivery system using acoustic resonance (AR) technology and freeze-drying technology. This system can effectively improve the solubility and dissolution properties of Tet, along with high stability and scale-up adaptability. Firstly, 54 stabilizers were screened simultaneously in a high-throughput manner with the help of AR technology to fully explore the optimal prescription space of tetrandrine nanosuspension (Tet-NS). The Plackett-Burman design was used to screen for critical variables severely affecting the quality of Tet-NS. The Box-Behnken design was used to investigate and optimize critical variables to obtain optimal nanosuspensions. The optimal prescription was successfully scaled up by 100 times, which was the initial exploration of its commercial scale production. Solidification studies have shown that formulations with 2.44% fructose as the cryoprotectant have excellent redispersibility. Compared with pure Tet, Tet in Tet-NS showed a significant increase in solubility and dissolution rate in water. Fourier transform infrared (FT-IR) demonstrated that no significant interactions occurred between the drug and excipients in Tet-NS. Powder x-ray diffraction analysis (PXRD) indicated that some of the Tet transformed into amorphous state during the preparation process. In short-term stability study, Tet-NS successfully maintained its physical stability. In summary, under the guidance of the QbD concept, this study rapidly developed Tet-NS using acoustic resonance technology, which can effectively improve the solubility and dissolution properties of Tet. During the development of Tet-NS, AR technology has demonstrated high particle size reduction capability, the ability to process multiple sets of formulations in parallel, and excellent scale-up capability. Meanwhile, the method and concept of this study are not limited to Tet, but also applicable to other poorly water-soluble drugs.

本研究的目的是利用声共振（AR）技术和冷冻干燥技术开发一种足够稳健的四氢化萘（Tet）纳米给药系统。该系统能有效提高 Tet 的溶解度和溶解性能，同时具有高稳定性和放大适应性。首先，利用声共振技术高通量地同时筛选了54种稳定剂，以充分探索四氢化萘磺酸纳米悬浮剂（Tet-NS）的最佳处方空间。采用褶皱-伯曼设计筛选严重影响 Tet-NS 质量的关键变量。盒-贝肯设计用于研究和优化关键变量，以获得最佳纳米悬浮剂。最佳处方成功放大了 100 倍，这是对其商业规模生产的初步探索。凝固研究表明，以 2.44% 的果糖作为低温保护剂的配方具有极佳的再分散性。与纯 Tet 相比，Tet-NS 中的 Tet 在水中的溶解度和溶解速率显著提高。傅立叶变换红外光谱（FT-IR）显示，Tet-NS 中的药物和辅料之间没有发生明显的相互作用。粉末 X 射线衍射分析（PXRD）表明，部分 Tet 在制备过程中转变为无定形状态。在短期稳定性研究中，Tet-NS 成功地保持了其物理稳定性。综上所述，本研究在 QbD 理念的指导下，利用声共振技术快速开发了 Tet-NS，有效改善了 Tet 的溶解性和溶出性能。在 Tet-NS 的开发过程中，AR 技术表现出了较高的粒径减小能力、并行处理多组制剂的能力以及出色的放大能力。同时，本研究的方法和理念不仅限于 Tet，也适用于其他水溶性较差的药物。

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引用次数: 0

Cancer cell membrane-camouflaged curcumin nanoparticles trigger ferroptosis for accurate gastric cancer therapy 癌细胞膜伪装姜黄素纳米粒子可触发铁蛋白沉积，实现胃癌精准治疗

IF 4.4 2区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutics and Biopharmaceutics

Pub Date : 2024-10-02 DOI: 10.1016/j.ejpb.2024.114509

Yuanyuan Fan , Xiqin Zhang , Jianqi Zhao , Suning Chen , Jingjing Liang

Curcumin (CUR) is a hydrophobic polyphenol with considerable antitumor efficiency, but its clinical application is limited because of its poor solubility and low stability in aqueous solution and lack of targeting in vivo. Herein, we fabricated a tumor-targeting drug delivery system by loading CUR and cloaking homologous cancer cell membrane (CM) onto mesoporous silica NPs (MSN-CUR@CM). Characterization analysis showed that MSN-CUR@CM with a size of approximately 70 nm showed high water solubility and biocompatibility. Besides, MSN-CUR@CM exhibited tumor-targeting and excellent anti-gastric cancer efficiency both in vitro and in vivo owing to the cellular self-recognition of CM. In the established xenograft tumor nude mouse model, it was still significantly drug accumulated at the tumor site 72 h post administration. In addition, the mean tumor volume and weight of the MSN-CUR@CM group were was 3.97 and 7.47 times smaller than those of the CUR group. Ferroptosis, a type of non-apoptotic regulated cell death accompanied by iron-dependent lipid peroxidation, was triggered by MSN-CUR@CM. Further analysis demonstrated that MSN-CUR@CUR upregulated heme oxygenase (HO-1) levels whereas it downregulated the expression of glutathione peroxidase 4 (GPX4) in SGC7901 cells in vitro, indicating that the canonical and noncanonical ferroptosis pathways were regulated by MSN-CUR@CM. In conclusion, our study demonstrated that MSN-CUR@CM with high water solubility, biocompatibility, and tumor-targeting properties inhibited gastric cancer both in vitro and in vivo by triggering ferroptosis and provided an admirable cancer therapy efficacy.

姜黄素（CUR）是一种疏水性多酚，具有相当高的抗肿瘤效率，但由于其在水溶液中溶解性差、稳定性低，且在体内缺乏靶向性，因此临床应用受到限制。在此，我们通过在介孔二氧化硅 NPs（MSN-CUR@CM）上载入 CUR 并包覆同源癌细胞膜（CM），制备了一种肿瘤靶向给药系统。表征分析表明，尺寸约为 70 nm 的 MSN-CUR@CM 具有很高的水溶性和生物相容性。此外，由于MSN-CUR@CM具有细胞自我识别能力，因此在体外和体内均表现出肿瘤靶向性和良好的抗胃癌效果。在已建立的异种移植肿瘤裸鼠模型中，给药后 72 小时，MSN-CUR@CM 在肿瘤部位仍有明显的药物蓄积。此外，MSN-CUR@CM 组的平均肿瘤体积和重量分别是 CUR 组的 3.97 倍和 7.47 倍。MSN-CUR@CM引发了铁凋亡，这是一种伴随着铁依赖性脂质过氧化的非凋亡调节性细胞死亡。进一步的分析表明，MSN-CUR@CUR可上调血红素加氧酶（HO）-1的水平，而下调谷胱甘肽过氧化物酶4（GPX4）在体外SGC7901细胞中的表达，这表明MSN-CUR@CM调节了典型和非典型的铁凋亡途径。总之，我们的研究表明，MSN-CUR@CM 具有高水溶性、生物相容性和肿瘤靶向性，可通过触发铁跃迁在体外和体内抑制胃癌，并提供令人钦佩的癌症治疗效果。

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引用次数: 0

Dosage by design − 3D printing individualized cabozantinib tablets with immediate release: Correspondence 剂量设计--3D 打印个性化卡博替尼片，立即释放：通讯

IF 4.4 2区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutics and Biopharmaceutics

Pub Date : 2024-10-02 DOI: 10.1016/j.ejpb.2024.114520

Hinpetch Daungsupawong , Viroj Wiwanitkit

引用次数: 0

Characterisation of skin penetration pathways using stimulated Raman scattering microscopy 利用受激拉曼散射显微镜鉴定皮肤渗透路径。

IF 4.4 2区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutics and Biopharmaceutics

Pub Date : 2024-10-01 DOI: 10.1016/j.ejpb.2024.114518

Anukrati Goel , Ruth Pendlington , Stephen Glavin , Tao Chen , Natalie A. Belsey

Understanding the mechanisms governing the penetration of substances into the skin is crucial for the development of safe and effective topical drug delivery systems and skincare products. This study examined the partitioning of model permeants into human skin, by assessing six substances with diverse logP values. We employed stimulated Raman scattering (SRS) microscopy, an ambient, label-free optical imaging technique known for its ability to provide chemical distribution with subcellular resolution. Our investigation assessed partitioning into the two primary pathways through which substances traverse the skin: the intercellular lipid matrix and the intracellular route via corneocyte cells. We observed that the partitioning behaviour was strongly influenced by the lipophilicity of the molecule, with lipophilic compounds showing greater affinity for intercellular matrix with increased lipophilicity. Conversely, hydrophilic molecules demonstrated a preference for corneocyte cells, with their affinity increasing with increased hydrophilicity. The findings contribute to our understanding of the mechanisms underlying topical delivery and offer important implications and new methods beneficial for the development of safe and effective topical products. In addition, the methods presented could be valuable to reveal changes in drug partitioning or to assess targeting approaches in diseased skin models.

了解物质渗透皮肤的机制对于开发安全有效的局部给药系统和护肤产品至关重要。本研究通过评估六种具有不同对数值的物质，研究了模型渗透剂在人体皮肤中的分配情况。我们采用了受激拉曼散射（SRS）显微镜，这是一种环境无标记光学成像技术，因其能够提供亚细胞分辨率的化学分布而闻名。我们的研究评估了物质穿过皮肤的两个主要途径：细胞间脂质基质和通过角质细胞的细胞内途径。我们观察到，分区行为受到分子亲脂性的强烈影响，亲脂性化合物随着亲脂性的增加而对细胞间基质表现出更大的亲和力。相反，亲水性分子则表现出对角质细胞的偏好，亲和力随着亲水性的增加而增加。这些发现有助于我们了解局部给药的基本机制，并为开发安全有效的局部产品提供了重要意义和新方法。此外，这些方法对于揭示药物分配的变化或评估病变皮肤模型的靶向方法也很有价值。

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引用次数: 0

Synergistic bactericidal effect of antimicrobial peptides and copper sulfide-loaded zeolitic imidazolate framework-8 nanoparticles with photothermal therapy 抗菌肽和硫化铜负载沸石咪唑啉框架-8 纳米粒子与光热疗法的协同杀菌效果。

IF 4.4 2区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutics and Biopharmaceutics

Pub Date : 2024-09-29 DOI: 10.1016/j.ejpb.2024.114516

Duoduo Zhang , Shiyue Bie , Mhd Anas Tomeh , Xinyu Zhang , Xiubo Zhao

Antimicrobial resistance (AMR) has emerged as a significant threat to human health. Antimicrobial peptides (AMPs) have proven to be an effective strategy against antibiotic-resistant bacteria, given their capacity to swiftly disrupt microorganism membranes and alter cell morphology. A common limitation, however, lies in the inherent toxicity of many AMPs and their vulnerability to protease degradation within the body. Photothermal therapy (PTT) stands out as a widely utilized approach in combating antibiotic-resistant bacterial infections, boasting high efficiency and non-invasive benefits. To enhance the stability and antibacterial efficacy of AMPs, a novel approach involving the combination of AMPs and PTT has been proposed. This study focuses on the encapsulation of At10 (an AMP designed by our group), and copper sulfide nanoparticles (CuS NPs) within zeolitic imidazolate framework-8 (ZIF-8) to form nanocomposites (At10/CuS@ZIF-8). The encapsulated CuS NPs exhibit notable photothermal properties upon exposure to near-infrared radiation. This induces the cleavage of ZIF-8, facilitating the release of At10, which effectively targets bacterial membranes to exert its antibacterial effects. Bacteria treated with At10/CuS@ZIF-8 under light radiation exhibited not only membrane folding and intracellular matrix outflow but also bacterial fracture. This synergistic antibacterial strategy, integrating the unique properties of AMPs, CuS NPs, and pH responsiveness of ZIF-8, holds promising potential for widespread application in the treatment of bacterial infections.

抗生素耐药性（AMR）已成为人类健康的重大威胁。抗菌肽（AMPs）能够迅速破坏微生物膜并改变细胞形态，因此已被证明是对付抗生素耐药性细菌的有效策略。然而，许多 AMPs 本身具有毒性，而且容易在体内被蛋白酶降解，这是它们的一个共同局限。光热疗法（PTT）是一种广泛应用于抗击抗生素耐药细菌感染的方法，具有高效、非侵入性等优点。为了提高 AMPs 的稳定性和抗菌功效，有人提出了一种将 AMPs 和 PTT 结合使用的新方法。本研究的重点是将 At10（本研究组设计的一种 AMP）和硫化铜纳米粒子（CuS NPs）封装在沸石咪唑啉框架-8（ZIF-8）中，形成纳米复合材料（At10/CuS@ZIF-8）。封装的 CuS NPs 在暴露于近红外辐射时会表现出显著的光热特性。这诱导了 ZIF-8 的裂解，促进了 At10 的释放，而 At10 能有效地针对细菌膜发挥抗菌作用。在光辐射下，用 At10/CuS@ZIF-8 处理的细菌不仅表现出膜折叠和胞内基质外流，还表现出细菌断裂。这种协同抗菌策略综合了 AMPs、CuS NPs 的独特性质和 ZIF-8 的 pH 响应性，有望广泛应用于细菌感染的治疗。

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引用次数: 0

Pharmacokinetic differences between subcutaneous injection and intradermal microneedle delivery of protein therapeutics 皮下注射和皮内微针给药的药代动力学差异。

IF 4.4 2区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutics and Biopharmaceutics

Pub Date : 2024-09-28 DOI: 10.1016/j.ejpb.2024.114517

Laura Koenitz, Abina Crean, Sonja Vucen

Protein therapeutics are essential in the treatment of various diseases, but most of them require parenteral administration. Since intravenous and subcutaneous injections are associated with discomfort and pain, other routes have been investigated including intradermal microneedle delivery. Microneedles are shorter than hypodermic needles and therefore minimize contact with pain receptors in deeper skin layers. But the differences in anatomical and physiological characteristics of dermis and subcutis can potentially result in varying protein penetration through the skin, absorption, and metabolism. This review summarizes pharmacokinetic studies that compare the administration of protein therapeutics by subcutaneous injections and different types of microneedles intradermally including hollow, dissolvable, coated, and hydrogel-forming microneedles. Across animal and human studies, hollow microneedle delivery resulted in quicker and higher peak plasma levels of proteins and comparable bioavailability to subcutaneous injections potentially due to the extensive network of lymphatic and blood vessels in the dermis. In case of dissolvable and coated microneedles, drug release kinetics depend on component materials. The dissolution of polymer excipients can slow the release and permeation of protein therapeutics at the administration site and thereby delay absorption. The understanding of drug penetration through different skin layers, its absorption into blood capillaries or lymphatics, and dermal metabolism remains limited. Additionally, the effects of these processes on the differences in pharmacokinetic profiles of proteins following intradermal microneedle administration are not well understood. Greater insights are required for the development of the next generation of intradermal microneedle biotherapeutics.

蛋白质疗法是治疗各种疾病的重要手段，但其中大多数需要肠外给药。由于静脉注射和皮下注射会带来不适和疼痛，因此人们研究了其他途径，包括皮内微针给药。微针比皮下注射针头短，因此能最大限度地减少与皮肤深层痛觉感受器的接触。但真皮层和皮下组织在解剖和生理特点上的差异可能会导致蛋白质在皮肤中的渗透、吸收和新陈代谢出现差异。本综述总结了通过皮下注射和不同类型的微针（包括空心微针、可溶微针、涂层微针和水凝胶微针）在皮肤内给药的药代动力学研究比较。在动物和人体研究中，空心微针给药使蛋白质的血浆峰值水平更快更高，生物利用度与皮下注射相当，这可能是由于真皮层有广泛的淋巴和血管网络。对于可溶解和涂层微针，药物释放动力学取决于组成材料。聚合物辅料的溶解会减缓蛋白质治疗药物在给药部位的释放和渗透，从而延迟吸收。人们对药物在不同皮肤层的渗透、毛细血管或淋巴管的吸收以及皮肤新陈代谢的了解仍然有限。此外，这些过程对皮内微针给药后蛋白质药代动力学特征差异的影响也不甚了解。开发新一代皮内微针生物治疗药物需要更深入的了解。

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引用次数: 0

Lyso-phosphatidylcholine as an interfacial stabilizer for parenteral monoclonal antibody formulations 溶血磷脂酰胆碱作为肠外单克隆抗体制剂的界面稳定剂。

IF 4.4 2区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutics and Biopharmaceutics

Pub Date : 2024-09-26 DOI: 10.1016/j.ejpb.2024.114514

Eleni Papadopoulos , Betharie Cendera Arrahmani , Katharina Beck , Wolfgang Friess

Therapeutic proteins suffer from physical and chemical instability in aqueous solution. Polysorbates and poloxamers are often added for protection against interfacial stress to prevent protein aggregation and particle formation. Previous studies have revealed that the hydrolysis and oxidation of polysorbates in parenteral formulations can lead to the formation of free fatty acid particles, insufficient long-term stabilization, and protein oxidation. Poloxamers, on the other hand, are considered to be less effective against protein aggregation. Here we investigated two lyso-phosphatidylcholines (LPCs) as potential alternative surfactants for protein formulations, focusing on their physicochemical behavior and their ability to protect against the formation of monoclonal antibody particles during mechanical stress.

The hemolytic activity of LPC was tested in varying ratios of plasma and buffer mixtures. LPC effectively stabilized mAb formulations when shaken at concentrations several orders of magnitude below the onset of hemolysis, indicating that the potential for erythrocyte damage by LPC is non-critical. LPC formulations subjected to mechanical stress through peristaltic pumping exhibited comparable protein particle formation to those containing polysorbate 80 or poloxamer 188. Profile analysis tensiometry and dilatational rheology indicated that the stabilizing effect likely arises from the formation of a viscoelastic film at approximately the CMC. Data gathered from concentration-gradient multi-angle light scattering and isothermal titration calorimetry support this finding. Surfactant desorption was evaluated through sub-phase exchange experiments. While LPCs readily desorbed from the interface, resorption occurred rapidly enough in the bulk solution to prevent protein adsorption. Overall, LPCs behave similarly to polysorbate with respect to interfacial stabilization and show promise as a potential substitute for polysorbate in parenteral protein formulations.

治疗用蛋白质在水溶液中存在物理和化学不稳定性。为了防止蛋白质聚集和颗粒形成，通常会添加聚山梨醇酯和聚氧乙烯酰胺来抵御界面应力。以往的研究表明，聚山梨醇酯在肠外制剂中的水解和氧化会导致游离脂肪酸颗粒的形成、长期稳定性不足以及蛋白质氧化。另一方面，聚氧乙烯酰胺被认为对防止蛋白质聚集的效果较差。在此，我们研究了两种溶血磷脂酰胆碱（LPC），将其作为蛋白质配方的潜在替代表面活性剂，重点关注它们的物理化学行为以及在机械应力作用下防止单克隆抗体颗粒形成的能力。在不同比例的血浆和缓冲液混合物中测试了 LPC 的溶血活性。当摇动浓度低于溶血起始浓度几个数量级时，LPC 可有效稳定 mAb 制剂，这表明 LPC 对红细胞的潜在破坏并不严重。通过蠕动泵施加机械应力的 LPC 制剂与含有聚山梨醇酯 80 或 poloxamer 188 的制剂相比，蛋白质颗粒的形成情况相当。剖面分析张力测定法和扩张流变学表明，稳定效果可能来自于在大约 CMC 处形成的粘弹性薄膜。浓度梯度多角度光散射和等温滴定量热法收集的数据也支持这一结论。通过亚相交换实验对表面活性剂解吸进行了评估。虽然 LPC 很容易从界面上解吸，但在大体积溶液中的再吸附速度很快，足以阻止蛋白质的吸附。总之，LPC 在界面稳定方面的表现与聚山梨醇酯类似，有望成为肠外蛋白质制剂中聚山梨醇酯的潜在替代品。

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引用次数: 0

Inhalable nano-structured microparticles for extracellular matrix modulation as a potential delivery system for lung cancer 用于调节细胞外基质的可吸入纳米结构微颗粒是一种潜在的肺癌给药系统。

IF 4.4 2区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutics and Biopharmaceutics

Pub Date : 2024-09-26 DOI: 10.1016/j.ejpb.2024.114512

Salma M. Abdel-Hafez , Markus Gallei , Sylvia Wagner , Marc Schneider

The use of inhalable nanoparticulate-based systems in the treatment of lung cancer allows for efficient localized delivery to the lungs with less undesirable systemic exposure. For this to be attained, the inhaled particles should have optimum properties for deposition and at the same time avoid pulmonary clearance mechanisms. Drug delivery to solid tumors is furthermore challenging, due to dense extracellular matrix (ECM) formation, which hinders the penetration and diffusion of therapeutic agents. To this end, the aim of the current work is to develop an ECM-modulating nano-structured microparticulate carrier, that not only enables the delivery of therapeutic nanoparticles (NPs) to the lungs, but also enhances their intratumoral penetration. The system is composed of acetalated maltodextrin (AcMD) NPs embedded into a water-soluble trehalose/leucine matrix, in which collagenase was loaded with different mass concentrations (10 %, 30 % and 50 %). The collagenase-containing AcMD nano-structured microparticles (MPs) exhibited suitable median volume diameters (2.58 ± 1.35 to 3.01 ± 0.68 µm), hollow corrugated morphology, sufficient redispersibility, low residual moisture content (2.71 ± 0.17 % to 3.10 ± 0.20 %), and favorable aerodynamic properties (Mass median aerodynamic diameter (MMAD): 1.93 ± 0.06 to 2.80 ± 0.10 µm and fine particle fraction (FPF): 68.02 ± 6.86 % to 69.62 ± 2.01 %). Importantly, collagenase retained as high as 89.5 ± 6.7 % of its enzymatic activity after spray drying. MPs containing 10 % mass content of collagenase did not show signs of cytotoxicity on either human lung adenocarcinoma A549 cells or lung MRC-5 fibroblasts. The nanoparticle penetration was tested using adenocarcinoma A549/MRC-5 co-culture spheroid model, where the inclusion of collagenase resulted in deeper penetration depth of AcMD-NPs.

在肺癌治疗中使用可吸入纳米微粒系统可以有效地将药物输送到肺部局部，减少不良的全身接触。要做到这一点，吸入的微粒应具有最佳的沉积特性，同时避免肺部清除机制。此外，由于致密细胞外基质（ECM）的形成阻碍了治疗药物的渗透和扩散，因此向实体瘤给药具有更大的挑战性。为此，当前工作的目标是开发一种可调节 ECM 的纳米结构微粒载体，它不仅能将治疗用纳米粒子（NPs）输送到肺部，还能增强其瘤内渗透。该系统由嵌入水溶性三卤糖/亮氨酸基质的乙缩醛麦芽糊精（AcMD）NPs组成，其中装载了不同质量浓度（10%、30% 和 50%）的胶原酶。含胶原酶的 AcMD 纳米结构微粒（MPs）具有合适的中值体积直径（2.58 ± 1.35 至 3.01 ± 0.68 µm）、中空波纹状形态、足够的再分散性、较低的残余水分含量（2.71 ± 0.17 % 至 3.10 ± 0.20 %）和良好的空气动力学特性（质量中值空气动力学直径 (MMAD)：1.93 ± 0.06 至 2.80 ± 0.10 µm 和细颗粒分数 (FPF)：68.02 ± 6.86 % 至 69.62 ± 2.01 %）。重要的是，胶原酶在喷雾干燥后的酶活性保持率高达 89.5 ± 6.7%。含有 10% 质量分数胶原蛋白酶的 MPs 对人类肺腺癌 A549 细胞或肺 MRC-5 成纤维细胞均无细胞毒性迹象。使用腺癌 A549/MRC-5 共培养球形模型测试了纳米粒子的渗透性，结果表明，加入胶原酶后，AcMD-NPs 的渗透深度更深。

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