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

Exosome-membrane and polymer-based hybrid-complex for systemic delivery of plasmid DNA into brains for the treatment of glioblastoma 外泌体膜和基于聚合物的混合复合物用于质粒DNA系统递送到脑内治疗胶质母细胞瘤

IF 10.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Asian Journal of Pharmaceutical Sciences

Pub Date : 2025-02-01 DOI: 10.1016/j.ajps.2024.101006

Youngki Lee , Subin Kang , Le Thi Thuy , Mincheol Son , Jae Young Park , Sung Bin Ahn , Minji Kang , Jihun Oh , Joon Sig Choi , Minhyung Lee

Herpes simplex virus thymidine kinase (HSVtk) gene therapy is a promising strategy for glioblastoma therapy. However, delivery of plasmid DNA (pDNA) encoding HSVtk into the brain by systemic administration is a challenge since pDNA can hardly penetrate the blood-brain barrier. In this study, an exosome-membrane (EM) and polymer-based hybrid complex was developed for systemic delivery of pDNA into the brain. Histidine/arginine-linked polyamidoamine (PHR) was used as a carrier. PHR binds to pDNA by electrostatic interaction. The pDNA/PHR complex was mixed with EM and subjected to extrusion to produce pDNA/PHR-EM hybrid complex. For glioblastoma targeting, T7 peptide was attached to the pDNA/PHR-EM complex. Both pDNA/PHR-EM and T7-decorated pDNA/PHR-EM (pDNA/PHR-EM-T7) had a surface charge of –5 mV and a size of 280 nm. Transfection assays indicated that pDNA/PHR-EM-T7 enhanced the transfection to C6 cells compared with pDNA/PHR-EM. Intravenous administration of pHSVtk/PHR-EM-T7 showed that pHSVtk/PHR-EM and pHSVtk/PHR-EM-T7 delivered pHSVtk more efficiently than pHSVtk/lipofectamine and pHSVtk/PHR into glioblastoma in vivo. pHSVtk/PHR-EM-T7 had higher delivery efficiency than pHSVtk/PHR-EM. As a result, the HSVtk expression and apoptosis levels in the tumors of the pHSVtk/PHR-EM-T7 group were higher than those of the other control groups. Therefore, the pDNA/PHR-EM-T7 hybrid complex is a useful carrier for systemic delivery of pHSVtk to glioblastoma.

单纯疱疹病毒胸苷激酶（HSVtk）基因治疗是一种很有前途的胶质母细胞瘤治疗策略。然而，编码HSVtk的质粒DNA （pDNA）通过全身给药进入大脑是一个挑战，因为pDNA很难穿透血脑屏障。在这项研究中，开发了一种外泌体-膜（EM）和基于聚合物的杂交复合物，用于将pDNA全身递送到大脑中。以组氨酸/精氨酸连接聚酰胺胺（PHR）为载体。PHR通过静电相互作用与pDNA结合。将pDNA/PHR配合物与EM混合，挤压得到pDNA/PHR-EM杂化配合物。针对胶质母细胞瘤，T7肽被附着在pDNA/ phrr - em复合物上。pDNA/PHR-EM和t7修饰的pDNA/PHR-EM （pDNA/PHR-EM- t7）表面电荷均为-5 mV，尺寸为280 nm。转染实验表明，与pDNA/PHR-EM相比，pDNA/PHR-EM- t7对C6细胞的转染增强。静脉给药pHSVtk/PHR- em - t7显示pHSVtk/PHR- em和pHSVtk/PHR- em - t7在体内比pHSVtk/脂质体和pHSVtk/PHR更有效地将pHSVtk输送到胶质母细胞瘤中。pHSVtk/PHR-EM- t7的输送效率高于pHSVtk/PHR-EM。结果显示，pHSVtk/ phrr - em - t7组肿瘤中HSVtk的表达和凋亡水平均高于其他对照组。因此，pDNA/ phrr - em - t7杂交复合体是将pHSVtk系统递送至胶质母细胞瘤的有用载体。

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引用次数: 0

Biofunctional supramolecular injectable hydrogel with spongy-like metal-organic coordination for effective repair of critical-sized calvarial defects 具有海绵状金属-有机配位的生物功能超分子可注射水凝胶用于修复临界尺寸颅骨缺损

IF 10.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Asian Journal of Pharmaceutical Sciences

Pub Date : 2025-02-01 DOI: 10.1016/j.ajps.2024.100988

Yingqi Chen , Zuocheng Qiu , Xueling Hu , Tiehua Wang , Guoqing Li , Ziling Tang , Chongzhou Fang , Weibei Sheng , Jin Zhao , Fei Yu , Jian Weng , Anjaneyulu Udduttula , Geetha Manivasagam , Hui Zeng

In clinical settings, regenerating critical-sized calvarial bone defects presents substantial problems owing to the intricacy of surgical methods, restricted bone growth medications, and a scarcity of commercial bone grafts. To treat this life-threatening issue, improved biofunctional grafts capable of properly healing critical-sized bone defects are required. In this study, we effectively created anti-fracture hydrogel systems using spongy-like metal-organic (magnesium-phosphate) coordinated chitosan-modified injectable hydrogels (CPMg) loaded with a bioinspired neobavaisoflavone (NBF) component. The CPMg-NBF hydrogels showed outstanding anti-fracture capabilities during compression testing and retained exceptional mechanical stability even after 28 d of immersion in phosphate-buffered saline. They also demonstrated prolonged and stable release profiles of Mg²⁺ and NBF. Importantly, CPMg-NBF hydrogels revealed robust biphasic mineralization and were non-toxic to MC3T3-E1 cells. To better understand the underlying mechanism of Mg²⁺ and NBF component, as well as their synergistic effect on osteogenesis, we investigated the expression of key osteogenic proteins in the p38 MAPK and NOTCH pathways. Our results showed that CPMg-NBF hydrogels greatly increased the expression of osteogenic proteins (Runx2, OCN, OPN, BMPS and ALP). In vivo experiments showed that the implantation of CPMg-NBF hydrogels resulted in a significant increase in new bone growth within critical-sized calvarial defects. Based on these findings, we expect that the CPMg-NBF supramolecular hydrogel has tremendous promise for use as a therapeutic biomaterial for treating critical-sized calvarial defects.

在临床环境中，由于手术方法的复杂性、限制性骨生长药物和商业骨移植物的稀缺性，再生临界尺寸的颅骨骨缺损提出了实质性的问题。为了治疗这一危及生命的问题，需要改进的生物功能移植物，能够正确愈合临界大小的骨缺损。在这项研究中，我们使用海绵状金属有机（磷酸镁）配位壳聚糖修饰的可注射水凝胶（CPMg）有效地创建了抗断裂水凝胶体系，CPMg负载生物诱导的新巴瓦异黄酮（NBF）成分。CPMg-NBF水凝胶在压缩测试中表现出出色的抗断裂能力，即使在磷酸盐缓冲盐水中浸泡28天后，也保持了出色的机械稳定性。他们还展示了Mg2+和NBF的持久和稳定的释放特征。重要的是，CPMg-NBF水凝胶显示出强大的双相矿化，并且对MC3T3-E1细胞无毒。为了更好地了解Mg2+和NBF成分的潜在机制，以及它们对成骨的协同作用，我们研究了p38 MAPK和NOTCH通路中关键成骨蛋白的表达。结果显示，CPMg-NBF水凝胶可显著提高成骨蛋白（Runx2、OCN、OPN、BMPS和ALP）的表达。体内实验表明，植入CPMg-NBF水凝胶可显著增加临界尺寸颅骨缺损内的新骨生长。基于这些发现，我们期望CPMg-NBF超分子水凝胶作为治疗临界尺寸颅骨缺损的治疗性生物材料具有巨大的前景。

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引用次数: 0

Efficient anticancer drug delivery using nano-colloids self-assembled with an unconventional amphiphile bearing pumpkin-shaped host molecule 利用带有南瓜形宿主分子的非常规两亲体自组装的纳米胶体高效抗癌药物递送

IF 10.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Asian Journal of Pharmaceutical Sciences

Pub Date : 2025-02-01 DOI: 10.1016/j.ajps.2024.101014

Kyeng Min Park

A new type of amphiphiles bearing macrocycle such as cucurbit[7]uril (CB[7]) spontaneously forms a nanomaterial in water, specifically vesicles (tACB[7] vesicles) with a positive surface charge, verified through various analytical techniques including TIRF, DLS and TEM. Functional validation not only reveals the accessibility of the CB[7] portal on these vesicles allowing CB[7]-based host-guest interactions with various functional guest molecules such as fluorescein isothiocyanate conjugated adamantylammonium and spermine (FITC-AdA and FITC-SPM, respectively) using confocal laser scanning microscopy, but also showcases the effective internalization of tACB[7] vesicles into cancer cells with the anticancer drug oxaliplatin (OxPt), as a guest to CB[7], through in vitro cell experiments. Hence, this study provides a blueprint to impart amphiphilic properties to CB[7] through synthetic design and highlights the potential of CB[7] derivatives as a new class of unconventional amphiphiles self-assembling into functional nanomaterials for advanced drug delivery.

一种新型的含大环的两亲分子如葫芦bb[7] （CB[7]）在水中自发形成纳米材料，特别是表面带正电荷的囊泡（tACB[7]囊泡），通过各种分析技术包括TIRF， DLS和TEM进行了验证。功能验证不仅揭示了CB[7]入口在这些囊泡上的可达性，允许基于CB[7]的宿主与各种功能客体分子（如异硫氰酸荧光素共轭adamantylamium和精胺（分别为FITC-AdA和FITC-SPM））相互作用，而且还展示了tACB[7]囊泡与抗癌药物奥沙利铂（OxPt）作为CB[7]的客体有效内化到癌细胞中。通过体外细胞实验。因此，本研究为通过合成设计赋予CB[7]两亲性提供了蓝图，并强调了CB[7]衍生物作为一类新的非常规两亲性自组装成高级药物递送功能纳米材料的潜力。

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引用次数: 0

Biomimetic nanoparticles co-deliver hirudin and lumbrukinase to ameliorate thrombus and inflammation for atherosclerosis therapy 仿生纳米颗粒共同递送水蛭素和蚓激酶以改善动脉粥样硬化治疗中的血栓和炎症

IF 10.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Asian Journal of Pharmaceutical Sciences

Pub Date : 2025-02-01 DOI: 10.1016/j.ajps.2024.100990

Mengying Cheng , Tianxiang Yue , Hong Wang , Lai Jiang , Qiaoling Huang , Fanzhu Li

Atherosclerosis (AS) is a progressive inflammatory disease, and thrombosis most likely leads to cardiovascular morbidity and mortality globally. Thrombolytic drugs alone cannot completely prevent thrombotic events, and treatments targeting thrombosis also need to regulate the inflammatory process. Based on the dynamic pathological development of AS, biomimetic thrombus-targeted nanoparticles HMTL@PM were prepared. Hirudin and lumbrukinase, effective substances of traditional Chinese medicine, were self-assembled under the action of tannic acid and Mn²⁺. HMTL@PM dissociated in the weakly acidic microenvironment of atherosclerosis and exhibited excellent therapeutic effects, including alleviating inflammation, dissolving thrombus, anticoagulation, and promoting cholesterol efflux. HMTL@PM effectively regulated the progression of AS and provided a new perspective for the development of drug delivery systems for AS therapy, which holds important research significance for reducing the mortality of cardiovascular and cerebrovascular diseases.

动脉粥样硬化（AS）是一种进行性炎症性疾病，在全球范围内，血栓形成最可能导致心血管疾病的发病率和死亡率。单独的溶栓药物不能完全预防血栓事件，针对血栓形成的治疗也需要调节炎症过程。基于AS的动态病理发展，制备了仿生血栓靶向纳米颗粒HMTL@PM。水蛭素和蚓激酶是中药有效物质，在单宁酸和Mn2+的作用下自组装。HMTL@PM在动脉粥样硬化的弱酸性微环境中解离，表现出良好的治疗效果，包括减轻炎症、溶解血栓、抗凝、促进胆固醇外排。HMTL@PM有效调节AS的进展，为AS治疗药物递送系统的开发提供了新的视角，对降低心脑血管疾病死亡率具有重要的研究意义。

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引用次数: 0

Enhancing chemoimmunotherapy for colorectal cancer with paclitaxel and alantolactone via CD44-Targeted nanoparticles: A STAT3 signaling pathway modulation approach 通过靶向cd44纳米颗粒增强紫杉醇和阿兰妥内酯对结直肠癌的化学免疫治疗：STAT3信号通路调节方法

IF 10.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Asian Journal of Pharmaceutical Sciences

Pub Date : 2025-02-01 DOI: 10.1016/j.ajps.2024.100993

Fugen Wu , Xingsi An , Shize Li , Chenyu Qiu , Yixuan Zhu , Zhanzheng Ye , Shengnan Song , Yunzhi Wang , Dingchao Shen , Xinyu Di , Yinsha Yao , Wanling Zhu , Xinyu Jiang , Xianbao Shi , Ruijie Chen , Longfa Kou

Chemoimmunotherapy has the potential to enhance chemotherapy and modulate the immunosuppressive tumor microenvironment by activating immunogenic cell death (ICD), making it a promising strategy for clinical application. Alantolactone (A) was found to augment the anticancer efficacy of paclitaxel (P) at a molar ratio of 1:0.5 (P:A) through induction of more potent ICD via modulation of STAT3 signaling pathways. Nano drug delivery systems can synergistically combine natural drugs with conventional chemotherapeutic agents, thereby enhancing multi-drug chemoimmunotherapy. To improve tumor targeting ability and bioavailability of hydrophobic drugs, an amphiphilic prodrug conjugate (HA-PTX) was chemically modified with paclitaxel (PTX) and hyaluronic acid (HA) as a backbone. Based on this concept, CD44-targeted nanodrugs (A@HAP NPs) were developed for co-delivery of A and P in colorectal cancer treatment, aiming to achieve synergistic toxicity-based chemo-immunotherapy. The uniform size and high drug loading capacity of A@HAP NPs facilitated their accumulation within tumors through enhanced permeability and retention effect as well as HA-mediated targeting, providing a solid foundation for subsequent synergistic therapy and immunoregulation. In vitro and in vivo studies demonstrated that A@HAP NPs exhibited potent cytotoxicity against tumor cells while also remodeling the immune-suppressive tumor microenvironment by promoting antigen presentation and inducing dendritic cell maturation, thus offering a novel approach for colorectal cancer chemoimmunotherapy.

化学免疫疗法有可能通过激活免疫原性细胞死亡（immunogenic cell death， ICD）来增强化疗和调节免疫抑制性肿瘤微环境，使其成为一种有前景的临床应用策略。Alantolactone (A)通过调节STAT3信号通路诱导更有效的ICD，以1:0.5 （P:A）的摩尔比增强紫杉醇(P)的抗癌功效。纳米给药系统可以将天然药物与常规化疗药物协同结合，从而增强多药化学免疫治疗。为了提高疏水药物的肿瘤靶向能力和生物利用度，以紫杉醇（PTX）和透明质酸（HA）为骨架对两亲性前药偶联物（HA-PTX）进行了化学修饰。基于这一概念，开发了靶向cd44的纳米药物（A@HAP NPs），用于在结直肠癌治疗中共同递送A和P，旨在实现基于毒性的协同化学免疫治疗。A@HAP NPs的均匀大小和高载药量，通过增强通透性和滞留效应以及ha介导的靶向作用，促进了其在肿瘤内的积累，为后续的协同治疗和免疫调节提供了坚实的基础。体外和体内研究表明，A@HAP NPs对肿瘤细胞具有强大的细胞毒性，同时还通过促进抗原呈递和诱导树突状细胞成熟来重塑免疫抑制的肿瘤微环境，从而为结直肠癌的化学免疫治疗提供了一种新的途径。

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引用次数: 0

Deep-insights: Nanoengineered gel-based localized drug delivery for arthritis management 深入见解：纳米工程凝胶为基础的局部药物递送关节炎管理

IF 10.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Asian Journal of Pharmaceutical Sciences

Pub Date : 2025-02-01 DOI: 10.1016/j.ajps.2024.101012

Anitha Sriram , Harshada Ithape , Pankaj Kumar Singh

Arthritis is an inflammatory joint disorder that progressively impairs function and diminishes quality of life. Conventional therapies often prove ineffective, as oral administration lacks specificity, resulting in off-target side effects like hepatotoxicity and GIT-related issues. Intravenous administration causes systemic side effects. The characteristic joint-localized symptoms such as pain, stiffness, and inflammation make the localized drug delivery suitable for managing arthritis. Topical/transdermal/intra-articular routes have become viable options for drug delivery in treating arthritis. However, challenges with those localized drug delivery routes include skin barrier and cartilage impermeability. Additionally, conventional intra-articular drug delivery also leads to rapid clearance of drugs from the synovial joint tissue. To circumvent these limitations, researchers have developed nanocarriers that enhance drug permeability through skin and cartilage, influencing localized action. Gel-based nanoengineered therapy employs a gel matrix to incorporate the drug-encapsulated nanocarriers. This approach combines the benefits of gels and nanocarriers to enhance therapeutic effects and improve patient compliance. This review emphasizes deep insights into drug delivery using diverse gel-based novel nanocarriers, exploring their various applications embedded in hyaluronic acid (biopolymer)–based gels, carbopol-based gels, and others. Furthermore, this review discusses the influence of nanocarrier pharmacokinetics on the localization and therapeutic manipulation of macrophages mediated by nanocarriers. The ELVIS (extravasation through leaky vasculature and inflammatory cell-mediated sequestration) effect associated with arthritis is advantageous in drug delivery. Simply put, the ELVIS effect refers to the extravasation of nanocarriers through leaky vasculatures, which finally results in the accumulation of nanocarriers in the joint cavity.

关节炎是一种炎症性关节疾病，会逐渐损害功能，降低生活质量。常规疗法往往无效，因为口服给药缺乏特异性，导致脱靶副作用，如肝毒性和git相关问题。静脉给药会引起全身副作用。特有的关节局部症状，如疼痛、僵硬和炎症，使得局部给药适合于治疗关节炎。局部/透皮/关节内途径已成为治疗关节炎的药物递送的可行选择。然而，这些局部药物输送途径的挑战包括皮肤屏障和软骨不渗透性。此外，传统的关节内给药也会导致滑膜关节组织中药物的快速清除。为了规避这些限制，研究人员开发了纳米载体，增强药物通过皮肤和软骨的渗透性，影响局部作用。凝胶基纳米工程疗法采用凝胶基质结合药物包封的纳米载体。这种方法结合了凝胶和纳米载体的优点，增强了治疗效果，提高了患者的依从性。这篇综述强调了使用各种凝胶基新型纳米载体对药物传递的深入了解，探索了它们在透明质酸（生物聚合物）凝胶、碳水化合物凝胶等中的各种应用。此外，本文还讨论了纳米载体药代动力学对纳米载体介导的巨噬细胞定位和治疗操作的影响。与关节炎相关的ELVIS（渗漏血管外渗和炎症细胞介导的隔离）效应在给药中是有利的。简单地说，猫王效应是指纳米载体通过渗漏的血管外渗，最终导致纳米载体在关节腔内积聚。

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引用次数: 0

Electrically conductive “SMART” hydrogels for on-demand drug delivery 用于按需给药的导电“SMART”水凝胶

IF 10.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Asian Journal of Pharmaceutical Sciences

Pub Date : 2025-02-01 DOI: 10.1016/j.ajps.2024.101007

Soumajyoti Ghosh , Nikhil Kumar , Santanu Chattopadhyay

In the current transformative era of biomedicine, hydrogels have established their presence in biomaterials due to their superior biocompatibility, tuneability and resemblance with native tissue. However, hydrogels typically exhibit poor conductivity due to their hydrophilic polymer structure. Electrical conductivity provides an important enhancement to the properties of hydrogel-based systems in various biomedical applications such as drug delivery and tissue engineering. Consequently, researchers are developing combinatorial strategies to develop electrically responsive “SMART” systems to improve the therapeutic efficacy of biomolecules. Electrically conductive hydrogels have been explored for various drug delivery applications, enabling higher loading of therapeutic cargo with on-demand delivery. This review emphasizes the properties, mechanisms, fabrication techniques and recent advancements of electrically responsive “SMART” systems aiding on-site drug delivery applications. Additionally, it covers prospects for the successful translation of these systems into clinical research.

在当前生物医学的变革时代，水凝胶由于其优越的生物相容性、可调节性和与天然组织的相似性而在生物材料中建立了自己的存在。然而，由于其亲水性聚合物结构，水凝胶通常表现出较差的导电性。导电性为水凝胶系统在各种生物医学应用（如药物输送和组织工程）中的性能提供了重要的增强。因此，研究人员正在开发组合策略来开发电响应“SMART”系统，以提高生物分子的治疗效果。导电性水凝胶已被探索用于各种药物递送应用，使按需递送的治疗货物负载更高。本文综述了电响应“SMART”系统的特性、机制、制造技术和最新进展，以辅助现场给药应用。此外，它还涵盖了这些系统成功转化为临床研究的前景。

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引用次数: 0

CeO2 nanozyme-embedded thermal-deformative polymer for site-specific chemotherapy via HIF-1α-P-gp/lipolysis axis reversal 通过HIF-1α-P-gp/脂解轴反转，CeO2纳米酶包埋热变形聚合物用于部位特异性化疗

IF 10.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Asian Journal of Pharmaceutical Sciences

Pub Date : 2025-01-31 DOI: 10.1016/j.ajps.2025.101023

Zhiyuan Tang , Yuening Sun , Quanhua Yi , Qian Ding , Yang Ding , Jianfei Huang

The effective intracellular accumulation of doxorubicin (DOX) is crucial for improving antitumor efficacy, which is severely impeded by limited drug penetration, uncontrollable drug release, and drug resistance. In this study, a thermal-deformative polymer embedding ultrasmall ceria (CeO₂) was rationally designed for deep tumor drug shuttling and hypoxia reversal to improve chemotherapy. Structurally, the CeO₂ nanozyme was covalently grafted with a polymer of p(NIPAM-co-AM) that could sharply shrink for DOX loading, which was consolidated with polydopamine (PDA) film encapsulation. Thereafter, a tumor penetration guide of apolipoprotein A-I (apoA-I) conjugated iRGD peptide (apoA-I-iRGD) was further decorated onto the PDA shell via Michael addition for preparing CeO₂P/DOX@iAPDA. With the aid of apoA-I-iRGD, CeO₂P/DOX@iAPDA penetrated both the tumor spheroids (∼78 µm) and the tumors of the mouse model deeply. After internalization by tumor cells and triggering by low pH in lysosomes, rapid DOX release was achieved by peeling off the PDA shell and thermosensitive deformation of p(NIPAM-co-AM). CeO₂P/DOX@iAPDA provided 66.4 % tumor suppression in 4T1-derived tumor spheroids and 63.2 % in 4T1-tumor-bearing mice, respectively. Preliminary mechanistic research involving western blotting and immunohistochemistry revealed that CeO₂P/DOX@iAPDA reversed resistance through the through HIF-1α-P-gp/lipid axis. Collectively, this study intelligently integrated CeO₂ nanozymes, temperature-sensitive polymers, and imitated biochemical modifications to improve chemotherapy for breast cancer.

多柔比星（doxorubicin， DOX）在细胞内的有效蓄积对提高抗肿瘤疗效至关重要，但药物渗透有限、药物释放不可控和耐药严重阻碍了DOX的蓄积。本研究合理设计了一种热变形聚合物包埋超小二氧化铈（CeO2），用于肿瘤深部药物穿梭和缺氧逆转，以改善化疗。在结构上，CeO2纳米酶与p（NIPAM-co-AM）聚合物共价接枝，该聚合物可以在DOX负载下急剧收缩，并用聚多巴胺（PDA）薄膜封装巩固。随后，将载脂蛋白a -i （apoA-I）结合的iRGD肽（apoA-I-iRGD）的肿瘤穿透指南进一步通过Michael加成修饰到PDA外壳上，制备CeO2P/DOX@iAPDA。在apoA-I-iRGD的帮助下，CeO2P/DOX@iAPDA深入穿透肿瘤球体（~ 78µm）和小鼠模型的肿瘤。经肿瘤细胞内化和溶酶体低pH触发后，通过剥离PDA外壳和p（NIPAM-co-AM）的热敏变形实现DOX的快速释放。CeO2P/DOX@iAPDA分别对4t1源性肿瘤球体和4t1荷瘤小鼠的肿瘤抑制率分别为66.4 %和63.2 %。western blotting和免疫组化的初步机制研究显示CeO2P/DOX@iAPDA通过HIF-1α-P-gp/脂质轴逆转耐药。总的来说，这项研究智能地整合了CeO2纳米酶、温度敏感聚合物和模拟生化修饰，以改善乳腺癌的化疗。

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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 : 2025-01-23 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

Immune response recalibration using immune therapy and biomimetic nano-therapy against high-grade gliomas and brain metastases 利用免疫疗法和仿生纳米疗法对高级别胶质瘤和脑转移瘤的免疫反应重新校准

IF 10.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Asian Journal of Pharmaceutical Sciences

Pub Date : 2025-01-17 DOI: 10.1016/j.ajps.2025.101021

Puja Sandhbor , Geofrey John , Sakshi Bhat , Jayant S. Goda

Although with aggressive standards of care like surgical resection, chemotherapy, and radiation, high-grade gliomas (HGGs) and brain metastases (BM) treatment has remained challenging for more than two decades. However, technological advances in this field and immunotherapeutic strategies have revolutionized the treatment of HGGs and BM. Immunotherapies like immune checkpoint inhibitors, CAR-T targeting, oncolytic virus-based therapy, bispecific antibody treatment, and vaccination approaches, etc., are emerging as promising avenues offering new hope in refining patient's survival benefits. However, selective trafficking across the blood-brain barrier (BBB), immunosuppressive tumor microenvironment (TME), metabolic alteration, and tumor heterogeneity limit the therapeutic efficacy of immunotherapy for HGGs and BM. Furthermore, to address this concern, the NanoBioTechnology-based bioinspired delivery system has been gaining tremendous attention in recent years. With technological advances such as Trojan horse targeting and infusing/camouflaging nanoparticles surface with biological molecules/cells like immunocytes, erythrocytes, platelets, glioma cell lysate and/or integrating these strategies to get hybrid membrane for homotypic recognition. These biomimetic nanotherapy offers advantages over conventional nanoparticles, focusing on greater target specificity, increased circulation stability, higher active loading capacity, BBB permeability (inherent inflammatory chemotaxis of neutrophils), decreased immunogenicity, efficient metabolism-based combinatorial effects, and prevention of tumor recurrence by induction of immunological memory, etc. provide new age of improved immunotherapies outcomes against HGGs and BM. In this review, we emphasize on neuro-immunotherapy and the versatility of these biomimetic nano-delivery strategies for precise targeting of hard-to-treat and most lethal HGGs and BM. Moreover, the challenges impeding the clinical translatability of these approaches were addressed to unmet medical needs of brain cancers.

尽管采用了手术切除、化疗和放疗等积极的治疗标准，但高级别胶质瘤（HGGs）和脑转移瘤（BM）的治疗在20多年来仍然具有挑战性。然而，该领域的技术进步和免疫治疗策略已经彻底改变了hgg和BM的治疗。免疫疗法，如免疫检查点抑制剂、CAR-T靶向、溶瘤病毒治疗、双特异性抗体治疗和疫苗接种方法等，正在成为有前途的途径，为改善患者的生存效益提供了新的希望。然而，选择性穿越血脑屏障（BBB）、免疫抑制肿瘤微环境（TME）、代谢改变和肿瘤异质性限制了免疫疗法对HGGs和BM的治疗效果。此外，为了解决这一问题，基于纳米生物技术的生物启发给药系统近年来受到了极大的关注。随着技术的进步，如特洛伊木马靶向和注入/伪装纳米颗粒表面的生物分子/细胞，如免疫细胞，红细胞，血小板，胶质瘤细胞裂解液和/或整合这些策略得到杂交膜进行同型识别。与传统纳米颗粒相比，这些仿生纳米疗法具有更大的靶向特异性、更高的循环稳定性、更高的活性负荷能力、血脑屏障通透性（中性粒细胞固有的炎症趋化性）、降低的免疫原性、高效的基于代谢的组合效应、以及通过诱导免疫记忆预防肿瘤复发等优势，为改善HGGs和BM的免疫治疗结果提供了新的时代。在这篇综述中，我们强调神经免疫疗法和这些仿生纳米递送策略的多功能性，以精确靶向难以治疗和最致命的hgg和BM。此外，针对脑癌未满足的医疗需求，解决了阻碍这些方法临床可翻译性的挑战。

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引用次数: 0