International Journal of Pharmaceutics最新文献

Chitosan gel loaded with carbon dots and mesoporous hydroxyapatite nanoparticles as a topical formulation for skin regeneration: An animal study 壳聚糖凝胶负载碳点和介孔羟基磷灰石纳米颗粒，作为皮肤再生的局部配方：动物实验

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2024-10-14 DOI: 10.1016/j.ijpharm.2024.124828

Background

Carbon dots (CDs) are the research hotspots in antimicrobial applications. Also, due to the importance of calcium ions in skin regeneration, mesoporous hydroxyapatite nanoparticles (mHAP NPs) were prepared. This study aimed to evaluate the wound healing efficiency of both CD and mHAP NPs simultaneously.

Methods

We doped Fluorine (F) and Copper (Cu) in CDs to prepare Cu*F-doped CDs (Cu.CDs). For the rapid release of calcium ions, a novel double-surfactant system (CTAB/F-127) was used for the synthesis of mHAP NPs. Then, we loaded both Cu.CDs and mHAP NPs simultaneously into the chitosan (CTS) gel.

Results

The released calcium for mHAP NPs prepared using CTAB/F-127 was proved about 30 % higher than that prepared using only CTAB, after one day. The BET-specific surface area for mHAP NPs prepared using CTAB/F-127 was 23.17 % more than that prepared using only CTAB. This high porosity improves wound exudate absorption. Rheological analysis showed that the addition of both mHAP NPs and Cu.CD decreases the viscosity of CTS gel and thereby makes it suitable for topical applications. CTS gel containing mHAP + Cu.CDs indicated exceptional antibacterial properties even without light and/or H₂O₂ with an inhibition zone diameter of 35 and 17 mm for E. coli and S. aureus species, respectively. CTS gel containing mHAP + Cu.CDs also showed significantly higher wound closure efficacy, greater inflammation inhibition, and better re-epithelialization than the other groups in rats with full-thickness skin wounds.

Conclusion

The CTS gel containing both Cu.CD and mHAP NPs can be proposed as a new therapeutic gel for wound healing.

背景碳点（CD）是抗菌应用领域的研究热点。同时，由于钙离子在皮肤再生中的重要性，人们制备了介孔羟基磷灰石纳米颗粒（mHAP NPs）。本研究旨在同时评估 CD 和 mHAP NPs 的伤口愈合效率。方法我们在 CD 中掺入氟（F）和铜（Cu），制备出 Cu*F 掺杂 CD（Cu.CDs）。为了快速释放钙离子，我们使用了一种新型的双表面活性剂体系（CTAB/F-127）来合成 mHAP NPs。结果一天后，使用 CTAB/F-127 制备的 mHAP NPs 的钙释放量比仅使用 CTAB 制备的高出约 30%。使用 CTAB/F-127 制备的 mHAP NPs 的 BET 比表面积比仅使用 CTAB 制备的 mHAP NPs 高 23.17%。这种高孔隙率提高了伤口渗出物的吸收率。流变学分析表明，同时添加 mHAP NPs 和 Cu.CD 可降低 CTS 凝胶的粘度，从而使其适合局部应用。含有 mHAP + Cu.CDs 的 CTS 凝胶即使在没有光和/或 H2O2 的情况下也具有卓越的抗菌性能，对大肠杆菌和金黄色葡萄球菌的抑制区直径分别为 35 毫米和 17 毫米。含有 mHAP + Cu.CDs 的 CTS 凝胶对全厚皮肤伤口大鼠的伤口闭合效果、炎症抑制效果和上皮再形成效果也明显高于其他组别。

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引用次数: 0

Quality by design-based optimization of teriflunomide and quercetin combinational topical transferosomes for the treatment of rheumatoid arthritis 基于设计的特立氟胺和槲皮素组合外用转移体的质量优化，用于治疗类风湿性关节炎

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2024-10-13 DOI: 10.1016/j.ijpharm.2024.124829

Rheumatoid arthritis (RA) is an immune-mediated inflammatory disease. Combination therapy is anticipated to surpass monotherapy by targeting multiple pathways involved in RA progression. The present aim is to develop a combination of Teriflunomide (TFD) and Quercetin (QCN) loaded transferosomal gel to enhance permeability and achieve localized delivery to joint tissues. TFD or QCN transferosomes were optimized employing a 3-level, 3-factorial design Box-Behnken design (BBD). The transferosomes exhibited sustained in-vitro drug release. The topical combination gel underwent thorough evaluation of rheology, and also ex-vivo studies showed enhanced permeability through rat skin. The synergistic combination of TFD and QCN effectively suppressed NO, TNF-α and IL-6 levels in in-vitro RAW 264.7 cells. The cytotoxicity in HaCaT cell lines indicates non-toxicity of the gel, further confirmed by skin irritation study conducted in rats. The in-vivo anti-arthritic activity was evaluated in complete freund’s adjuvant induced rat paw edema model illustrates the effectiveness of the combination transferosomal gel compared to other treatment groups. In conclusion, the topical delivery of TFD and QCN combination transferosomal gel demonstrated anti-arthritic activity through localized delivery whichallows for dose reduction, thereby may reduce the systemic drug exposure and mitigate the side effects associated with oral administration of TFD.

类风湿性关节炎（RA）是一种免疫介导的炎症性疾病。通过靶向参与类风湿关节炎进展的多种途径，联合疗法有望超越单一疗法。本研究旨在开发一种特立氟胺（TFD）和槲皮素（QCN）负载型转运体凝胶组合，以增强渗透性并实现向关节组织的局部给药。采用 3 级 3 因子设计方框-贝肯设计（BBD）对 TFD 或 QCN 转运体进行了优化。转移体在体外表现出持续的药物释放。对外用组合凝胶的流变性进行了全面评估，体内外研究也显示其在大鼠皮肤中的渗透性有所提高。TFD 和 QCN 的协同组合能有效抑制体外 RAW 264.7 细胞中的 NO、TNF-α 和 IL-6 水平。对 HaCaT 细胞系的细胞毒性表明凝胶无毒性，对大鼠皮肤的刺激性研究进一步证实了这一点。在完全弗伦德佐剂诱导的大鼠爪水肿模型中对体内抗关节炎活性进行了评估，结果表明与其他治疗组相比，转运体凝胶组合具有很好的疗效。总之，局部给药的 TFD 和 QCN 组合转运体凝胶通过局部给药显示了抗关节炎活性，从而可以减少剂量，减少全身药物暴露，减轻与口服 TFD 相关的副作用。

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引用次数: 0

Silk fibroin/chitosan thiourea hydrogel scaffold with vancomycin and quercetin-loaded PLGA nanoparticles for treating chronic MRSA osteomyelitis in rats 蚕丝纤维素/壳聚糖硫脲水凝胶支架与万古霉素和槲皮素负载的 PLGA 纳米粒子用于治疗大鼠慢性 MRSA 骨髓炎

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2024-10-12 DOI: 10.1016/j.ijpharm.2024.124826

Chronic osteomyelitis presents significant treatment challenges, necessitating an efficient system for infection elimination and bone repair. This study developed a natural hydrogel scaffold using silk fibroin (SF) and chitosan thiourea (CST), incorporating vancomycin (VC) and quercetin (QC) loaded PLGA nanoparticles (NPs) for dual-purpose treatment. SF/CST hydrogel scaffolds exhibited homogeneous porosity and smaller interconnected pore size than pure SF and pure CST hydrogel scaffolds. Optimal PLGA/QC NPs measured 206 nm in size, displayed spherical morphology, had uniform distribution, and achieved 87 % QC loading. The release study showed sustained long-term release of VC and QC from the hydrogel scaffolds for over 20 days. Biocompatibility tests indicated that hydrogel scaffolds promoted osteoblast adhesion without cytotoxicity, with QC-containing scaffolds enhancing osteoblast growth. Antibacterial tests confirmed retained VC activity against methicillin-resistant Staphylococcus aureus (MRSA) in SF/CST. An experimental study assessed the efficacy of the hydrogel scaffolds in a MRSA-infected rat osteomyelitis model. Radiographic scores demonstrated a significant reduction for SF/CST-VC-PLGA/QC NPs compared to control, indicating reduced osteomyelitis effects. Macroscopic evaluations showed notable reductions in gross pathological effects for VC-containing groups. Histopathological assessments revealed significantly lower osteomyelitis scores and higher healing scores in the SF/CST-VC-PLGA/QC NPs, with reduced inflammatory cell infiltration and more organized connective tissue formation. In conclusion, SF/CST-VC-PLGA/QC NPs is an effective dual drug delivery system for osteomyelitis treatment, demonstrating significant antibacterial activity, enhanced bone regeneration, and reduced infection rate.

慢性骨髓炎给治疗带来了巨大挑战，需要一种高效的系统来消除感染和修复骨骼。本研究利用蚕丝纤维素（SF）和壳聚糖硫脲（CST）开发了一种天然水凝胶支架，并加入了万古霉素（VC）和槲皮素（QC）负载的聚乳酸（PLGA）纳米颗粒（NPs），用于双重治疗。与纯 SF 和纯 CST 水凝胶支架相比，SF/CST 水凝胶支架显示出均匀的孔隙率和较小的互连孔径。最佳的 PLGA/QC NPs 大小为 206 nm，呈球形，分布均匀，QC 负载率达到 87%。释放研究显示，VC 和 QC 从水凝胶支架中长期持续释放超过 20 天。生物相容性测试表明，水凝胶支架可促进成骨细胞粘附，且无细胞毒性，含 QC 的支架可促进成骨细胞生长。抗菌测试证实，SF/CST 对耐甲氧西林金黄色葡萄球菌（MRSA）保持了 VC 活性。一项实验研究评估了水凝胶支架在 MRSA 感染的大鼠骨髓炎模型中的功效。与对照组相比，SF/CST-VC-PLGA/QC NPs 的放射学评分明显降低，这表明骨髓炎效应有所减弱。宏观评估显示，含 VC 组的大体病理效应明显降低。组织病理学评估显示，SF/CST-VC-PLGA/QC NPs 组的骨髓炎评分明显较低，愈合评分较高，炎性细胞浸润减少，结缔组织形成更有组织。总之，SF/CST-VC-PLGA/QC NPs 是一种治疗骨髓炎的有效双重给药系统，具有显著的抗菌活性，能促进骨再生并降低感染率。

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引用次数: 0

Erlotinib and curcumin-loaded nanoparticles embedded in thermosensitive chitosan hydrogels for enhanced treatment of head and neck cancer 嵌入热敏壳聚糖水凝胶的厄洛替尼和姜黄素负载纳米粒子用于增强头颈癌的治疗效果

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2024-10-12 DOI: 10.1016/j.ijpharm.2024.124825

Head and neck squamous cell carcinoma (HNSCC) remain a major oncological challenge with significant morbidity and mortality rates. Erlotinib (Er) and Curcumin (Cm) are potential therapeutic agents for HNSCC, yet they are hindered by poor solubility and bioavailability. This study explored the optimization of poly(lactic-co-glycolic acid) nanoparticles co-loaded with Er and Cm (Er/Cm-NP), prepared via a D-optimal response surface design-guided nanoprecipitation process. The optimized formulation, optEr/Cm-NP, was then incorporated into chitosan/β-glycerophosphate hydrogels (optEr/Cm-NP-HG) to create an injectable intratumoral (IT) nanocomposite hydrogel (HG) delivery system. Physicochemical properties of the formulations, including gelation time, injectability, mechanical strength and drug release profiles were assessed alongside hemolytic activity. Compared to optEr/Cm-NP alone, the NP-loaded HG formulation exhibited a more pronounced modulation effect, enabling sustained and controlled drug release. The cytotoxicity of the developed formulations was evaluated using the FaDu HNSCC cancer cell line. Both optEr/Cm-NP and optEr/Cm-NP-HG21 displayed enhanced cytotoxicity compared to free drugs. Confocal laser microscopy and flow cytometry confirmed superior cellular uptake of Er and Cm when delivered via NPs or NP-loaded HG. Furthermore, a significant increase in apoptotic cell death upon treatment with optEr/Cm-NP was observed, highlighting its potential for HNSCC therapy. In vivo studies conducted on a xenograft HNSCC mouse model revealed the significant capacity of the intratumorally-injected optEr/Cm-NP-HG21 formulation to retard the tumor growth. Conclusively, the results presented herein report the successful development of a nanocomposite HG system incorporating NPs co-loaded with Er and Cm that could be efficiently utilized in the treatment of HNSCC.

头颈部鳞状细胞癌（HNSCC）仍是一项重大的肿瘤挑战，发病率和死亡率都很高。厄洛替尼（Er）和姜黄素（Cm）是治疗 HNSCC 的潜在药物，但它们的溶解性和生物利用度较差。本研究探讨了优化聚（乳酸-共聚乙醇酸）纳米粒子与 Er 和 Cm（Er/Cm-NP）共载的问题，该纳米粒子是通过 D-最佳响应面设计引导的纳米沉淀工艺制备的。然后将优化配方 optEr/Cm-NP 加入壳聚糖/β-甘油磷酸酯水凝胶（optEr/Cm-NP-HG）中，制成可注射的瘤内（IT）纳米复合水凝胶（HG）递送系统。在评估溶血活性的同时，还评估了制剂的理化特性，包括凝胶时间、可注射性、机械强度和药物释放曲线。与单独使用 optEr/Cm-NP 相比，负载 NP 的 HG 制剂表现出更明显的调节作用，能实现持续、可控的药物释放。使用 FaDu HNSCC 癌细胞系对所开发制剂的细胞毒性进行了评估。与游离药物相比，optEr/Cm-NP 和 optEr/Cm-NP-HG21 均显示出更强的细胞毒性。激光共聚焦显微镜和流式细胞术证实，通过 NPs 或 NP-loaded HG 给药时，细胞对 Er 和 Cm 的吸收率更高。此外，在使用 optEr/Cm-NP 治疗时，观察到凋亡细胞的数量明显增加，这突显了它在 HNSCC 治疗中的潜力。在异种移植 HNSCC 小鼠模型上进行的体内研究显示，瘤内注射 optEr/Cm-NP-HG21 制剂能显著延缓肿瘤生长。总之，本文介绍的结果报告了一种纳米复合 HG 系统的成功开发，该系统包含了共同负载 Er 和 Cm 的 NPs，可有效用于治疗 HNSCC。

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引用次数: 0

Influence of L-leucine content on the aerosolization stability of spray-dried protein dry powder inhalation (DPI) 左旋亮氨酸含量对喷雾干燥蛋白质干粉吸入剂（DPI）气溶胶稳定性的影响

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2024-10-12 DOI: 10.1016/j.ijpharm.2024.124822

Inhalable formulations of medicines intended to act locally in the lung are therapeutically effective at lower doses with targeted delivery, compared to parenteral or oral administration. Meanwhile, different APIs, including biologics, have proven to be challenging regarding formulation and final bioavailability. This study focuses on the production, improved stability performance, and delivery of spray-dried, inhalable protein powders to the lungs. By spray-drying 11 aqueous formulations of proteinX with varying L-leucine content and by employing a Design of Experiment (DoE), two formulations have been selected for stability studies based on the highest fine particle fraction (FPF), highest monomer content, and lowest particle size. We found that 5 %w/w L-leucine (based on protein content) resulted in similar or higher FPF at 2–8 °C and 25 °C/60 %RH (67.12 % and 48.50 %) stored for six months than 10 %w/w L-leucine (68.49 % and 35.04 %). This indicates that less leucine may be sufficient to produce stable, spray-dried inhalable particles with an improved FPF, and by doubling the leucine content, the aerosolization stability can deteriorate. We have discussed the postulated hypothesis underlying the observed stability behavior based on solid-state and morphological analysis. Our results suggest that spray-dried proteinX-leu-powders can be delivered to the lung at a lower dose than for intravenous administration.

与肠外或口服给药相比，吸入式药物制剂能以较低的剂量在肺部局部发挥作用，具有靶向给药的治疗效果。与此同时，不同的原料药（包括生物制剂）在配方和最终生物利用度方面已被证明具有挑战性。本研究的重点是喷雾干燥可吸入蛋白粉的生产、稳定性能的改善以及向肺部的给药。通过喷雾干燥 11 种左旋亮氨酸含量不同的蛋白质 X 水溶液配方，并采用实验设计法（DoE），根据最高的细颗粒分数（FPF）、最高的单体含量和最低的粒度，选择了两种配方进行稳定性研究。我们发现，与 10 %w/w L-亮氨酸（68.49 % 和 35.04 %）相比，5 %w/w L-亮氨酸（基于蛋白质含量）在 2-8 °C 和 25 °C/60 %RH 下储存 6 个月的 FPF（67.12 % 和 48.50 %）相似或更高。这表明，较少的亮氨酸可能就足以生产出稳定的喷雾干燥可吸入颗粒，并改善 FPF，而亮氨酸含量增加一倍，气溶胶稳定性就会降低。我们讨论了基于固态和形态分析观察到的稳定性行为的假设。我们的研究结果表明，与静脉注射相比，喷雾干燥的蛋白质 X-leu 粉末能以更低的剂量输送到肺部。

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引用次数: 0

Nasal administration of Xingnaojing biomimetic nanoparticles for the treatment of ischemic stroke 治疗缺血性中风的鼻腔给药仿生纳米颗粒（Xingnaojing biomimetic nanoparticles

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2024-10-12 DOI: 10.1016/j.ijpharm.2024.124830

Xingnaojing injection (XNJ), is the first-line Chinese medicine injection approved for treating ischemic stroke (IS). XNJ can attenuate the inflammatory responses and oxidative stress, thus reversing neuronal damage of IS. This study aims to prepare the biomimetic nanoparticles (Bo-GEVs/XNJM) of nasal administration for IS treatment. The grapefruit extracellular vesicles (GEVs) loaded with microemulsions sourced from Xingnaojing injection (XNJM) are modified with borneol (Bo) to bypass the blood–brain barrier (BBB). Bo-GEVs/XNJM has the property of brain-targeting, and in vivo and in vitro experiments have validated that it has positive effects in reducing apoptosis, inhibiting oxidative stress, anti-inflammation, protecting mitochondrial function, and protecting the BBB. In summary, Bo-GEVs/XNJM has good neuroprotective effects, and provides an interventional method for the treatment of ischemic stroke.

心脑静注射液（XNJ）是获准用于治疗缺血性中风（IS）的一线中药注射剂。杏核净注射液能减轻炎症反应和氧化应激，从而逆转缺血性中风对神经元的损伤。本研究旨在制备鼻腔给药的仿生物纳米颗粒（Bo-GEVs/XNJM），用于治疗缺血性中风。柚子细胞外囊泡（GEVs）负载的微乳液来源于兴那景注射液（XNJM），并用龙脑（Bo）进行修饰，以绕过血脑屏障（BBB）。Bo-GEVs/XNJM具有脑靶向特性，体内和体外实验验证了它在减少细胞凋亡、抑制氧化应激、抗炎、保护线粒体功能和保护 BBB 方面的积极作用。总之，Bo-GEVs/XNJM 具有良好的神经保护作用，为缺血性脑卒中的治疗提供了一种介入方法。

引用次数: 0

Modulation of IFN-γ induced macrophage inflammatory responses via indomethacin-loaded NLCs for OA management 通过负载吲哚美辛的 NLCs 调节 IFN-γ 诱导的巨噬细胞炎症反应，以治疗 OA

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2024-10-11 DOI: 10.1016/j.ijpharm.2024.124823

Macrophages are the main cells present in the synovial membrane. They play an important role in the development and progression of osteoarthritis (OA). After the establishment of the disease macrophages mostly adopt a pro-inflammatory secretory phenotype (OA phenotype) further inducing cartilage degradation. Indomethacin (IND) is a non-steroidal anti-inflammatory drug (NSAID) able to inhibit the synthesis of prostaglandins mediated by both cyclooxygenase isoforms depicting a potent anti-inflammatory capacity. However, the lack of specificity and short half-like of free drugs within the joint cavity limits its utility in controlling inflammation after intra-articular administration. This study aims at developing IND loaded glycosylated nanostructured lipid carriers (NLCs) to selectively target macrophages and promote their reprogramming to an anti-inflammatory phenotype. This approach focused on the local administration of the NLCs, offers a promising therapeutic strategy for treating OA by modulating the inflammatory environment within the joint. NLCs will be designed by combining experimental and in silico docking analyses, and thoroughly characterized to obtain drug delivery systems with high stability and suitable physicochemical properties. The proposed mannose-functionalized systems exhibited adequate particle sizes (≈ 70 nm) and positive surface charges (> 20 mV) to be efficiently retained in the joint cavity. Moreover, the developed NLCs demonstrated effective and specific uptake by OA-like macrophages leading to a significant decrease in the secretion of the pro-inflammatory cytokines IL-6, IL-8 and TNF-α similarly to the free drug. Therefore, these systems effectively reprogrammed OA-associated macrophages to adopt a more regenerative phenotype, offering a promising strategy for managing inflammation in OA.

巨噬细胞是滑膜中的主要细胞。它们在骨关节炎（OA）的发生和发展过程中扮演着重要角色。发病后，巨噬细胞大多采用促炎分泌表型（OA 表型），进一步诱导软骨降解。吲哚美辛（IND）是一种非甾体抗炎药（NSAID），能够抑制两种环氧化酶同工酶介导的前列腺素合成，具有很强的抗炎能力。然而，由于缺乏特异性以及游离药物在关节腔内的半衰期较短，限制了其在关节内给药后控制炎症的作用。本研究旨在开发 IND 负载糖基化纳米结构脂质载体（NLCs），以选择性地靶向巨噬细胞，并促进其重新编程为抗炎表型。这种方法侧重于 NLCs 的局部给药，通过调节关节内的炎症环境，为治疗 OA 提供了一种前景广阔的治疗策略。我们将结合实验和硅学对接分析来设计 NLCs，并对其进行彻底表征，以获得具有高稳定性和合适理化特性的给药系统。所提出的甘露糖官能化系统具有足够的粒径（≈ 70 nm）和正表面电荷（> 20 mV），能有效地保留在关节腔内。此外，所开发的 NLCs 还能被 OA 样巨噬细胞有效、特异地吸收，从而显著减少促炎细胞因子 IL-6、IL-8 和 TNF-α 的分泌，与游离药物类似。因此，这些系统能有效重编程 OA 相关巨噬细胞，使其采用更具再生能力的表型，为控制 OA 中的炎症提供了一种前景广阔的策略。

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引用次数: 0

A manganese-oxide nano-rambutan as the intrinsic modifier for hypericin delivery and triple-negative breast cancer treatment 锰氧化物纳米拉姆丁作为金丝桃素输送和三阴性乳腺癌治疗的内在修饰剂

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2024-10-11 DOI: 10.1016/j.ijpharm.2024.124824

The anti-tumor efficacy of naturally derived photosensitizer-hypericin (Hy) is dampened by hypoxia and over-expressed glutathione in the tumor microenvironment (TME). For rewiring the TME, we encapsulated Hy to an intrinsic modifier-manganese oxide-formed nanorambutan (MnO_x-Hy NR). In triple-negative breast cancer cells, MnO_x-Hy NR not only consumed glutathione through Mn²⁺ and hypericin release but also facilitated O₂ production to relieve hypoxia, through which the reactive oxygen species (ROS) generation was strengthened by endoplasmic reticulum targeting hypericin. In the meantime, glutathione consumption-induced glutathione peroxidase 4 (GPX4) inactivation and the elevation of lipid hydroperoxide (LPO) level further triggered ferroptosis. Then, the combination of PDT and ferroptosis contributed to a synergic immunogenic cell death (ICD) effect in 4 T1 cells, facilitating the adaptive anti-tumor immune response activation. Thereby, MnO_x-Hy NR exhibited excellent anti-tumor effects both in primary and distant tumors through the abscopal effect, as well as significant lung metastasis inhibition in the 4 T1 mouse metastatic tumor model.

天然光敏剂金丝桃素（Hy）的抗肿瘤功效会受到肿瘤微环境（TME）中缺氧和谷胱甘肽过度表达的影响。为了重新连接肿瘤微环境，我们将 Hy 封装到一种内在修饰剂--氧化锰形成的纳米红豆（MnOx-Hy NR）中。在三阴性乳腺癌细胞中，MnOx-Hy NR不仅通过Mn2+和金丝桃素的释放消耗谷胱甘肽，还促进了氧气的产生以缓解缺氧。与此同时，谷胱甘肽消耗引起的谷胱甘肽过氧化物酶 4（GPX4）失活和脂质过氧化物（LPO）水平升高进一步引发了铁变态反应。然后，PDT 和铁突变的结合有助于在 4 T1 细胞中产生协同免疫性细胞死亡（ICD）效应，促进适应性抗肿瘤免疫反应的激活。因此，MnOx-Hy NR 在原发性肿瘤和远处肿瘤中都表现出了卓越的抗肿瘤效果，并在 4 T1 小鼠转移瘤模型中发挥了显著的肺转移抑制作用。

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引用次数: 0

‘Exploring the preparation of griseofulvin CAMS with amino acids of different hydrophobicity as co-formers using a modified hot-melt extrusion process’ 探索使用改良热熔挤出工艺制备以不同疏水性氨基酸为共聚物的鬼臼毒素 CAMS"。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2024-10-10 DOI: 10.1016/j.ijpharm.2024.124818

Co-amorphous systems (CAMS) of griseofulvin (GRI) with the amino acids (AA): L-lysine (LYS), L-valine (VAL) and L-methionine (MET) of increasing hydrophobicity were prepared using a solvent assisted hot-melt extrusion (HME). Co-formability was evaluated by thermodynamic miscibility prediction, thermal analysis (DSC), powder crystallography (pXRD) and vibrational spectroscopy (ATR-FTIR). Decomposition temperature range was defined by thermogravimetry (TGA) and DSC. Solubilities of crystalline and amorphous drug were determined by the UV-extinction method. The physical stability of GRI/AA CAMS was evaluated by accelerated tests and for ratios 1:1 and 1:2 was excellent. Non-sink dissolution tests of equimolar CAMS of the more hydrophobic MET and VAL revealed long lasting supersaturation, above the solubility of amorphous drug, whereas ratios 2:1 and 1:2 gave lower supersaturation due to partial recrystallization during dissolution, despite the good physical stability. CAMS of the hydrophilic LYS were physically stable but showed poor dissolution, possibly due to self-association of LYS in water. Addition of wetting agent in the dissolution medium improved dissolution without altering the profile. Since previous attempts to formulate GRI/AA CAMS with purely mechanical methods found only moderate success, the feed pretreatment HME method employed in this work makes an excellent alternative for drug/AA CAMS where mechanical or solvent evaporation methods fail.

采用溶剂辅助热熔挤出法制备了格列齐芬（GRI）与氨基酸（AA）的共晶体系（CAMS）：采用溶剂辅助热熔挤出法（HME）制备了疏水性递增的 L-赖氨酸（LYS）、L-缬氨酸（VAL）和 L-蛋氨酸（MET）共聚物。通过热力学混溶性预测、热分析（DSC）、粉末晶体学（pXRD）和振动光谱（ATR-FTIR）对共形性进行了评估。热重分析法（TGA）和 DSC 确定了分解温度范围。用紫外消光法测定了结晶和无定形药物的溶解度。通过加速试验评估了 GRI/AA CAMS 的物理稳定性，其中 1:1 和 1:2 比率的物理稳定性极佳。对疏水性较强的 MET 和 VAL 的等摩尔 CAMS 进行的非沉降溶解测试表明，超饱和度持续时间较长，高于无定形药物的溶解度，而 2:1 和 1:2 的配比尽管具有良好的物理稳定性，但由于在溶解过程中部分再结晶，超饱和度较低。亲水性 LYS 的 CAMS 物理稳定，但溶解性较差，可能是由于 LYS 在水中的自结合。在溶解介质中添加润湿剂可提高溶解度，但不会改变溶解曲线。由于以前尝试用纯机械方法配制 GRI/AA CAMS 只取得了一定的成功，因此本研究采用的进料预处理 HME 方法是机械或溶剂蒸发方法失败时配制药物/AA CAMS 的绝佳替代方法。

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引用次数: 0

WaSPred: A reliable AI-based water solubility predictor for small molecules WaSPred：基于人工智能的可靠小分子水溶性预测器。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2024-10-09 DOI: 10.1016/j.ijpharm.2024.124817

A rapid and reliable evaluation of the aqueous solubility of small molecules is a hot topic for the scientific community and represents a field of particular interest in drug discovery. In fact, aqueous solubility significantly impacts various aspects that collectively influence a drug’s overall pharmacokinetics, including absorption, distribution and metabolism. For this reason, in silico approaches that provide fast and cost-effective solubility predictions, can serve as invaluable tools in the early stages of drug development. Although additional molecular features should be considered, accurate solubility predictions can help medicinal chemists rationally planning the synthesis of compounds more likely to exhibit desirable pharmacokinetic properties and in selecting the most promising candidates for further biological testing (e.g., cellular assays) from an initial pool of hit compounds with detected preliminary bioactivity. In this context, we herein report the development and evaluation of WaSPred, our AI-based water solubility predictor for small molecules. WaSPred not only showed high reliability in water solubility predictions performed on structurally heterogeneous compounds, belonging to multiple external datasets, but also demonstrated superior performance compared to a set of other commonly used water solubility predictors, thus confirming its state-of the-art robustness and its usefulness as an in silico approach for water solubility evaluations..

对小分子水溶性进行快速、可靠的评估是科学界的一个热门话题，也是药物发现领域特别关注的一个领域。事实上，水溶性对药物的整体药代动力学，包括吸收、分布和代谢等各个方面都有重大影响。因此，在药物开发的早期阶段，能够快速、经济高效地预测溶解度的硅学方法是非常宝贵的工具。虽然还需要考虑其他分子特征，但准确的溶解度预测可以帮助药物化学家合理规划更有可能表现出理想药代动力学特性的化合物的合成，并从初步检测出生物活性的热门化合物中挑选出最有希望的候选化合物进行进一步的生物学测试（如细胞检测）。在此背景下，我们报告了基于人工智能的小分子水溶性预测工具 WaSPred 的开发和评估情况。WaSPred 不仅在对属于多个外部数据集的结构异构化合物进行水溶性预测时表现出高度可靠性，而且与一组其他常用的水溶性预测器相比也表现出更优越的性能，从而证实了其先进的鲁棒性及其作为水溶性评估的硅方法的实用性。

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