Asian Journal of Pharmaceutical Sciences最新文献_第6页

Functionalized chitosan as nano-delivery platform for CRISPR-Cas9 in cancer treatment 功能化壳聚糖作为CRISPR-Cas9在癌症治疗中的纳米递送平台

IF 10.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Asian Journal of Pharmaceutical Sciences

Pub Date : 2025-06-01 Epub Date: 2025-02-26 DOI: 10.1016/j.ajps.2025.101041

Asif Nawaz , Nur Syamimi Ariffin , Tin Wui Wong

CRISPR-Cas system permanently deletes any harmful gene-of-interest to combat cancer growth. Chitosan (CS) is a potential cancer therapeutic that mediates via PI3K/Akt/mTOR, MAPK and NF-kβ signaling pathway modulation. CS and its covalent derivatives have been designed as nanocarrier of CRISPR-Cas9 alone (plasmid or ribonucleoprotein) or in combination with chemical drug for cancer treatment. The nanocarrier was functionalized with polyethylene glycol (PEG), targeting ligand, cell penetrating ligand and its inherent positive zeta potential to mitigate premature clearance and particulate aggregation, and promote cancer cell/nucleus targeting and permeabilization to enable CRISPR-Cas9 acting on the host DNA. Different physicochemical attributes are required for the CS-based nanocarrier to survive from the administration site, through the systemic circulation-extracellular matrix-mucus-mucosa axis, to the nucleus target. CRISPR-Cas9 delivery is met with heterogeneous uptake by the cancer cells. Choice of excipients such as targeting ligand and PEG may be inappropriate due to lacking overexpressed cancer receptor or availability of excessive metabolizing enzyme and immunoglobulin that defies the survival and action of these excipients rendering nanocarrier fails to reach the target site. Cancer omics analysis should be implied to select excipients which meet the pathophysiological needs, and chitosan nanocarrier with a “transformative physicochemical behavior” is essential to succeed CRISPR-Cas9 delivery.

CRISPR-Cas系统永久删除任何有害基因，以对抗癌症的生长。壳聚糖（CS）通过介导PI3K/Akt/mTOR、MAPK和NF-kβ信号通路，是一种潜在的癌症治疗药物。CS及其共价衍生物已被设计为CRISPR-Cas9单独（质粒或核糖核蛋白）或与化学药物联合的纳米载体，用于癌症治疗。利用聚乙二醇（PEG）功能化纳米载体，靶向配体、细胞穿透配体及其固有的正zeta电位，减轻过早清除和颗粒聚集，促进癌细胞/细胞核的靶向和渗透，使CRISPR-Cas9能够作用于宿主DNA。基于cs的纳米载体需要不同的物理化学特性才能从给药部位存活下来，通过体循环-细胞外基质-粘液-粘膜轴，到达细胞核靶点。CRISPR-Cas9递送会被癌细胞异质摄取。由于缺乏过表达的癌症受体，或存在过多的代谢酶和免疫球蛋白，导致辅料如靶向配体和PEG的选择不合适，导致纳米载体无法到达靶部位。通过肿瘤组学分析，选择符合病理生理需要的赋形剂，而具有“转化物理化学行为”的壳聚糖纳米载体是CRISPR-Cas9成功递送的必要条件。

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引用次数: 0

Enhancing HepG2 cell apoptosis with a combined nanoparticle delivery of miR-128–3p agomir and Oroxin B: A novel drug delivery approach based on PI3K-AKT and VEGF pathway crosstalk 用纳米颗粒联合递送 miR-128-3p agomir 和 Oroxin B 增强 HepG2 细胞凋亡：一种基于 PI3K-AKT 和 VEGF 通路串联的新型给药方法

IF 10.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Asian Journal of Pharmaceutical Sciences

Pub Date : 2025-06-01 Epub Date: 2024-04-02 DOI: 10.1016/j.ajps.2024.100909

Hechen Wang, Xudan Shen, Jiatong Liu, Xinlan Zhu, Su Zeng, Sheng Cai

Hepatocellular carcinoma (HCC) shows the highest morbidity among liver cancers and is a major contributor to cancer-associated mortality. It is characterized by genetic mutations in hepatocytes, leading to uncontrolled cell growth and proliferation. Current treatment include surgery, chemotherapy and immunotherapy; however, chemotherapeutics, which focus on single-targeted drug therapy, are still associated with certain limitations and may affect the treatment outcomes. Compared with chemotherapy drugs, natural products also show the anticancer effect of HCC and hypotoxicity, but overall low activity of natural products limits their further application. MmiRNAs can modulate post-transcriptional functions of target genes. An increasing body of evidence has demonstrated that miRNAs are the key regulators in HCC by targeting different molecules in different signaling pathways. However, miRNAs are fragile and liable to catabolism by RNases in serum and other body fluids and small molecules separated from natural products may have limited bio-availability. According to this background, a chitosan based, targeted sustained-release nanoparticle delivery miR-128–3p agomir (NA-miR-128–3p) was developed in this work. This nanoparticle was prepared by pentasodium tripolyphosphate (TPP), chitosan hydrochloride, and miR-128–3p agomir with target aptamer which was loaded into the chitosan nanoparticle by self-assembly. It can intervene in HCC progress by affecting AKT1 expression. Based on this, a novel, efficient, long-acting, multi-mechanism, low-dosage combination drug delivery strategy was proposed in this work and showed a prominent anti-tumor effect. NA-miR-128–3p combined with natural product Oroxin B significantly affected HCC progression by the interference with VEGF and PI3K-AKT pathways, better than using NA-miR-128–3p and Oroxin B alone. Taken together, this nanoparticle and combinative administration compensate for the shortcomings of the fragile RNA drugs and the low activity of natural products, with high prospects in HCC treatment.

肝细胞癌（HCC）是肝癌中发病率最高的一种，也是导致全球癌症相关死亡率的主要因素。其特点是肝细胞发生基因突变，导致细胞生长和增殖失控。治疗 HCC 的方法包括手术、化疗和免疫疗法。但以单一靶向药物治疗为主的化疗药物仍存在一定的局限性，可能会影响治疗效果。与化疗药物相比，天然产物也具有抗 HCC 和降毒性的作用，但天然产物整体活性较低，限制了其进一步应用。MiRNA 可调节靶基因转录后的功能。越来越多的证据表明，miRNAs 通过靶向不同信号通路中的不同分子，成为 HCC 的关键调控因子。然而，miRNAs 很脆弱，容易在血清和其他体液中被 RN 酶分解，而且从天然产品中分离出来的小分子可能生物利用度有限。根据这一背景，本研究开发了一种基于壳聚糖的靶向缓释纳米颗粒递送 miR-128-3p 激动剂（NA-miR-128-3p）。该纳米粒子由三聚磷酸钠（TPP）、盐酸壳聚糖和miR-128-3p激动剂制备而成。它可以通过影响 AKT1 的表达来干预 HCC 的进展。在此基础上，该研究提出了一种新型、高效、长效、多机制、低剂量的联合给药策略，并显示出显著的抗肿瘤效果。通过干扰血管内皮生长因子和 PI3K-AKT 通路，NA-miR-128-3p 与天然产物 Oroxin B 联用可显著影响 HCC 的进展，效果优于单独使用 NA-miR-128-3p 和 Oroxin B。总之，这种纳米颗粒和联合用药弥补了易碎RNA药物和天然产物活性低的缺点，在HCC治疗中具有很高的应用前景。

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引用次数: 0

Enhanced lymphatic transportation of SLN by mimicking oligopeptide transportation route 通过模拟寡肽运输途径增强SLN的淋巴运输

IF 10.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Asian Journal of Pharmaceutical Sciences

Pub Date : 2025-06-01 Epub Date: 2025-01-10 DOI: 10.1016/j.ajps.2025.101019

Fuya Jia , Xiaoxing Fan , Licheng Wu , Yating Wang , Jisen Zhang , Zhou Zhou , Lian Li , Jingyuan Wen , Yuan Huang

Solid lipid nanoparticles (SLN) could enhance the oral bioavailability of loaded protein and peptide drugs through lymphatic transport. Natural oligopeptides regulate nearly all vital processes and serve as a nitrogen source for nourishment. They are mainly transported by oligopeptide transporter-1 (PepT-1) which are primarily expressed in the intestine with the characteristics of high-capacity and low energy consumption. Our preliminary research discovered the transmembrane transport of SLN could be improved by stimulating the oligopeptide absorption pathway. This implied the potential of combining the advantages of SLN with oligopeptide transporter mediated transportation. Herein, two kinds of dipeptide modified SLN were designed with insulin and glucagon like peptide-1 (GLP-1) analogue exenatide as model drugs. These drugs loaded SLN showed enhanced oral bioavailability and hypoglycemic effect in both type I diabetic C57BL/6 mice and type II diabetic KKAy mice. Compared with un-modified SLN, dipeptide-modified SLN could be internalized by intestinal epithelial cells via PepT-1-mediated endocytosis with higher uptake. Interestingly, after internalization, more SLN could access the systemic circulation via lymphatic transport pathway, highlighting the potential to combine the oligopeptide-absorption route with SLN for oral drug delivery.

固体脂质纳米颗粒（SLN）可通过淋巴运输提高载蛋白和多肽药物的口服生物利用度。天然寡肽调节几乎所有的生命过程，并作为营养的氮源。它们主要通过寡肽转运体-1 （PepT-1）运输，主要在肠道内表达，具有高容量、低能耗的特点。我们的初步研究发现，通过刺激寡肽吸收途径可以改善SLN的跨膜转运。这意味着将SLN的优势与寡肽转运体介导的转运结合起来的潜力。本实验以胰岛素和胰高血糖素样肽-1 （GLP-1）类似物艾塞那肽为模型药物，设计了两种二肽修饰的SLN。这些药物负载SLN在I型糖尿病小鼠C57BL/6和II型糖尿病小鼠KKAy中均表现出增强的口服生物利用度和降糖作用。与未修饰的SLN相比，二肽修饰的SLN可以通过pept -1介导的内吞作用被肠上皮细胞内化，并且摄取更高。有趣的是，内化后，更多的SLN可以通过淋巴运输途径进入体循环，这突出了将寡肽吸收途径与SLN结合用于口服给药的潜力。

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引用次数: 0

Advanced drug delivery platforms target cancer stem cells 先进的药物输送平台靶向癌症干细胞

IF 10.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Asian Journal of Pharmaceutical Sciences

Pub Date : 2025-06-01 Epub Date: 2025-02-19 DOI: 10.1016/j.ajps.2025.101036

MirAhmad Mazloomi , Abolfazl Doustmihan , Sajjad Alimohammadvand , Hamed Hamishehkar , Michael R. Hamblin , Rana Jahanban Esfahlan

Cancer stem cells (CSCs) are a major challenge in cancer therapy. Stem cell-like cells form a unique subpopulation within many tumors, which govern the degree of malignancy by promoting metastasis, recurrence, heterogeneity, and resistance to drug and radiation. Furthermore, these cells can persist in patients even after undergoing multiple cycles of conventional cancer therapy via dormancy, where they no longer dividing but remain active. These may cause cancer recurrence at any time, even years after a supposed cure, and remain invisible to the immune system. Targeting specific surface markers, signaling pathways and tumor microenvironment, which all have a significant effect on CSC function and maintenance, could help to eradicate CSCs and improve patient survival. Combinations of traditional therapies with nano-based drug delivery systems can efficiently target CSCs. Considering the biology and properties of CSCs, we classify recent approaches involving nanoparticle engineering, extracellular matrix modulation, cocktail strategies, multi-stage therapy, CSC defanging, Trojan horse systems, targeted therapy and organelle targeting. We highlight the most recent advances in nanocarrier design and drug delivery technologies to target CSCs, combined with conventional treatment in preclinical and clinical trials. The prospects of these approaches for CSCs elimination and recurrent cancer treatment are discussed.

肿瘤干细胞（CSCs）是癌症治疗中的一个主要挑战。干细胞样细胞在许多肿瘤中形成一个独特的亚群，通过促进转移、复发、异质性和对药物和放疗的抵抗来控制恶性程度。此外，即使经过多次常规癌症治疗后，这些细胞也能在患者体内持续存在，因为它们不再分裂，但仍保持活性。这些可能在任何时候导致癌症复发，甚至在所谓的治愈多年后，免疫系统仍然不可见。靶向特异性表面标记物、信号通路和肿瘤微环境对CSC功能和维持均有显著影响，有助于根除CSC，提高患者生存率。传统疗法与纳米药物传递系统的结合可以有效地靶向csc。考虑到CSC的生物学和特性，我们对最近的方法进行了分类，包括纳米颗粒工程、细胞外基质调节、鸡尾酒策略、多阶段治疗、CSC去毒化、特洛伊木马系统、靶向治疗和细胞器靶向。我们重点介绍了靶向CSCs的纳米载体设计和药物输送技术的最新进展，并结合临床前和临床试验中的常规治疗。讨论了这些方法在消除CSCs和治疗复发性癌症中的应用前景。

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引用次数: 0

Endosomal disruption by co-encapsulating gentamicin in lipid nanoparticles for efficient siRNA delivery and cancer therapy 通过在脂质纳米颗粒中共包封庆大霉素以实现高效siRNA递送和癌症治疗的内体破坏

IF 10.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Asian Journal of Pharmaceutical Sciences

Pub Date : 2025-06-01 Epub Date: 2024-12-16 DOI: 10.1016/j.ajps.2024.101011

Ning Yang , Qi Sun , Yaoqi Wang , Dong Mei , Xiaoling Wang , Jie Zhang , Danni Liu , Ran Huo , Yang Tian , Yan Su , Shuang Zhang , Chunying Cui

Efficient siRNA delivery is highly desirable for disease treatment. However, the application of conventional nanoparticles is limited by the inability to escape from endo-lysosomes. Herein, we report a strategy using small-molecule drugs to enhance siRNA endo‐lysosomal release,addressing this challenge. We encapsulated gentamicin(GM) into the marketed Onpattro® formulation to establish LNP-siRNA/GM nanoparticles that promote siRNA endo‐lysosomal escape through endosomal disruption, mechanistically exhibiting unique functionality and synergistic effects of LNP-siRNA/GM to improve cancer therapy. Besides, GM induced reactive oxygen species (ROS) and phospholipids accumulation in endo‐lysosomes, as well as the physical characteristics of lipid nanoparticles (LNPs) were preserved. We also revealed that GM causes endo‐lysosomal swelling and disrupts the endosomal membrane to enable siRNA release, as confirmed by Galectin 3 recruitment and acridine orange release. This approach achieved ∼81% mRNA-EGFR silencing, which is more than LNP-siEGFR (∼56.23%) by enhancing siRNA endo‐lysosomal escape efficiency. Meanwhile, LNP-siEGFR/GM exhibited significant biological activities in HepG2 cells, driven by the synergistic effects of siEGFR and GM with the VEGF and CXCL12 downregulation of, and ROS and phospholipids upregulation. Furthermore, tumor growth was notably suppressed after intravenous injection of LNP-siEGFR/GM in tumor-bearing nude mice. The combination of EGFR-siRNA and GM could also greatly inhibit angiogenesis, be antiproliferative, and induce tumor cells apoptosis. Therefore, this GM and siRNA co-delivery system would provide an efficient strategy for siRNA endosomal escape, significantly improving knockdown in various LNPs based siRNA delivery systems and efficiently enhancing cancer therapy.

高效的siRNA递送对于疾病治疗是非常理想的。然而，传统纳米颗粒的应用受到无法从内溶酶体中逃逸的限制。在此，我们报告了一种使用小分子药物来增强siRNA内溶酶体释放的策略，以解决这一挑战。我们将庆大霉素（GM）封装到已上市的Onpattro®制剂中，建立LNP-siRNA/GM纳米颗粒，通过内体破坏促进siRNA内溶酶体逃逸，在机制上表现出LNP-siRNA/GM的独特功能和协同效应，以改善癌症治疗。此外，转基因诱导的活性氧（ROS）和磷脂在内溶酶体中积累，以及脂质纳米颗粒（LNPs）的物理特性被保留。我们还发现，转基因引起内溶酶体肿胀，破坏内体膜，使siRNA释放，正如半乳糖凝集素3募集和吖啶橙释放所证实的那样。该方法通过提高siRNA内溶酶体逃逸效率，实现了约81%的mRNA-EGFR沉默，高于LNP-siEGFR（约56.23%）。同时，LNP-siEGFR/GM在HepG2细胞中表现出显著的生物活性，这是由于siEGFR和GM与VEGF、CXCL12下调、ROS和磷脂上调协同作用所致。此外，静脉注射LNP-siEGFR/GM后，荷瘤裸鼠的肿瘤生长明显受到抑制。EGFR-siRNA与GM联合使用还能显著抑制血管生成、抑制肿瘤细胞增殖、诱导肿瘤细胞凋亡。因此，这种GM和siRNA共递送系统将为siRNA内体逃逸提供一种有效的策略，显著改善各种基于LNPs的siRNA递送系统的敲低，并有效地增强癌症治疗。

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引用次数: 0

Multifunctional Prussian blue nanoparticles loading with Xuetongsu for efficient rheumatoid arthritis therapy through targeting inflammatory macrophages and osteoclasts 负载血通素的多功能普鲁士蓝纳米颗粒通过靶向炎性巨噬细胞和破骨细胞有效治疗类风湿关节炎

IF 10.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Asian Journal of Pharmaceutical Sciences

Pub Date : 2025-06-01 Epub Date: 2025-02-22 DOI: 10.1016/j.ajps.2025.101037

Yasi Deng , Bin Li , Hao Zheng , Ling Liang , Yupei Yang , Shiqi Liu , Mengyun Wang , Caiyun Peng , Bin Liu , Wei Wang , Huanghe Yu

Abnormal activation of macrophages and osteoclasts (OCs) contributes significantly to rheumatoid arthritis (RA) development by secretion of numerous inflammatory factors. Notably, these cells exhibit significant upregulation of folate receptor proteins on their surfaces. Unfortunately, there is a current lack of safe and effective therapeutic drugs for RA. Xuetongsu (XTS), a triterpenoid compound extracted from Kadsura heteroclita Roxb Craib, has demonstrated the ability to significantly inhibit the proliferation of RA fibroblast-like synoviocytes (RAFLS). However, its clinical application is hampered by poor targeting and short half-life. To address these drawbacks, we previously developed a nano-drug system named HRPS nanoparticles (NPs), which effectively targets RAFLS and inhibits synovial hyperplasia. However, this system overlooked the essential role of OCs in RA-related bone destruction. Therefore, we designed a novel folate-modified biomimetic Prussian blue (PB)-XTS NP (FMPX NP) for the selective delivery of XTS into inflammatory macrophages and OCs. The NP exhibits an excellent photothermal effect when assisted by laser irradiation, facilitating targeted release of XTS within inflammatory macrophages and OCs. The synergistic anti-inflammatory and reactive oxygen species scavenging effects of PB NPs and XTS are mediated by the inhibition of the NF-κB signaling pathway in inflammatory macrophages and RANK/RANKL/NFATc1 signaling pathway in OCs. In vivo experiments showed that FMPX NPs extended the half-life of XTS by 2.32 times, decreased hind foot swelling from 12.10 ± 0.49 mm to 8.24 ± 0.09 mm in the model group, and prevented bone damage. In conclusion, this study introduces a novel dual-targeted nano-based therapy for RA joints and highlights its potential for biochemical photothermal triple therapy for RA. FMPX NPs inhibit arthritis-related inflammation and bone destruction through a dual-target strategy, providing new insights for targeted drug therapies in clinical RA treatment.

巨噬细胞和破骨细胞（OCs）的异常激活通过分泌多种炎症因子在类风湿关节炎（RA）的发展中起着重要作用。值得注意的是，这些细胞表面叶酸受体蛋白显著上调。不幸的是，目前缺乏安全有效的类风湿性关节炎治疗药物。雪通素（XTS）是一种从鹿角草（Kadsura heteroclita Roxb Craib）中提取的三萜化合物，已被证明能够显著抑制RA成纤维细胞样滑膜细胞（RAFLS）的增殖。但其靶向性差、半衰期短，阻碍了其临床应用。为了解决这些问题，我们之前开发了一种名为HRPS纳米颗粒（NPs）的纳米药物系统，它可以有效地靶向RAFLS并抑制滑膜增生。然而，该系统忽略了OCs在ra相关骨破坏中的重要作用。因此，我们设计了一种新的叶酸修饰的仿生普鲁士蓝(PB)-XTS NP (FMPX NP)，用于选择性地将XTS递送到炎性巨噬细胞和oc中。NP在激光照射下表现出良好的光热效应，促进炎症性巨噬细胞和oc内XTS的靶向释放。PB NPs和XTS的协同抗炎和活性氧清除作用是通过抑制炎性巨噬细胞中NF-κB信号通路和OCs中RANK/RANKL/NFATc1信号通路介导的。体内实验表明，FMPX NPs能使XTS半衰期延长2.32倍，使模型组大鼠后足肿胀从12.10±0.49 mm减少到8.24±0.09 mm，并能防止骨损伤。综上所述，本研究介绍了一种新型的双靶向纳米治疗RA关节，并强调了其生物化学光热三联治疗RA的潜力。FMPX NPs通过双靶点策略抑制关节炎相关炎症和骨破坏，为临床治疗RA的靶向药物治疗提供了新的见解。

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引用次数: 0

Enhancing temozolomide in vivo stability and efficacy through hybrid nanoconjugate approach for improved glioblastoma multiforme treatment 通过混合纳米偶联方法提高替莫唑胺在体内的稳定性和有效性，以改善胶质母细胞瘤多形性治疗

IF 10.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Asian Journal of Pharmaceutical Sciences

Pub Date : 2025-06-01 Epub Date: 2025-01-23 DOI: 10.1016/j.ajps.2025.101022

Prabhjeet Singh , Deepak Kumar Sahel , Reena Jatyan , Kiran Bajaj , Anupama Mittal , Deepak Chitkara

Temozolomide (TMZ) is considered as a standard-of-care DNA alkylating agent for treating glioblastoma multiforme. Despite being a highly potent molecule, TMZ poses several limitations, including short half-life, rapid metabolism, low brain bioavailability and dose-dependent toxicities. Attempts have been made to improve the delivery of TMZ that mainly exhibited nominal therapeutic outcomes. In the current study, we have conjugated TMZ to mPEG-b-P(CB-{g-COOH}) copolymer to obtain mPEG-b-P(CB-{g-COOH; g-TMZ_n}) that demonstrated improvement in stability and efficacy. Further, a hybrid TMZ nanoconjugate formulation was developed using mPEG-b-P(CB-{g-COOH; g-TMZ₄₀}) and mPEG-polylactic acid (mPEG-PLA) showed an average size of 105.7 nm with narrow PDI of <0.2 and TMZ loading of 21.6 %. Stability was assessed under physiological conditions wherein TMZ was found to be stable with a half-life of ∼194 h compared to 1.8 h for free TMZ. The Hybrid TMZ nanoconjugates showed improved intracellular uptake and reduced IC₅₀ values in C6 and U87MG glioma cells. Furthermore, they exhibited better in vivo therapeutic outcome, i.e., reduced brain weight, hemispherical width ratio and improved survival rate in C6-cell induced orthotropic glioma model in Sprague Dawley rats compared to the free TMZ-treated and positive control animals. Histopathological evaluation also revealed reduced cell infiltration in the lungs and reduced toxicity in major organs. Overall, the hybrid nanoconjugates of TMZ significantly improved its stability and efficacy in the GBM model, thereby opening newer avenues for treatment.

替莫唑胺（TMZ）被认为是治疗多形性胶质母细胞瘤的标准护理DNA烷基化剂。尽管TMZ是一种非常有效的分子，但它也存在一些局限性，包括半衰期短、代谢快、脑生物利用度低和剂量依赖性毒性。已经尝试改善TMZ的递送，主要表现出名义上的治疗结果。在本研究中，我们将TMZ偶联到mPEG-b-P（CB-{g-COOH}）共聚物上，得到mPEG-b-P(CB-{g-COOH}；g-TMZn})，显示出稳定性和疗效的改善。进一步，利用mPEG-b-P(CB-{g-COOH；g-TMZ40})和mpeg -聚乳酸（mPEG-PLA）的平均尺寸为105.7 nm， PDI窄为<；0.2， TMZ负载为21.6% %。在生理条件下评估稳定性，发现TMZ稳定，半衰期为~ 194 h，而自由TMZ的半衰期为1.8 h。杂交TMZ纳米偶联物在C6和U87MG胶质瘤细胞中表现出改善细胞内摄取和降低IC50值的作用。此外，与游离tmz治疗和阳性对照动物相比，它们在体内表现出更好的治疗效果，即c6细胞诱导的Sprague Dawley大鼠脑重量、半球宽度比和存活率降低。组织病理学评估也显示肺细胞浸润减少，主要器官毒性降低。总的来说，TMZ的杂化纳米偶联物显著提高了其在GBM模型中的稳定性和疗效，从而开辟了新的治疗途径。

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引用次数: 0

All-stage targeted nanodiscs for glioma treatment by inducing cuproptosis and apoptosis of cancer cells and cancer stem cells 靶向纳米片通过诱导肿瘤细胞和肿瘤干细胞的铜增生和凋亡来治疗胶质瘤

IF 10.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Asian Journal of Pharmaceutical Sciences

Pub Date : 2025-04-01 Epub Date: 2024-12-17 DOI: 10.1016/j.ajps.2024.101010

Yuan Ding , Ruohan Chen , Jianfen Zhou , Yanning Bao , Nana Meng , Xudong Zheng , Shengmin Yang , Jiasheng Lu , Zhixuan Jiang , Yu Liu , Cao Xie , Linwei Lu , Weiyue Lu

There remain several intractable challenges for chemotherapy in glioma treatment, including the blood-brain barrier (BBB), blood-brain tumor barrier (BBTB), and tumor heterogeneity caused by cancer stem cells (CSCs), which are resistant to conventional chemotherapy. Here, we established a nano strategy to kill glioma cells and CSCs, combining carfilzomib and bis(diethyldithiocarbamate)copper. The synergistic drug combination disturbed cell protein metabolism at different stages and induced apoptosis and cuproptosis. The Y-shaped targeting ligand pHA-VAP-modified nanodiscs were designed to help the chemotherapeutic agents cross the BBB/BBTB and finally accumulate in tumor site. This all-stage targeting and all-stage treatment nanomedicine significantly prolonged the survival in glioma-bearing mice and might inspire the rational design of advanced drug delivery platforms.

化疗在胶质瘤治疗中仍然存在一些棘手的挑战，包括血脑屏障（BBB）、血脑肿瘤屏障（BBTB）和肿瘤干细胞（CSCs）引起的肿瘤异质性，这些对传统化疗具有耐药性。在这里，我们建立了一种纳米策略来杀死胶质瘤细胞和CSCs，结合卡非佐米和双（二乙基二硫代氨基甲酸盐）铜。协同用药干扰不同阶段细胞蛋白代谢，诱导细胞凋亡和铜坏死。设计了y形靶向配体pha - vap修饰的纳米圆盘，帮助化疗药物穿过血脑屏障/血脑屏障，最终在肿瘤部位积累。这种全阶段靶向、全阶段治疗的纳米药物显著延长了胶质瘤小鼠的生存期，并可能启发先进给药平台的合理设计。

引用次数: 0

Albumin nanoassembly bi-directionally manipulated ferroptosis in tumor and CD8+ T cells for triple-negative breast cancer therapy 白蛋白纳米组装双向操纵肿瘤和CD8+ T细胞中的铁下垂用于三阴性乳腺癌治疗

IF 10.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Asian Journal of Pharmaceutical Sciences

Pub Date : 2025-04-01 Epub Date: 2024-10-01 DOI: 10.1016/j.ajps.2024.100970

Ting Yang , Zihan Liu , Zixuan Fu , Xiaojie Zhang , Yongjin Cao , Qiangwei Liang , Jiale Miao , Hao Yang , Tong Zhang , Jing Hei , Weiqing Ni , Yanhua Liu

Ferroptosis can serve as a potent strategy for regulating cell death via lipid peroxidation and the imbalance of the antioxidant system resulting from iron accumulation in triple-negative breast cancer (TNBC) therapy. However, the ferroptosis accompanied with down-regulation of glutathione peroxidase 4 (GPX4) lead to CD36-mediated tumor-infiltrating CD8⁺ T cells uptaking fatty acids, resulting in the negative action on immunotherapeutic efficacy. Herein, the albumin nanoparticles, abbreviated as LHS NPs, were designed by co-assembly of hemin, linoleic acid-cystamine, and a CD36 inhibitor sulfosuccinimide oleate, to bi-directionally manipulated ferroptosis in tumor and CD8⁺ T cells for TNBC therapy. LHS NPs exerted more efficient reactive oxygen species generation, glutathione depletion and malondialdehyde production by the combinatory strategy of classical and non-classical ferroptosis modes, which amplified the positive action on ferroptosis in tumor cells. Meanwhile, LHS manipulated the negative action of ferroptosis by inhibiting the CD36 mediated-lipid peroxidation in CD8⁺ T cells, thereby activating the immunotherapeutic efficacy with the improvements on induction of immunogenic cell death, proliferation of CD4⁺CD8⁺ T cells and natural killer cells, alleviation immunosuppressive regulatory T cells and myeloid-derived suppressor cells, and repolarization of the M2- to M1-phenotype tumor-associated macrophages. Thus, LHS NPs demonstrated an improved antitumor efficacy in suppressing the tumor growth and lung metastasis of 4T1-tumor mice. Our work gives novel insights for the bi-directionally manipulating ferroptosis in tumor and CD8⁺ T cells on TNBC chemoimmunotherapy.

在三阴性乳腺癌（TNBC）治疗中，铁凋亡可以作为一种有效的策略，通过脂质过氧化和由铁积累引起的抗氧化系统失衡来调节细胞死亡。然而，铁下沉伴随着谷胱甘肽过氧化物酶4 （GPX4）的下调，导致cd36介导的肿瘤浸润性CD8+ T细胞摄取脂肪酸，从而对免疫治疗效果产生负面作用。本文中，白蛋白纳米颗粒（简称LHS NPs）由血红蛋白、亚油酸半胱胺和CD36抑制剂油酸磺基琥珀酰亚胺共组装而成，用于双向操纵肿瘤和CD8+ T细胞中的铁凋亡，用于TNBC治疗。LHS NPs通过经典和非经典铁下沉模式的组合策略，更有效地产生活性氧、谷胱甘肽消耗和丙二醛产生，从而放大了对肿瘤细胞铁下沉的积极作用。同时，LHS通过抑制CD36介导的CD8+ T细胞脂质过氧化来调控铁沉的负作用，从而激活免疫治疗效果，诱导免疫原性细胞死亡，促进CD4+CD8+ T细胞和自然杀伤细胞的增殖，减轻免疫抑制性调节性T细胞和髓源性抑制细胞，促进M2-向m1表型肿瘤相关巨噬细胞的复极化。由此可见，LHS NPs在抑制4t1肿瘤小鼠的肿瘤生长和肺转移方面具有较好的抗肿瘤作用。我们的工作为双向操纵肿瘤和CD8+ T细胞在TNBC化学免疫治疗中的铁下垂提供了新的见解。

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引用次数: 0

Single-dose oral administration of drug-loaded magnetic 3D-printed microbullets for eradication of Helicobacter pylori 单剂量口服载药磁性3d打印微弹根除幽门螺杆菌

IF 10.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Asian Journal of Pharmaceutical Sciences

Pub Date : 2025-04-01 Epub Date: 2025-01-03 DOI: 10.1016/j.ajps.2024.101013

Hua Xie , Dongdong Liu , Jintao Shen , Wenrui Yan , Meng Wei , Yingbao Sun , Yubao Fang , Bochuan Yuan , Pei Deng , Yiguang Jin

Infections of Helicobacter pylori (H. pylori) affect 42.1 % of the Chinese population and 43.1 % of the world population. H. pylori inhabits the mucous sublayer at the pylorus, leading to gastric ulcers, gastritis, and even cancer. Oral antibiotics are usually used to treat H. pylori infections, whereas traditional quadruple therapy has side effects including headaches, nausea, diarrhea, intestinal dysbacteriosis, antibiotic resistance, and repeat infections. Here, a drug-loaded magnetic microbullet was designed to realize long-term retention in the stomach for one-shot treatment for H. pylori infections. It comprises a hollow cylinder wherein eight microneedles homogenously distribute at the top and several round pores located at the bottom. It was three-dimensional (3D)-printed by stereolithography. A clarithromycin (CAM) ground mixture (CGM) was prepared to improve solubility. Enough CGM powders were filled into the cylinder, covered by a small round magnet, and sealed to form a CAM-loaded magnetic microbullet (CMMB). CAM continually released from CMMBs for >24 h. With outside magnetic guidance, an oral CMMB targeted the pylorus site and the microneedles immediately headed into the mucosa followed by long-term local drug release. The in vitro and in vivo safety of CMMBs was confirmed, where their swelling rates were low, and the oral CMMB was finally completely evacuated. An oral CMMB was administered to H. pylori-infected mice and maintained in the stomach for 36 h with magnetic guidance, and the successful eradication of H. pylori was confirmed after single-dose administration. Oral CMMBs are a convenient medication for the eradication of H. pylori.

幽门螺杆菌（h.p ylori）感染影响了42.1% %的中国人口和43.1% %的世界人口。幽门螺旋杆菌寄生于幽门的粘膜下层，可导致胃溃疡、胃炎甚至癌症。口服抗生素通常用于治疗幽门螺杆菌感染，而传统的四联疗法有副作用，包括头痛、恶心、腹泻、肠道菌群失调、抗生素耐药性和重复感染。在这里，一种装载药物的磁性微子弹被设计成在胃中长期保留，用于一次治疗幽门螺杆菌感染。它包括一个中空圆柱体，其中八个微针均匀分布在顶部，几个圆形孔位于底部。它是用立体光刻技术三维打印的。制备了一种克拉霉素（CAM）研磨混合物（CGM），以提高其溶解度。将足够的CGM粉末填充到圆柱体中，用小圆形磁铁覆盖，并密封形成装载cam的磁微弹（CMMB）。CAM从CMMB中持续释放24小时。在外部磁引导下，口服CMMB靶向幽门部位，微针立即进入粘膜，随后长期局部释放药物。证实了CMMB的体外和体内安全性，其肿胀率低，口服CMMB最终完全排出。将CMMB口服给药幽门螺杆菌感染小鼠，并在磁场引导下在胃中维持36 h，单次给药后证实幽门螺杆菌成功根除。口服CMMBs是一种方便的根除幽门螺杆菌的药物。

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引用次数: 0