Pharmaceutics最新文献_第4页

Influence of Aza-Glycine Substitution on the Internalization of Penetratin 氮杂甘氨酸取代对 Penetratin 内化的影响

Pharmaceutics

Pub Date : 2024-03-30 DOI: 10.3390/pharmaceutics16040477

Karima Tarchoun, Dóra Soltész, Viktor Farkas, Ho-Jin Lee, Ildikó Szabó, Z. Bánóczi

The cell-penetrating peptide (CPP) penetratin has gained much attention over many years due to its potential role as a transporter for a broad range of cargo into cells. The modification of penetratin has been extensively investigated too. Aza-peptides are peptide analogs in which one or more of the amino residues are replaced by a semicarbazide. This substitution results in conformational restrictions and modifications in hydrogen bonding properties, which affect the structure and may lead to enhanced activity and selectivity of the modified peptide. In this work, the Trp residues of penetratin were substituted by aza-glycine or glycine residues to examine the effect of these modifications on the cellular uptake and the internalization mechanism. The substitution of Trp48 or Trp48,56 dramatically reduced the internalization, showing the importance of Trp48 in cellular uptake. Interestingly, while aza-glycine in the position of Trp56 increased the cellular uptake, Gly reduced it. The two Trp-modified derivatives showed altered internalization pathways, too. Based on our knowledge, this is the first study about the effect of aza-amino acid substitution on the cell entry of CPPs. Our results suggest that aza-amino acid insertion is a useful modification to change the internalization of a CPP.

多年来，细胞穿透肽（CPP）穿透素一直备受关注，因为它具有将多种货物转运到细胞的潜在作用。对穿透肽的修饰也进行了广泛的研究。氮杂肽是一种肽类似物，其中一个或多个氨基残基被一种氨基脲取代。这种取代会导致构象限制和氢键性质的改变，从而影响结构，并可能提高修饰肽的活性和选择性。在这项研究中，用偶氮甘氨酸或甘氨酸残基取代了穿透素的 Trp 残基，以研究这些修饰对细胞摄取和内化机制的影响。Trp48或Trp48,56的取代大大降低了内化程度，显示了Trp48在细胞摄取中的重要性。有趣的是，在 Trp56 位置上的偶氮甘氨酸增加了细胞摄取，而 Gly 则减少了细胞摄取。两种 Trp 修饰衍生物的内化途径也发生了改变。据我们所知，这是首次研究偶氮氨基酸取代对 CPPs 进入细胞的影响。我们的研究结果表明，氮-氨基酸插入是改变 CPP 内化的一种有效修饰。

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引用次数: 0

Antimicrobial Effects of Some Natural Products on Adhesion and Biofilm Inhibition of Clostridioides difficile 一些天然产品对艰难梭菌粘附和生物膜抑制的抗菌作用

Pharmaceutics

Pub Date : 2024-03-30 DOI: 10.3390/pharmaceutics16040478

D. Wultańska, M. Piotrowski, H. Pituch

Understanding the potential antimicrobial properties of natural compounds and their impacts on Clostridioides difficile virulence factors may aid in developing alternative strategies for preventing and treating C. difficile infections (CDI). In this study, we investigated the bactericidal effects of ginger oil (GO), peppermint oil (PO), curcumin (CU), cinnamon aldehyde (CI), and trans-cinnamaldehyde (TCI) on the adhesion and biofilm disruption of C. difficile. We used three reference and five clinical C. difficile strains of different ribotypes. The bactericidal activity was assessed using the broth microdilution method. The adhesion was evaluated using human epithelial cell lines, and biofilm formation was visualized by confocal laser scanning microscopy. All tested strains exhibited susceptibility to CU, with minimum inhibitory concentration (MIC) values ranging from 128 µg/mL to 2048 µg/mL. Similarly, all strains were susceptible to CI and TCI, with MIC values ranging from 6.25% (v/v) to 25% (v/v). Most of the tested substances reduced the adhesion of C. difficile strains, while two tested strains showed significantly higher adhesion when co-incubated with the tested substances. Similar observations were made for biofilm formation, with observed density and morphology varied depending on the strain. In conclusion, the tested products demonstrated bactericidal activity and reduced the adhesion of C. difficile strains. They may be considered for further studies as potential antimicrobial agents targeting biofilm-related infections.

了解天然化合物的潜在抗菌特性及其对艰难梭菌毒力因子的影响有助于开发预防和治疗艰难梭菌感染（CDI）的替代策略。在这项研究中，我们调查了生姜油（GO）、薄荷油（PO）、姜黄素（CU）、肉桂醛（CI）和反式肉桂醛（TCI）对艰难梭菌的粘附和生物膜破坏的杀菌效果。我们使用了三种参考菌株和五种不同核型的临床艰难梭菌菌株。使用肉汤微稀释法评估了杀菌活性。利用人体上皮细胞系评估了粘附性，并通过共焦激光扫描显微镜观察了生物膜的形成。所有受测菌株都对 CU 具有敏感性，最低抑菌浓度 (MIC) 值从 128 微克/毫升到 2048 微克/毫升不等。同样，所有菌株对 CI 和 TCI 都有敏感性，最低抑菌浓度值从 6.25% (v/v) 到 25% (v/v)不等。大多数受测物质都能降低艰难梭菌菌株的粘附力，而两种受测菌株在与受测物质共培养时，粘附力明显增强。对生物膜的形成也有类似的观察结果，观察到的密度和形态因菌株而异。总之，受测产品具有杀菌活性，并能降低艰难梭菌菌株的粘附性。可以考虑将它们作为针对生物膜相关感染的潜在抗菌剂进行进一步研究。

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引用次数: 0

Transcriptomics- and Genomics-Guided Drug Repurposing for the Treatment of Vesicular Hand Eczema 转录组学和基因组学指导下的药物再利用以治疗手部水泡性湿疹

Pharmaceutics

Pub Date : 2024-03-30 DOI: 10.3390/pharmaceutics16040476

F. M. Rosenberg, Zoha Kamali, A. Voorberg, T. O. Oude Munnink, Peter J. van der Most, H. Snieder, Ahmad Vaez, M. Schuttelaar

Vesicular hand eczema (VHE), a clinical subtype of hand eczema (HE), showed limited responsiveness to alitretinoin, the only approved systemic treatment for severe chronic HE. This emphasizes the need for alternative treatment approaches. Therefore, our study aimed to identify drug repurposing opportunities for VHE using transcriptomics and genomics data. We constructed a gene network by combining 52 differentially expressed genes (DEGs) from a VHE transcriptomics study with 3 quantitative trait locus (QTL) genes associated with HE. Through network analysis, clustering, and functional enrichment analyses, we investigated the underlying biological mechanisms of this network. Next, we leveraged drug–gene interactions and retrieved pharmaco-transcriptomics data from the DrugBank database to identify drug repurposing opportunities for (V)HE. We developed a drug ranking system, primarily based on efficacy, safety, and practical and pricing factors, to select the most promising drug repurposing candidates. Our results revealed that the (V)HE network comprised 78 genes that yielded several biological pathways underlying the disease. The drug–gene interaction search together with pharmaco-transcriptomics lookups revealed 123 unique drug repurposing opportunities. Based on our drug ranking system, our study identified the most promising drug repurposing opportunities (e.g., vitamin D analogues, retinoids, and immunomodulating drugs) that might be effective in treating (V)HE.

水泡型手部湿疹（VHE）是手部湿疹（HE）的一种临床亚型，它对阿维A酸的反应有限，而阿维A酸是唯一获准用于治疗严重慢性手部湿疹的系统疗法。这强调了替代治疗方法的必要性。因此，我们的研究旨在利用转录组学和基因组学数据确定针对手部湿疹的药物再利用机会。我们将 VHE 转录组学研究中的 52 个差异表达基因（DEGs）与 3 个与 HE 相关的定量性状位点（QTL）基因相结合，构建了一个基因网络。通过网络分析、聚类和功能富集分析，我们研究了该网络的潜在生物学机制。接下来，我们利用药物与基因之间的相互作用，并从 DrugBank 数据库中检索药物转录组学数据，以确定针对 (V)HE 的药物再利用机会。我们开发了一个药物排名系统，主要基于疗效、安全性、实用性和价格因素，以选择最有前景的再利用候选药物。我们的研究结果表明，(V)HE 网络由 78 个基因组成，这些基因构成了该疾病的多个生物学通路。药物与基因相互作用搜索以及药物转录组学查询揭示了 123 个独特的药物再利用机会。根据我们的药物排序系统，我们的研究确定了可能有效治疗（V）HE 的最有前景的药物再利用机会（如维生素 D 类似物、维甲酸和免疫调节药物）。

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引用次数: 0

Understanding the Interaction of Thermal, Rheological, and Mechanical Parameters Critical for the Processability of Polyvinyl Alcohol-Based Systems during Hot Melt Extrusion 了解热熔挤压过程中对聚乙烯醇基体系加工性能至关重要的热、流变和机械参数的相互作用

Pharmaceutics

Pub Date : 2024-03-28 DOI: 10.3390/pharmaceutics16040472

Florian Hess, Thomas Kipping, W. Weitschies, Julius Krause

Hot melt extrusion (HME) is a common manufacturing process used in the pharmaceutical industry to improve the solubility of poorly soluble active pharmaceutical ingredients (API). The goal is to create an amorphous solid dispersion (ASD) where the amorphous form of the API is stabilized within a polymer matrix. Traditionally, the development of pharmaceutically approved polymers has focused on requirements such as thermal properties, solubility, drug–polymer interactions, and biocompatibility. The mechanical properties of the material have often been neglected in the design of new polymers. However, new downstream methods require more flexible polymers or suitable plasticizer polymer combinations. In this study, two grades of the polymer polyvinyl alcohol (PVA), which is already established for HME, are investigated in terms of their mechanical, rheological, and thermal properties. The mechanical properties of the extruded filaments were tested by the three-point bending test. The rheological behavior was analyzed by oscillating plate measurements. Thermal analysis was performed by differential scanning calorimetry (DSC). In addition, the solid and liquid plasticizers mannitol, sorbitol, triacetin, triethyl citrate, polyethylene glycol, and glycerol were evaluated for use with PVA and their impact on the polymer properties was elaborated. Finally, the effects of the plasticizers are compared to each other, and the correlations are analyzed statistically using principal component analysis (PCA). Thereby, a clear ranking of the plasticizer effects was established, and a deeper understanding of the polymer–plasticizer interactions was created.

热熔挤出（HME）是制药业常用的一种生产工艺，用于提高溶解性差的活性药物成分（API）的溶解度。其目的是制造一种无定形固体分散体 (ASD)，将原料药的无定形形式稳定在聚合物基质中。传统上，药用聚合物的开发主要关注热性能、溶解性、药物与聚合物的相互作用以及生物相容性等要求。在设计新型聚合物时，材料的机械性能往往被忽视。然而，新的下游方法需要更具柔韧性的聚合物或合适的增塑剂聚合物组合。在本研究中，对两种等级的聚合物聚乙烯醇（PVA）进行了机械、流变和热性能方面的研究。挤出丝的机械性能通过三点弯曲试验进行测试。流变行为通过振动板测量进行分析。热分析是通过差示扫描量热法（DSC）进行的。此外，还评估了固体和液体增塑剂甘露醇、山梨醇、三醋精、柠檬酸三乙酯、聚乙二醇和甘油与 PVA 配合使用的情况，并阐述了它们对聚合物特性的影响。最后，对增塑剂的影响进行了比较，并使用主成分分析法（PCA）对相关性进行了统计分析。因此，对增塑剂的影响进行了明确的排序，并加深了对聚合物与增塑剂之间相互作用的理解。

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引用次数: 0

Antiviral Effect of Antimicrobial Peptoid TM9 and Murine Model of Respiratory Coronavirus Infection 抗菌肽 TM9 的抗病毒作用和呼吸道冠状病毒感染小鼠模型

Pharmaceutics

Pub Date : 2024-03-27 DOI: 10.20944/preprints202402.1253.v1

Maxim Lebedev, Aaron B. Benjamin, Sathish Kumar, N. Molchanova, Jennifer S. Lin, Kent J. Koster, Julian L. Leibowitz, A. Barron, Jeffrey D. Cirillo

New antiviral agents are essential to improving treatment and control of SARS-CoV-2 infections that can lead to the disease COVID-19. Antimicrobial peptoids are sequence-specific oligo-N-substituted glycine peptidomimetics that emulate the structure and function of natural antimicrobial peptides but are resistant to proteases. We demonstrate antiviral activity of a new peptoid (TM9) against the coronavirus, murine hepatitis virus (MHV), as a closely related model for the structure and antiviral susceptibility profile of SARS-CoV-2. This peptoid mimics the human cathelicidin LL-37, which has also been shown to have antimicrobial and antiviral activity. In this study, TM9 was effective against three murine coronavirus strains, demonstrating that the therapeutic window is large enough to allow the use of TM9 for treatment. All three isolates of MHV generated infection in mice after 15 min of exposure by aerosol using the Madison aerosol chamber, and all three viral strains could be isolated from the lungs throughout the 5-day observation period post-infection, with the peak titers on day 2. MHV-A59 and MHV-A59-GFP were also isolated from the liver, heart, spleen, olfactory bulbs, and brain. These data demonstrate that MHV serves as a valuable natural murine model of coronavirus pathogenesis in multiple organs, including the brain.

SARS-CoV-2 感染可导致 COVID-19 疾病，新的抗病毒药物对改善治疗和控制至关重要。抗菌肽是一种序列特异的寡-N-取代甘氨酸拟肽物，它模仿天然抗菌肽的结构和功能，但对蛋白酶具有抗性。我们展示了一种新型拟肽类化合物（TM9）对冠状病毒--小鼠肝炎病毒（MHV）的抗病毒活性，MHV 是一种与 SARS-CoV-2 的结构和抗病毒敏感性特征密切相关的模型。这种蛋白胨模仿人类柔毛素 LL-37，后者也被证明具有抗菌和抗病毒活性。在这项研究中，TM9 对三种小鼠冠状病毒株都有效，这表明治疗窗口足够大，可以使用 TM9 进行治疗。在使用麦迪逊气溶胶室进行气溶胶暴露 15 分钟后，所有三种 MHV 分离物都会在小鼠体内产生感染，在感染后的 5 天观察期内，所有三种病毒株都能从肺部分离出来，滴度在第 2 天达到峰值。从肝脏、心脏、脾脏、嗅球和大脑中也分离到了 MHV-A59 和 MHV-A59-GFP。这些数据表明，MHV 是冠状病毒在包括大脑在内的多个器官中致病的一种有价值的天然小鼠模型。

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引用次数: 0

Novel Dry Hyaluronic Acid–Vancomycin Complex Powder for Inhalation, Useful in Pulmonary Infections Associated with Cystic Fibrosis 新型吸入用透明质酸-万古霉素复合干粉，可用于治疗与囊性纤维化有关的肺部感染

Pharmaceutics

Pub Date : 2024-03-22 DOI: 10.3390/pharmaceutics16040436

María S. Magi, Yanina de Lafuente, Eride Quarta, M. Palena, Perla del R. Ardiles, Paulina L. Páez, F. Sonvico, F. Buttini, A. Jimenez‐Kairuz

Polyelectrolyte–drug complexes are interesting alternatives to improve unfavorable drug properties. Vancomycin (VAN) is an antimicrobial used in the treatment of methicillin-resistant Staphylococcus aureus pulmonary infections in patients with cystic fibrosis. It is generally administered intravenously with a high incidence of adverse side effects, which could be reduced by intrapulmonary administration. Currently, there are no commercially available inhalable formulations containing VAN. Thus, the present work focuses on the preparation and characterization of an ionic complex between hyaluronic acid (HA) and VAN with potential use in inhalable formulations. A particulate–solid HA-VAN25 complex was obtained by spray drying from an aqueous dispersion. FTIR spectroscopy and thermal analysis confirmed the ionic interaction between HA and VAN, while an amorphous diffraction pattern was observed by X-ray. The powder density, geometric size and morphology showed the suitable aerosolization and aerodynamic performance of the powder, indicating its capability of reaching the deep lung. An in vitro extended-release profile of VAN from the complex was obtained, exceeding 24 h. Microbiological assays against methicillin-resistant and -sensitive reference strains of Staphylococcus aureus showed that VAN preserves its antibacterial efficacy. In conclusion, HA-VAN25 exhibited interesting properties for the development of inhalable formulations with potential efficacy and safety advantages over conventional treatment.

聚电解质药物复合物是改善药物不良特性的有趣替代品。万古霉素（VAN）是一种抗菌药，用于治疗囊性纤维化患者的耐甲氧西林金黄色葡萄球菌肺部感染。该药一般采用静脉注射，不良副作用发生率较高，而肺内给药可减少不良副作用。目前，市场上还没有含 VAN 的可吸入制剂。因此，本研究的重点是制备透明质酸（HA）和 VAN 之间的离子复合物并确定其特性，该复合物有望用于吸入制剂。通过喷雾干燥从水分散液中获得了颗粒状固体 HA-VAN25 复合物。傅立叶变换红外光谱和热分析证实了 HA 和 VAN 之间的离子相互作用，而 X 射线则观察到了无定形衍射图样。粉末密度、几何尺寸和形态显示了粉末的气溶胶化和空气动力学性能，表明其能够进入肺部深处。针对耐甲氧西林和对甲氧西林敏感的金黄色葡萄球菌参考菌株的微生物学检测表明，VAN 保持了其抗菌功效。总之，HA-VAN25 具有令人感兴趣的特性，可用于开发可吸入制剂，与传统疗法相比，具有潜在的疗效和安全性优势。

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引用次数: 0

Improving the Efficacy of Common Cancer Treatments via Targeted Therapeutics towards the Tumour and Its Microenvironment 通过针对肿瘤及其微环境的靶向治疗提高常见癌症疗法的疗效

Pharmaceutics

Pub Date : 2024-01-26 DOI: 10.3390/pharmaceutics16020175

Daniel Cecchi, Nolan Jackson, Wayne Beckham, D. Chithrani

Cancer is defined as the uncontrolled proliferation of heterogeneous cell cultures in the body that develop abnormalities and mutations, leading to their resistance to many forms of treatment. Left untreated, these abnormal cell growths can lead to detrimental and even fatal complications for patients. Radiation therapy is involved in around 50% of cancer treatment workflows; however, it presents significant recurrence rates and normal tissue toxicity, given the inevitable deposition of the dose to the surrounding healthy tissue. Chemotherapy is another treatment modality with excessive normal tissue toxicity that significantly affects patients’ quality of life. To improve the therapeutic efficacy of radiotherapy and chemotherapy, multiple conjunctive modalities have been proposed, which include the targeting of components of the tumour microenvironment inhibiting tumour spread and anti-therapeutic pathways, increasing the oxygen content within the tumour to revert the hypoxic nature of the malignancy, improving the local dose deposition with metal nanoparticles, and the restriction of the cell cycle within radiosensitive phases. The tumour microenvironment is largely responsible for inhibiting nanoparticle capture within the tumour itself and improving resistance to various forms of cancer therapy. In this review, we discuss the current literature surrounding the administration of molecular and nanoparticle therapeutics, their pharmacokinetics, and contrasting mechanisms of action. The review aims to demonstrate the advancements in the field of conjugated nanomaterials and radiotherapeutics targeting, inhibiting, or bypassing the tumour microenvironment to promote further research that can improve treatment outcomes and toxicity rates.

癌症是指体内异质细胞不受控制地增殖，出现异常和突变，导致对多种治疗方式产生抗药性。如果不及时治疗，这些异常增生的细胞会给患者带来有害甚至致命的并发症。放射治疗约占癌症治疗流程的 50%，但由于放射剂量不可避免地会沉积到周围的健康组织，因此复发率和正常组织毒性都很高。化疗是另一种正常组织毒性过大的治疗方式，严重影响患者的生活质量。为了提高放疗和化疗的疗效，人们提出了多种联合治疗方式，包括针对肿瘤微环境中抑制肿瘤扩散和抗治疗途径的成分，增加肿瘤内的氧含量以恢复恶性肿瘤的缺氧特性，利用金属纳米粒子改善局部剂量沉积，以及将细胞周期限制在放射敏感期内。肿瘤微环境在很大程度上抑制了肿瘤本身对纳米粒子的捕获，并提高了对各种癌症疗法的抗药性。在这篇综述中，我们将讨论有关分子和纳米粒子疗法的用药、药代动力学和作用机制对比的现有文献。该综述旨在展示靶向、抑制或绕过肿瘤微环境的共轭纳米材料和放射治疗领域的进展，以促进可改善治疗效果和毒性率的进一步研究。

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引用次数: 0

Gemcitabine-Vitamin E Prodrug-Loaded Micelles for Pancreatic Cancer Therapy 用于胰腺癌治疗的吉西他滨-维生素 E 原药载体胶束

Pharmaceutics

Pub Date : 2024-01-10 DOI: 10.3390/pharmaceutics16010095

M. Pereira-Silva, Darío Miranda-Pastoriza, Luis Diaz-Gomez, Eddy Sotelo, A. C. Paiva-Santos, Francisco Veiga, A. Concheiro, C. Alvarez‐Lorenzo

Pancreatic cancer (PC) is an aggressive cancer subtype presenting unmet clinical challenges. Conventional chemotherapy, which includes antimetabolite gemcitabine (GEM), is seriously undermined by a short half-life, its lack of targeting ability, and systemic toxicity. GEM incorporation in self-assembled nanosystems is still underexplored due to GEM’s hydrophilicity which hinders efficient encapsulation. We hypothesized that vitamin E succinate–GEM prodrug (VES-GEM conjugate) combines hydrophobicity and multifunctionalities that can facilitate the development of Pluronic®F68 and Pluronic®F127 micelle-based nanocarriers, improving the therapeutic potential of GEM. Pluronic®F68/VES-GEM and Pluronic®F127/VES-GEM micelles covering a wide range of molar ratios were prepared by solvent evaporation applying different purification methods, and characterized regarding size, charge, polydispersity index, morphology, and encapsulation. Moreover, the effect of sonication and ultrasonication and the influence of a co-surfactant were explored together with drug release, stability, blood compatibility, efficacy against tumour cells, and cell uptake. The VES-GEM conjugate-loaded micelles showed acceptable size and high encapsulation efficiency (>95%) following an excipient reduction rationale. Pluronic®F127/VES-GEM micelles evidenced a superior VES-GEM release profile (cumulative release > 50%, pH = 7.4), stability, cell growth inhibition (<50% cell viability for 100 µM VES-GEM), blood compatibility, and extensive cell internalization, and therefore represent a promising approach to leveraging the efficacy and safety of GEM for PC-targeted therapies.

胰腺癌（PC）是一种具有侵袭性的癌症亚型，其临床挑战尚未得到解决。包括抗代谢药物吉西他滨（GEM）在内的传统化疗因半衰期短、缺乏靶向能力和全身毒性而受到严重破坏。由于吉西他滨（GEM）的亲水性阻碍了其有效封装，因此在自组装纳米系统中加入 GEM 的研究仍显不足。我们假设维生素 E 琥珀酸盐-GEM 原药（VES-GEM 共轭物）兼具疏水性和多功能性，可以促进基于 Pluronic®F68 和 Pluronic®F127 胶束的纳米载体的开发，提高 GEM 的治疗潜力。采用不同的纯化方法，通过溶剂蒸发制备了不同摩尔比的 Pluronic®F68/VES-GEM 和 Pluronic®F127/VES-GEM 胶束，并对其尺寸、电荷、多分散指数、形态和包封性进行了表征。此外，还探讨了超声和超声处理的效果以及辅助表面活性剂的影响，以及药物的释放、稳定性、血液相容性、对肿瘤细胞的疗效和细胞吸收。通过减少辅料，VES-GEM 共轭胶束显示出可接受的尺寸和较高的封装效率（>95%）。Pluronic®F127/VES-GEM胶束具有优异的VES-GEM释放特性（累积释放>50%，pH = 7.4）、稳定性、细胞生长抑制（100 µM VES-GEM的细胞存活率<50%）、血液相容性和广泛的细胞内化，因此是利用GEM的有效性和安全性进行PC靶向治疗的一种很有前景的方法。

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引用次数: 0

A New Bevacizumab Carrier for Intravitreal Administration: Focus on Stability. 一种新的贝伐单抗玻璃体内给药载体:关注稳定性。

IF 5.4

Pharmaceutics

Pub Date : 2021-04-15 DOI: 10.3390/pharmaceutics13040560

Daniela Chirio, Elena Peira, Simona Sapino, Giulia Chindamo, Simonetta Oliaro-Bosso, Salvatore Adinolfi, Chiara Dianzani, Francesca Baratta, Marina Gallarate

Bevacizumab (BVZ) is a monoclonal antibody that binds to human vascular endothelial growth factor A (VEGF-A) and inhibits the interaction between VEGF-A and VEGF receptors, thus blocking the angiogenesis. Repeated intravitreal injections of BVZ for the treatment of ocular pathologies that present an excessive proliferation results in a low patience compliance. BVZ is specially indicated for the treatment of diabetic and degenerative retinopathy. In the present study, we designed lipid nanoparticles (NPs) as a BVZ sustained drug delivery system for reducing the frequency of administration. We used a simple and highly efficient procedure, "Cold dilution of microemulsions", to obtain spherical NPs with mean diameters of 280-430 nm, Zeta potentials between -17 and -31 mV, and drug entrapment efficiencies between 50 to 90%. This study focused on the biochemical and biophysical stabilities of BVZ after entrapment in NPs. SDS-PAGE electrophoretic analysis and circular dichroism, dynamic light scattering, and scanning electron microscopy were used to characterize BVZ-loaded NPs. The biocompatibility was assessed by in vitro cell compatibility studies using the ARPE-19 cell line. Thus, in this work, a stable BVZ-loaded system was obtained. In addition, several studies have shown that BVZ is released slowly from the lipid matrix and that this system is biocompatible. The results are promising and the developed NPs could be exploited to create a new, potentially effective and minimally invasive treatment of intraocular diseases.

贝伐单抗(Bevacizumab, BVZ)是一种与人血管内皮生长因子a (VEGF- a)结合，抑制VEGF- a与VEGF受体相互作用，从而阻断血管生成的单克隆抗体。玻璃体内反复注射BVZ治疗过度增生的眼部病变导致患者依从性低。BVZ特别适用于糖尿病和退行性视网膜病变的治疗。在本研究中，我们设计了脂质纳米颗粒(NPs)作为BVZ持续给药系统，以减少给药频率。我们使用了一种简单高效的方法，即“微乳冷稀释”，获得了平均直径为280-430 nm的球形NPs, Zeta电位在-17到-31 mV之间，药物包封效率在50%到90%之间。本研究的重点是BVZ在NPs中包埋后的生化和生物物理稳定性。利用SDS-PAGE电泳分析、圆二色性、动态光散射和扫描电镜对负载bvz的NPs进行表征。采用ARPE-19细胞系进行体外细胞相容性研究，评价其生物相容性。因此，在这项工作中，得到了一个稳定的bvz负载系统。此外，一些研究表明BVZ从脂质基质中缓慢释放，并且该系统具有生物相容性。结果是有希望的，开发的NPs可以用来创造一种新的、潜在有效的微创眼内疾病治疗方法。

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引用次数: 9

The Current Status of Clinical Research Involving Microneedles: A Systematic Review. 微针的临床研究现状:系统综述。

IF 5.4

Pharmaceutics

Pub Date : 2020-11-19 DOI: 10.3390/pharmaceutics12111113

Seung-Yeon Jeong, Jung-Hwan Park, Ye-Seul Lee, Youn-Sub Kim, Ji-Yeun Park, Song-Yi Kim

In recent years, a number of clinical trials have been published on the efficacy and safety of drug delivery using microneedles (MNs). This review aims to systematically summarize and analyze the current evidence including the clinical effect and safety of MNs. Three electronic databases, including PubMed, were used to search the literature for randomized controlled trials (RCTs) and clinical controlled trials (CCTs) that evaluated the therapeutic efficacy of MNs from their inception to 28 June 2018. Data were extracted according to the characteristics of study subjects; disorder, types, and details of the intervention (MNs) and control groups; outcome measurements; effectiveness; and incidence of adverse events (AEs). Overall, 31 RCTs and seven CCTs met the inclusion criteria. Although MNs were commonly used in skin-related studies, evaluating the effects of MNs was difficult because many studies did not provide adequate comparison values between groups. For osteoporosis treatment, vaccine, and insulin delivery studies, MNs were comparable to or more effective than the gold standard. Regarding the safety of MNs, most AEs reported in each study were minor (grade 1 or 2). A well-designed RCT is necessary to clearly evaluate the effectiveness of MNs in the future.

近年来，许多关于微针给药的有效性和安全性的临床试验已经发表。本综述旨在系统总结和分析目前的证据，包括MNs的临床疗效和安全性。包括PubMed在内的三个电子数据库用于检索随机对照试验(rct)和临床对照试验(cct)的文献，这些试验评估了MNs从成立到2018年6月28日的治疗效果。根据研究对象的特征提取数据;干预(MNs)和对照组的障碍、类型和细节;测量结果;有效性;不良事件(ae)的发生率。总的来说，31项随机对照试验和7项随机对照试验符合纳入标准。虽然MNs通常用于皮肤相关研究，但评估MNs的效果是困难的，因为许多研究没有提供足够的组间比较值。在骨质疏松治疗、疫苗和胰岛素递送研究中，MNs与金标准相当或比金标准更有效。关于MNs的安全性，每项研究中报道的大多数ae都是轻微的(1级或2级)。为了清晰地评估MNs的有效性，需要设计良好的随机对照试验。

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引用次数: 25