International Journal of Pharmaceutics最新文献_第8页

Targeting cancer stem cells: Dual-drug delivery systems and their role in cancer therapy 靶向肿瘤干细胞：双药传递系统及其在癌症治疗中的作用。

IF 5.2 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2026-02-20 Epub Date: 2026-01-12 DOI: 10.1016/j.ijpharm.2026.126588

Chengfeng Yin , Chen Chen , Zihan Chen , Zhaohui Song , Fengyun Li

Cancer stem cells (CSCs) represent a distinct subpopulation within tumors, intricately linked to tumorigenesis, progression, drug resistance, recurrence, and metastasis. Therefore, targeting CSCs is essential for achieving a definitive cure for cancer. The concomitant administration of two drugs, aimed at both tumor cells and CSCs, presents a promising strategy for the comprehensive eradication of tumors. However, ensuring the synergistic efficacy and targeted delivery of these dual drugs at the tumor site remains a significant challenge. This review begins by elucidating the biological characteristics of CSCs, with a particular focus on their differentiation and self-renewal capabilities. It then provides a comprehensive overview of common therapeutic approaches targeting CSCs, highlighting the benefits of dual-drug combination therapy. The subsequent sections concentrate on the application of dual-drug delivery systems in CSC therapy, detailing various dual drug-loading strategies, including co-loading at the same site, loading at different sites, physical mixing, and self-assembly. Additionally, it also summarizes multimodal treatment strategies that integrate dual-drug delivery systems with other therapeutic modalities. Finally, the challenges associated with dual-drug delivery systems in CSC therapy are discussed, along with potential future developments in this field. This review aims to offer a theoretical foundation and methodological reference for the treatment of CSCs, ultimately contributing to the overarching goal of curing cancer.

肿瘤干细胞（CSCs）是肿瘤中一个独特的亚群，与肿瘤的发生、进展、耐药、复发和转移有着复杂的联系。因此，靶向csc对于最终治愈癌症至关重要。同时使用两种药物，针对肿瘤细胞和csc，是一种很有希望的全面根除肿瘤的策略。然而，确保这些双重药物在肿瘤部位的协同作用和靶向递送仍然是一个重大挑战。本文首先阐述了干细胞的生物学特性，重点介绍了它们的分化和自我更新能力。然后，它提供了针对CSCs的常见治疗方法的全面概述，强调了双药联合治疗的益处。接下来的章节集中讨论了双药传递系统在CSC治疗中的应用，详细介绍了各种双药装载策略，包括在同一位点共装载、在不同位点装载、物理混合和自组装。此外，它还总结了将双药传递系统与其他治疗方式相结合的多模式治疗策略。最后，讨论了CSC治疗中与双药递送系统相关的挑战，以及该领域的潜在未来发展。本文旨在为CSCs的治疗提供理论基础和方法参考，最终实现治愈癌症的总体目标。

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引用次数: 0

A quality by design strategy to develop curcumin and siRNA co-loaded lipoplexes to target osteoarthritis-related inflammation and oxidative stress 开发姜黄素和siRNA共载脂质体以靶向骨关节炎相关炎症和氧化应激的质量设计策略。

IF 5.2 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2026-02-20 Epub Date: 2025-12-24 DOI: 10.1016/j.ijpharm.2025.126532

Saketh Reddy Ranamalla , Lucia Tefas , Alina Porfire , Emilia Licarete , Rohith Pavan Parvathaneni , Oommen P. Varghese , Alina Sesarman , Monica Focsan , Ioan Tomuta , Manuela Banciu

Osteoarthritis (OA) is a prevalent, debilitating disease marked by joint degeneration, pain, and reduced mobility. Among the factors that influence the pathogenesis and progression of OA, oxidative stress and inflammation are of major importance. As curcumin downregulates the expression of many inflammatory cytokines, scavenges free radicals, and upregulates the levels of collagen and aggrecan, it therefore reduces pain and helps with regeneration. On the other hand, oligonucleotides have emerged as next-generation therapeutics, capable of modulating specific gene expression. In this context, delivery of small interfering RNAs (siRNAs) through lipoplexes is a promising approach for repairing damaged cartilage tissues. Our study focused on developing lipoplexes for efficient co-delivery of curcumin and therapeutic siRNA in chondrocytes. In the first step, the Quality-by-design (QbD) principles guided the development of curcumin-loaded cationic liposomes (CLCL) and the selection of the optimum formulation. Further, optimum curcumin-loaded cationic liposomes (Opt-CLCL) were complexed with IL-6 and IL-8 siRNA to form co-loaded lipoplexes. The Opt-CLCL successfully reduced the oxidative stress levels in both patient-derived primary chondrocytes and a human chondrocyte cell line, while co-loaded lipoplexes transfected chondrocytes with no toxicity and efficiently reduced the inflammation markers. Thus, the developed co-loaded lipoplexes are promising for further testing in OA models. Moreover, the optimal vector designed within the study could serve as a platform for incorporating other lipophilic drugs and negatively charged oligonucleotides to address various ailments.

骨关节炎（OA）是一种普遍的、使人衰弱的疾病，其特征是关节变性、疼痛和活动能力降低。在影响OA发病和进展的因素中，氧化应激和炎症是重要的因素。由于姜黄素下调了许多炎症细胞因子的表达，清除自由基，并上调了胶原蛋白和聚集蛋白的水平，因此它可以减轻疼痛，帮助再生。另一方面，寡核苷酸已成为下一代治疗药物，能够调节特定的基因表达。在这种情况下，通过脂丛递送小干扰rna （sirna）是修复受损软骨组织的一种很有前途的方法。我们的研究重点是在软骨细胞中开发有效的姜黄素和治疗性siRNA共同递送的脂质体。第一步，以质量设计（QbD）原则指导姜黄素阳离子脂质体（CLCL）的研制和最佳配方的选择。此外，最佳的姜黄素负载阳离子脂质体（Opt-CLCL）与IL-6和IL-8 siRNA络合形成共负载脂质体。Opt-CLCL成功降低了患者源性原代软骨细胞和人软骨细胞系的氧化应激水平，而共负载脂丛转染的软骨细胞没有毒性，并有效降低了炎症标志物。因此，开发的共负载脂质体有望在OA模型中进一步测试。此外，本研究设计的最佳载体可以作为整合其他亲脂性药物和带负电荷的寡核苷酸的平台，以治疗各种疾病。

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引用次数: 0

Dissolution tests of pharmaceutical tablets using a novel gastric simulator 用新型胃模拟器测定药物片剂的溶出度

IF 5.2 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2026-02-20 Epub Date: 2026-01-12 DOI: 10.1016/j.ijpharm.2026.126589

I. Martínez-Camacho , L.F. Donis-Rabanales , S. Cortés-Lagunes , J.C. Durán-Álvarez , M.S. Córdova-Aguilar , A. Caballero-Ruiz , E.Brito-de la Fuente , M. Calderón-Santoyo , J.A. Ragazzo-Sánchez , G. Ascanio

A new device has been developed to examine how pharmaceutical tablets dissolve under conditions very similar to those in the human stomach. For that purpose, Prednisone USP compendial standard tablets were dissolved in two different apparatuses. On one side, a distal gastric simulator, known as the in vitro Distal Gastric Simulator (IV-DGS), was used. This simulator closely replicates the physiological conditions of the human stomach. It can mimic its operating environment, including peristaltic movement at 3 cycles per minute and an average maximum pressure of about 25 mm Hg. The results from the gastric simulator were compared with the dissolution rates measured using the United States Pharmacopeia-approved apparatus 2. The results show that after 12 min, the USP Apparatus 2 achieved 71.5% dissolution, while the IV-DGS reached 24.9%, indicating a slower dissolution rate but a more realistic gastric mixing. The dissolution data from both systems were modeled using a first-order and a Weibull model, with the latter providing a better fit. Although the results are not entirely comparable with USP 2, the gastric simulator offers a much more realistic alternative for in vitro drug dissolution studies.

一种新的设备已经被开发出来，用来检测药片在与人类胃非常相似的条件下是如何溶解的。为此，强的松USP药典标准片在两种不同的仪器中溶解。一侧使用远端胃模拟器，称为体外远端胃模拟器（IV-DGS）。这个模拟器精确地复制了人类胃的生理状况。它可以模拟其操作环境，包括每分钟3次的蠕动运动，平均最大压力约为25毫米汞柱。胃模拟器的结果与使用美国药典批准的仪器测量的溶出率进行了比较2。结果表明，12 min后，USP Apparatus 2溶出率为71.5%，而IV-DGS溶出率为24.9%，溶出率较慢，但胃混合更真实。两个体系的溶解数据分别使用一阶和威布尔模型建模，后者提供了更好的拟合。虽然结果不能完全与usp2相比较，但胃模拟器为体外药物溶出研究提供了一个更现实的选择。

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引用次数: 0

Enzymatically-responsive hyaluronan–glucose hydrogel supports MSC survival and preserves paracrine function under glucose deprivation 酶反应性透明质酸-葡萄糖水凝胶支持间充质干细胞存活并在葡萄糖剥夺下保持旁分泌功能。

IF 5.2 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2026-02-20 Epub Date: 2026-01-23 DOI: 10.1016/j.ijpharm.2026.126613

Paula Gonzalez-Fernandez , Luca Simula , Sébastien Jenni , Domitille Schvartz , Florina Moldovan , Olivier Jordan , Eric Allémann

Mesenchymal stem cell (MSC) therapy shows potential in regenerative medicine, particularly in treating osteoarthritis (OA). MSCs injected into the joint can secrete growth factors and extracellular matrix molecules, contributing to paracrine communication and cartilage regeneration. However, in the non-vascularized joint environment, MSCs lacking nutrient supply, starve and die too quickly to efficiently deliver enough of these factors. We have recently synthesized a new hydrogel containing hyaluronic acid and glucose (HA-GLC). This hydrogel allows MSCs to survive and proliferate in an environment with otherwise low glucose levels. Furthermore, it releases glucose through enzymatic cleavage by ß-glucosidase, an enzyme which we have shown to be available and active in human bone marrow mesenchymal stem cells (BM-MSCs). In this study, we did incorporate MSCs to this HA-GLC hydrogel. Proteomic analysis of the MSC secretome revealed that glucose deprivation modified the profile of secreted factors, inducing changes in several key pathways, including extra-cellular matrix production. We then tested the effect of glucose deprivation in MSC secretome on human chondrocyte (hCH) proliferation and IL-6 secretion. Our results showed an increase in hCH proliferation and a significant decrease in IL-6 expression, when cells were exposed to the secretome of MSCs cultured in glucose-provided media rather than glucose-deprived conditions. These findings highlighted the ability of this new technology (HA-GLC hydrogel) to modulate the MSC secretome function, potentially enhancing cartilage regeneration in OA.

间充质干细胞（MSC）治疗显示出再生医学的潜力，特别是在治疗骨关节炎（OA）方面。骨髓间充质干细胞注入关节后可分泌生长因子和细胞外基质分子，促进旁分泌通讯和软骨再生。然而，在非血管化的关节环境中，MSCs缺乏营养供应，饥饿和死亡太快，无法有效地提供足够的这些因子。我们最近合成了一种新的含透明质酸和葡萄糖的水凝胶（HA-GLC）。这种水凝胶允许间充质干细胞在低葡萄糖水平的环境中存活和增殖。此外，它通过ß-葡萄糖苷酶的酶裂解释放葡萄糖，我们已经证明，ß-葡萄糖苷酶在人骨髓间充质干细胞（BM-MSCs）中是可用的和活跃的。在本研究中，我们确实将MSCs掺入HA-GLC水凝胶中。MSC分泌组的蛋白质组学分析显示，葡萄糖剥夺改变了分泌因子的特征，诱导了几个关键通路的变化，包括细胞外基质的产生。然后，我们测试了MSC分泌组中葡萄糖剥夺对人软骨细胞（hCH）增殖和IL-6分泌的影响。我们的研究结果显示，当细胞暴露于葡萄糖培养基中培养的MSCs分泌组而不是葡萄糖剥夺条件下，hCH增殖增加，IL-6表达显著降低。这些发现强调了这种新技术（HA-GLC水凝胶）调节间充质干细胞分泌组功能的能力，可能会促进OA的软骨再生。

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引用次数: 0

A label-free multi-parameter screening method for predicting the stability of mRNA-LNP formulations 一种预测mRNA-LNP制剂稳定性的无标记多参数筛选方法。

IF 5.2 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2026-02-20 Epub Date: 2026-01-10 DOI: 10.1016/j.ijpharm.2026.126576

Yimei Sun , Cheng-Han Ye , Han Gao , Shang-Yin Wu , Wei-Jie Fang

With the rapid advancement of messenger RNA (mRNA) technologies, lipid nanoparticles (LNPs) have been widely adopted for vaccine and gene therapy applications. The stability of mRNA-LNP formulations is a critical determinant of their therapeutic efficacy; however, conventional stability prediction methods are often time-consuming and operationally complex. In this study, a label-free and real-time multi-parameter thermal profiling method was established to provide a rapid assessment of colloidal stability, simultaneously monitoring turbidity, cumulant radius (r_h), and scattering. Six formulations sharing the same mRNA cargo and lipid composition but differing in buffer, preservative, and pH were evaluated to examine the discriminatory power of this assay. A redefined aggregation-onset temperature (T_agg) was introduced as the primary thermal stability readout and combined with Δr_h to capture early structural perturbations under thermal stress, thereby enabling efficient parallel screening during early formulation development. Compared with conventional accelerated stability studies, this method markedly shortened the evaluation period while still capturing thermally induced colloidal-stability changes. Using T_agg and Δr_h in a logistic regression model, thermal-profiling-based “Qualified/Not Qualified” calls demonstrated good concordance with 40 °C accelerated stability outcomes, supporting the use of this strategy as an early-stage screening tool within this mRNA-LNP platform. Nevertheless, its broader applicability across different cargos and lipid chemistries will require further validation.

随着信使RNA （mRNA）技术的快速发展，脂质纳米颗粒（LNPs）已广泛应用于疫苗和基因治疗。mRNA-LNP制剂的稳定性是其治疗效果的关键决定因素；然而，传统的稳定性预测方法往往耗时且操作复杂。在这项研究中，建立了一种无标签的实时多参数热分析方法，以提供胶体稳定性的快速评估，同时监测浊度，累积半径（rh）和散射。六种配方具有相同的mRNA货物和脂质组成，但在缓冲液、防腐剂和pH值上不同，以评估该试验的鉴别能力。重新定义的聚集起始温度（Tagg）作为主要的热稳定性读数，并结合Δrh来捕获热应力下的早期结构扰动，从而在早期配方开发过程中实现有效的平行筛选。与传统的加速稳定性研究相比，该方法显著缩短了评估周期，同时仍能捕捉到热诱导的胶体稳定性变化。在逻辑回归模型中使用Tagg和Δrh，基于热分析的“合格/不合格”调用显示出与40 °C加速稳定性结果的良好一致性，支持将该策略用作mRNA-LNP平台的早期筛选工具。然而，其在不同货物和脂质化学中的更广泛适用性将需要进一步验证。

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引用次数: 0

Accelerating dataset generation for machine learning using large language models: a pharmaceutical additive manufacturing case 使用大型语言模型加速机器学习的数据集生成：一个制药增材制造案例。

IF 5.2 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2026-02-20 Epub Date: 2026-01-17 DOI: 10.1016/j.ijpharm.2026.126587

Paola Carou-Senra , Lucía Rodríguez-Pombo , Carmen Alvarez-Lorenzo , Alvaro Goyanes

Creating high-quality datasets for training machine learning models in specialized domains like pharmaceutical research is often constrained by the manual effort required to extract and compute critical parameters from heterogeneous literature. A novel deep prompt-engineering framework was developed to transform GPT-4 into a robust tool for automated and accelerated generation of structured datasets. Using a multi-set prompt strategy, GPT-4 analysed 70 full-text articles from literature on pharmaceutical inkjet printing to extract and compute 23 domain-relevant variables. These variables were organized into three main parameter groups: (i) printing parameters, (ii) rheological properties, and (iii) drug dose parameters, which were analysed using dedicated prompts. The outputs were benchmarked against a human-curated dataset compiled over four months by four domain experts, previously used to train machine learning models for predicting inkjet printability. Iterative prompt engineering yielded an overall accuracy of 0.942 across 4,217 individual variable-level data points, with computed variables reaching 0.983 accuracy despite multi-step calculations and unit conversions. Inter-day reproducibility was stable, and sensitivity, specificity, and predictive values all exceeded 0.900. Remarkably, the workflow reduced processing time from hours of human effort to <3.5 min per article. This novel prompt-engineering approach enabled GPT-4 to generate reliable, high-quality, literature-derived datasets, dramatically reducing manual effort while maintaining expert-level accuracy. Ultimately, this novel strategy facilitates the scalability of machine learning in pharmaceutical, and other data-intensive domains.

在制药研究等专业领域，为训练机器学习模型创建高质量的数据集，往往受到从异构文献中提取和计算关键参数所需的人工努力的限制。开发了一种新颖的深度提示工程框架，将GPT-4转变为自动化和加速生成结构化数据集的强大工具。采用多集提示策略，GPT-4分析了70篇医药喷墨打印文献全文，提取并计算了22个领域相关变量。这些变量被组织成三个主要参数组：(i)打印参数，（ii）流变特性和（iii）药物剂量参数，这些参数使用专用提示进行分析。这些输出是根据四位领域专家在四个多月的时间里编制的人工管理数据集进行基准测试的，这些数据集以前用于训练预测喷墨打印能力的机器学习模型。迭代提示工程在4217个单独的变量水平数据点上产生了0.942的总体精度，尽管有多步计算和单位转换，计算变量的精度达到0.983。日间重现性稳定，敏感性、特异性和预测值均超过0.900。值得注意的是，工作流将处理时间从几个小时的人工工作减少到

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引用次数: 0

A contact lens-embedded betaine ester polymer for pH-responsive release of an osmoprotectant to the corneal surface 一种隐形眼镜内嵌甜菜碱酯聚合物，用于渗透保护剂在角膜表面的ph响应释放。

IF 5.2 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2026-02-20 Epub Date: 2026-01-19 DOI: 10.1016/j.ijpharm.2026.126594

Dan Hawthorne , Cheng-Chun Peng , Emma Ward , Susan Sandeman , Ananth SV Pannala , Dharmendra Jani , Inna Maltseva , Andrew W Lloyd

Topical delivery of osmoprotectants to ocular surface has been shown to be a promising solution to ocular discomfort thought to be associated with corneal hyperosmolarity. Currently, most osmoprotectants are administrated by aqueous eyedrops, which are associated with poor bioavailability and short residence time in the tear film, requiring repeated dosing to maintain the osmoprotectant concentration above the effective level. In response to this challenge, this work describes poly(vinyl glycine betaine) (PV-GB), a degradable ester quat polymer which gradually releases the osmoprotectant, glycine betaine (GB), over a period of days to weeks, with release rate strongly dependent on pH of its surroundings. PV-GB was embedded into commercial contact lenses (CLs) alongside a polyanion, hyaluronic acid (HA), to provide extended release of GB during a period reflecting the typical usage of a daily disposable CL wear of 8 – 16 h. A GB release lifetime of ≪48 hrs was achieved from a system comprising PV-GB/HA embedded within an anionic CL using a simple soaking method. Further experiments indicated the polymer was stable to autoclave sterilisation, had a shelf-life of 6 + months (under optimised solution conditions), and was likely to be mucoadhesive, which would be expected to enhance bioavailability of GB at the ocular surface.

眼表局部递送渗透保护剂已被证明是一种有希望的解决与角膜高渗有关的眼部不适的方法。目前，大多数渗透保护剂是通过水滴眼液给药，这与生物利用度差和在泪膜中的停留时间短有关，需要反复给药以保持渗透保护剂浓度高于有效水平。为了应对这一挑战，本研究描述了聚乙烯基甜菜碱（PV-GB），一种可降解的酯类四元聚合物，在几天到几周的时间内逐渐释放渗透保护剂甜菜碱（GB），其释放速度强烈依赖于周围环境的pH值。将PV-GB与聚阴离子透明质酸（HA）一起嵌入商用隐形眼镜（CL）中，以提供GB在一段时间内的延长释放，反映每日一次性隐形眼镜佩戴8 - 16 h的典型使用情况。采用简单的浸泡方法，将PV-GB/HA嵌入阴离子CL中，使该系统的GB释放寿命≪48小时。进一步的实验表明，该聚合物在高压灭菌中是稳定的，保质期为6 + 个月（在优化的溶液条件下），并且可能具有黏附性，这有望提高GB在眼表的生物利用度。

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引用次数: 0

Synergistic photo/chemo-therapeutic liposome induced pyroptosis and anti-tumor immunity in head and neck squamous cell carcinoma 协同光/化学治疗脂质体诱导头颈部鳞状细胞癌的焦亡和抗肿瘤免疫。

IF 5.2 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2026-02-20 Epub Date: 2026-01-09 DOI: 10.1016/j.ijpharm.2026.126565

Yahui Zhang , Liya Yu , Yehui Kang , Yuxiang Zhang , Jiaxin Li , Yu Cai , Jiajie Xu

Head and Neck Squamous Cell Carcinoma (HNSCC), characterized by a propensity for recurrence and metastasis, underscores the inadequacies of existing treatments. In this research, a liposome called DI@Lipo was developed to co-deliver cisplatin (DDP) and indocyanine green (ICG), aiming to trigger synergistic pyroptosis to enhance antitumor immunity. DI@Lipo cleverly harnessed the light-activated powers of ICG, combined them with DDP’s tumor-killing ability, to induce activation of the NLRP3 inflammasome. This, in turn, spurred gasdermin D into action, setting off a fiery pyroptosis. This chain reaction triggered a substantial release of Damage-Associated Molecular Patterns (DAMPs) and inflammatory cytokines, which in turn stimulated dendritic cells to mature and attracted an influx of killer T cells. In murine models of HNSCC, this combination therapy not only effectively eliminated primary tumors but also induced a potent abscopal effect, suppressing untreated distant tumors. Importantly, this treatment improved overall survival rates without causing notable systemic toxicity. Additionally, the DI@Lipo platform facilitated fluorescence and photoacoustic imaging (PAI) for potential treatment monitoring. These findings highlight how DI@Lipo-triggered pyroptosis could effectively transform immunologically dormant tumors into responsive ones, presenting a practical therapeutic avenue to combat treatment resistance in head and neck squamous cell carcinoma.

头颈部鳞状细胞癌（HNSCC）以复发和转移倾向为特征，强调了现有治疗方法的不足。本研究开发了一种名为DI@Lipo的脂质体，用于共递送顺铂（DDP）和吲哚菁绿（ICG），旨在触发协同焦亡，增强抗肿瘤免疫。DI@Lipo巧妙地利用ICG的光激活能力，将它们与DDP的肿瘤杀伤能力结合起来，诱导NLRP3炎性体的激活。这反过来又刺激了气皮素D的作用，引发了炽热的焦亡。这一连锁反应引发了损伤相关分子模式（DAMPs）和炎症细胞因子的大量释放，进而刺激树突状细胞成熟并吸引杀伤T细胞的涌入。在HNSCC小鼠模型中，这种联合治疗不仅有效地消除了原发肿瘤，而且还诱导了强大的体外作用，抑制了未治疗的远处肿瘤。重要的是，这种治疗提高了总生存率，而没有引起明显的全身毒性。此外，DI@Lipo平台促进了荧光和光声成像（PAI）用于潜在治疗监测。这些发现突出了DI@Lipo-triggered焦亡如何有效地将免疫休眠的肿瘤转化为应答性肿瘤，为头颈部鳞状细胞癌的治疗抵抗提供了一种实用的治疗途径。

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引用次数: 0

Multiscale simulation of stratum corneum lipid mixtures: effects of ceramide headgroups on structural organization and hydrogen bonding networks 角质层脂质混合物的多尺度模拟：神经酰胺头基团对结构组织和氢键网络的影响。

IF 5.2 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2026-02-20 Epub Date: 2026-01-09 DOI: 10.1016/j.ijpharm.2026.126573

Chloe O. Frame , Christopher R. Iacovella , David J. Moore , Annette L. Bunge , Clare McCabe

The barrier function of the outermost layer of human skin, the stratum corneum (SC), arises from its multilamellar lipid matrix composed primarily of ceramides (CERs), cholesterol (CHOL), and free fatty acids (FFAs). Coarse-grained (CG) and atomistic molecular dynamics simulations have been used to study self-assembled multilayers comprising CERs NS, NP, AS, and AP, in pure CER systems and mixtures of CERs with CHOL and FFAs. Equilibrated CG configurations were reverse-mapped to recover atomistic details and analyzed to extract structures and hydrogen bonding. Simulations of pure CERs agreed with experimental trends: phytosphingosine CERs (NP and AP) exhibited more CO hydrogen bonds, consistent with lower amide I FTIR frequencies, than their sphingosine counterparts (NS and AS). Likewise, non-hydroxy CERs (NS and NP) exhibited more CO hydrogen bonding than their α-hydroxy analogs (AS and AP). CER mixtures with CHOL and FFA showed reduced CO hydrogen bonding compared to pure CERs, though this effect depended on water content. Hydroxyl location was critical: OH on the phytosphingosine base increased CO hydrogen bonding, whereas the α-hydroxy on the acyl chain reduced it. In CER NP:AP mixtures with CHOL and FFA, simulations reproduced the experimental repeat distances for NP-rich and AP-rich systems despite differences in hydrogen bonding. Simulations of multicomponent mixtures resembling the SC model of Bouwstra demonstrated the dominant effect of chain-length distribution, rather than CER hydrogen bonding, on permeability. This work shows how multiscale modeling integrated with experiments can uncover molecular mechanisms linking composition and SC barrier structure to interpret experimental results.

人体皮肤最外层角质层（SC）的屏障功能源于其多层脂质基质，主要由神经酰胺（CERs）、胆固醇（CHOL）和游离脂肪酸（FFAs）组成。粗粒度（CG）和原子分子动力学模拟被用于研究在纯CER体系和CER与CHOL和FFAs的混合物中，由CERs NS、NP、AS和AP组成的自组装多层膜。平衡的CG构型被反向映射以恢复原子细节，并分析提取结构和氢键。纯cer的模拟与实验趋势一致：植物鞘醇cer （NP和AP）比它们的鞘醇cer （NS和AS）表现出更多的CO氢键，与酰胺I FTIR频率较低一致。同样，非羟基cer （NS和NP）比α-羟基类似物（AS和AP）表现出更多的CO氢键。与纯CER相比，与CHOL和FFA混合的CER显示CO氢键减少，尽管这种影响取决于含水量。羟基的位置至关重要：植物鞘苷基上的羟基增加了CO的氢键，而酰基链上的α-羟基则减少了CO的氢键。在含有CHOL和FFA的CER NP:AP混合物中，模拟再现了富NP和富AP体系的实验重复距离，尽管氢键存在差异。对类似Bouwstra SC模型的多组分混合物的模拟表明，链长分布对渗透率的主要影响，而不是CER氢键。这项工作表明，多尺度建模与实验相结合，可以揭示分子机制连接组成和SC势垒结构，以解释实验结果。

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Multidisciplinary approaches for the prevention and management of capsular contracture: a review of clinical, pharmacological, and biomaterial-based strategies 预防和管理包膜挛缩的多学科方法：临床，药理学和生物材料为基础的策略综述。

IF 5.2 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2026-02-20 Epub Date: 2026-01-22 DOI: 10.1016/j.ijpharm.2026.126602

Mohuya Paul , Woo Jin Song , Jungkyun Im

Capsular contracture (CC) is the most frequent complication associated with silicone-based breast implant surgery and often leads to multiple revision surgeries. The implantation of a foreign object triggers the formation of a fibrous capsule around the silicone implant. Over time, excessive and uncontrollable fibrosis leads to capsule thickening and contraction, resulting in severe pain, discomfort, and implant distortion, all hallmarks of CC. Various strategies have been proposed to prevent or mitigate CC. One common strategy is surface modification of the silicone implant by introducing texture. Implant surface coating with antifibrotic and anti-inflammatory drugs is another common strategy to regulate CC. Anti-inflammatory drugs such as leukotriene inhibitor antagonists (LTRAs) and NSAIDs have demonstrated preventive effects against CC. Recently, the omega-3 polyunsaturated fatty acids (ω3 PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have emerged as promising candidates due to their anti-inflammatory and anti-fibrotic properties. These naturally abundant compounds have shown potential to reduce collagen deposition, thin the fibrotic capsule, and downregulate fibrosis-related inflammatory cytokines. We also discuss the molecular mechanisms by which ω3 PUFAs exert their effects and compare their advantages over conventional treatments. Overall, this narrative review outlines the current understanding of CC pathophysiology and highlights existing preventive strategies from clinical, pharmacological and biomaterial-based approaches, providing a foundation for future research on the prevention of CC.

囊膜挛缩（CC）是与硅胶乳房植入手术相关的最常见的并发症，经常导致多次翻修手术。异物的植入触发硅酮植入物周围纤维囊的形成。随着时间的推移，过度和不可控的纤维化导致囊膜增厚和收缩，导致严重的疼痛、不适和植入物变形，这些都是CC的特征。人们提出了多种策略来预防或减轻CC，一种常见的策略是通过引入质地来修饰硅胶植入物的表面。抗炎药物如白三烯抑制剂拮抗剂（LTRAs）和非甾体抗炎药（NSAIDs）等抗炎药物已被证明对CC有预防作用，最近，ω -3多不饱和脂肪酸（ω3 PUFAs）、二十碳五烯酸（EPA）和二十二碳六烯酸（DHA）因其抗炎和抗纤维化的特性而成为有希望的候选药物。这些天然丰富的化合物已显示出减少胶原沉积、使纤维化囊变薄和下调纤维化相关炎症细胞因子的潜力。我们还讨论了ω3 pufa发挥作用的分子机制，并比较了ω3 pufa相对于传统治疗的优势。总的来说，本文概述了目前对CC病理生理的理解，并强调了从临床、药理学和基于生物材料的方法中现有的预防策略，为未来的CC预防研究提供了基础。

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引用次数: 0