Asian Journal of Pharmaceutical Sciences最新文献_第2页

Revamping anti-cGAS-STING therapy via an injectable thermo-responsive supramolecular hydrogel for pathological retinal angiogenesis 通过一种可注射的热响应超分子水凝胶改造抗 GAS-STING 疗法，用于病理性视网膜血管生成

IF 10.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Asian Journal of Pharmaceutical Sciences

Pub Date : 2024-10-01 DOI: 10.1016/j.ajps.2024.100969

Dan Yan , Yuqian Wang , Weijie Ouyang , Caihong Huang , Qian Chen , Jiaoyue Hu , Zuguo Liu

Retinal neovascularization is a leading cause of blindness. While current anti-VEGF drugs effectively inhibit pathological angiogenesis, some patients develop resistance or reduced responsiveness to treatments over time, leading to diminished effectiveness. In this study, we identified high activation of the cGAS-STING signaling pathway, which exacerbated pathological neovascularization and vessel leakage. We developed an injectable thermo-responsive supramolecular hydrogel loaded with an anti-STING drug. The hydrogel, made of Pluronic F127 (PF·127) consisting of poly(ethylene oxide) and poly(propylene oxide) units, demonstrated excellent transparency and biocompatibility. Importantly, the thermo-sensitive property allowed for precise spatial release of the drug, extending the effective treatment duration of C-176, which suppressed STING activation in the retina, reduced inflammation, and protected retinal tissue. Hydro^C-176 effectively inhibited microglial cell infiltration and the release of inflammatory angiogenic factors, highlighting its enhanced efficacy. While demonstrating slightly lower effectiveness compared to traditional anti-VEGF therapy, Hydro^C-176 exhibited more robust capabilities in regulating ocular microenvironmental inflammation. This approach may assist in enhancing the sensitivity and effectiveness of anti-VEGF therapy for reducing ocular inflammation, potentially improving patients’ response to traditional treatment. These results have suggested innovative and comprehensive strategies for the management of retinal neovascularization.

视网膜新生血管是导致失明的主要原因。虽然目前的抗血管内皮生长因子药物能有效抑制病理性血管生成，但随着时间的推移，一些患者会产生耐药性或对治疗的反应性降低，导致疗效减弱。在这项研究中，我们发现 cGAS-STING 信号通路高度激活，加剧了病理性血管新生和血管渗漏。我们开发了一种装有抗 STING 药物的可注射热响应超分子水凝胶。这种水凝胶由聚环氧乙烷和聚环氧丙烷单元组成的 Pluronic F127（PF-127）制成，具有出色的透明度和生物相容性。重要的是，其热敏性能可实现药物的精确空间释放，延长了 C-176 的有效治疗时间，从而抑制了视网膜中 STING 的激活，减轻了炎症，保护了视网膜组织。HydroC-176能有效抑制小胶质细胞浸润和炎性血管生成因子的释放，突出了其更强的疗效。虽然与传统的抗血管内皮生长因子疗法相比，HydroC-176的疗效略低，但它在调节眼部微环境炎症方面表现出了更强大的能力。这种方法可能有助于提高抗血管内皮生长因子疗法对减轻眼部炎症的敏感性和有效性，从而改善患者对传统疗法的反应。这些结果为视网膜新生血管的治疗提出了创新和全面的策略。

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引用次数: 0

Intravitreal long-term sustained ranibizumab delivery using injectable microgel-embedded hydrogel 使用可注射微凝胶嵌入水凝胶在玻璃体内长期持续输送雷尼珠单抗

IF 10.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Asian Journal of Pharmaceutical Sciences

Pub Date : 2024-10-01 DOI: 10.1016/j.ajps.2024.100947

Simin Lee , Jun Young Park , Hye Kyoung Hong , Joo Young Son , Byungwook Kim , Jae Yong Chung , Se Joon Woo , Ki Dong Park

Retinal vascular disease is the leading cause of visual impairment. Although intravitreal drug injections are the most suitable approach for addressing retinal disorders, existing clinical treatments necessitate repeated administration, imposing a substantial burden on patients with various intraocular complications. This study introduces an injectable and biodegradable hyaluronan microgel (Hm)-embedded gelatin–poly(ethylene glycol)–tyramine hydrogel (HmGh) designed for sustained intravitreal ranibizumab (RBZ) delivery to reduce patient burden and minimize the side effects associated with frequent injections. Hm exhibited a controlled RBZ loading capacity and release profile. HmGh effectively controlled the initial burst release and overall release profile. Cytocompatibility and cellular drug efficacy were also demonstrated. In an animal study, HmGh maintained RBZ concentrations in the vitreous and retina for >120 d. Pharmacokinetic studies showed that the half-life of RBZ-loaded HmGh in the vitreous and retina was 2.55 and 2.05 times longer than that of RBZ-loaded Hm, respectively, and 9.58 and 38.46 times longer than that of RBZ solution, respectively. Importantly, the initial RBZ elimination from HmGh to the aqueous humor was significantly reduced compared to that from the Hm and RBZ solutions. Intraocular degradation and safety were comprehensively evaluated using fundus imaging and histological analyses. In conclusion, this injectable microgel-embedded hydrogel formulation is a promising prolonged drug delivery system for treating various posterior segment eye diseases.

视网膜血管疾病是视力受损的主要原因。虽然玻璃体内注射药物是治疗视网膜病变的最合适方法，但现有的临床治疗方法需要反复用药，给患者带来了很大负担，并引发各种眼内并发症。本研究介绍了一种可注射、可生物降解的透明质酸微凝胶（Hm）--嵌入明胶-聚乙二醇-酪胺水凝胶（HmGh），设计用于持续玻璃体内给药雷尼珠单抗（RBZ），以减轻患者负担并将频繁注射带来的副作用降至最低。Hm 具有可控的 RBZ 装载能力和释放曲线。HmGh 能有效控制初始迸发释放和整体释放曲线。细胞相容性和细胞药效也得到了证实。药代动力学研究表明，负载 RBZ 的 HmGh 在玻璃体和视网膜中的半衰期分别是负载 RBZ 的 Hm 的 2.55 倍和 2.05 倍，是 RBZ 溶液的 9.58 倍和 38.46 倍。重要的是，与 Hm 和 RBZ 溶液相比，RBZ 从 HmGh 进入房水的初始消除量明显减少。眼底成像和组织学分析对眼内降解和安全性进行了全面评估。总之，这种可注射的微凝胶包埋水凝胶配方是一种很有前景的长效给药系统，可用于治疗各种眼后节疾病。

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引用次数: 0

Extracellular vesicle-functionalized bioactive scaffolds for bone regeneration 用于骨再生的细胞外囊泡功能化生物活性支架

IF 10.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Asian Journal of Pharmaceutical Sciences

Pub Date : 2024-10-01 DOI: 10.1016/j.ajps.2024.100945

Taozhao Yu , Irene Shuping Zhao , Hongguang Pan , Jianhua Yang , Huanan Wang , Yongqiang Deng , Yang Zhang

The clinical need for effective bone regeneration in compromised conditions continues to drive demand for innovative solutions. Among emerging strategies, extracellular vesicles (EVs) have shown promise as an acellular approach for bone regeneration. However, their efficacy is hindered by rapid sequestration and clearance when administered via bolus injection. To address this challenge, EV-functionalized scaffolds have recently been proposed as an alternative delivery strategy to enhance EV retention and subsequent healing efficacy. This review aims to consolidate recent advancements in the development of EV-functionalized scaffolds for augmenting bone regeneration. It explores various sources of EVs and different strategies for integrating them into biomaterials. Furthermore, the mechanisms underlying their therapeutic effects in bone regeneration are elucidated. Current limitations in clinical translation and perspectives on the design of more efficient EVs for improved therapeutic efficacy are also presented. Overall, this review can provide inspiration for the development of novel EV-assisted grafts with superior bone regeneration potential.

在受损条件下进行有效骨再生的临床需求不断推动着对创新解决方案的需求。在新出现的策略中，细胞外囊泡（EVs）作为一种细胞外骨再生方法已显示出前景。然而，通过栓剂注射给药时，细胞外囊泡会迅速被螯合和清除，从而影响其功效。为了应对这一挑战，最近有人提出了 EV 功能化支架作为替代给药策略，以提高 EV 的保留率和随后的愈合效果。本综述旨在总结最近在开发用于促进骨再生的 EV 功能化支架方面取得的进展。文章探讨了 EVs 的各种来源以及将 EVs 整合到生物材料中的不同策略。此外，还阐明了它们在骨再生中的治疗作用机制。此外，还介绍了目前临床应用的局限性，以及设计更有效的 EVs 以提高疗效的前景。总之，本综述可为开发具有卓越骨再生潜力的新型 EV 辅助移植物提供灵感。

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引用次数: 0

Cell membrane-coated mRNA nanoparticles for enhanced delivery to dendritic cells and immunotherapy 细胞膜包覆的 mRNA 纳米颗粒，用于增强树突状细胞的输送和免疫疗法

IF 10.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Asian Journal of Pharmaceutical Sciences

Pub Date : 2024-09-24 DOI: 10.1016/j.ajps.2024.100968

Qiaoyun Li , Junho Byun , Dongyoon Kim, Yina Wu, Jaiwoo Lee, Yu-Kyoung Oh

Cationic polymers such as polyethylenimine have been considered promising carriers for mRNA vaccines. However, their application is hindered by their inherent toxicity and a lack of targeted delivery capability. These issues need to be addressed to develop effective cancer vaccines. In this study, we investigated whether dendritic cell membrane-coated polyethylenimine/mRNA nanoparticles (DPN) could effectively deliver mRNA to dendritic cells and induce immune responses. For comparison, we employed red blood cell membrane-coated polyethylenimine/mRNA (RPN) and plain polyethylenimine/mRNA polyplex (PN). The dendritic cell membrane coating altered the zeta potential values and surface protein patterns of PN. DPN demonstrated significantly higher uptake in dendritic cells compared to PN and RPN, and it also showed greater mRNA expression within these cells. DPN, carrying mRNA encoding luciferase, enhanced green fluorescent protein, or ovalbumin (OVA), exhibited higher protein expression in dendritic cells than the other groups. Additionally, DPN exhibited favorable mRNA escape from lysosomes post-internalization into dendritic cells. In mice, subcutaneous administration of DPN containing ovalbumin mRNA (DPN_OVA) elicited higher titers of anti-OVA IgG antibodies and a greater population of OVA-specific CD8⁺ T cells than the other groups. In a B16F10-OVA tumor model, DPN_OVA treatment resulted in the lowest tumor growth among the treated groups. Moreover, the population of OVA-specific CD8⁺ T cells was the highest in the DPN_OVA-treated group. While we demonstrated DPN's feasibility as an mRNA delivery system in a tumor model, the potential of DPN can be broadly extended for immunotherapeutic treatments of various diseases through mRNA delivery to antigen-presenting cells.

阳离子聚合物（如聚乙烯亚胺）一直被认为是很有前景的 mRNA 疫苗载体。然而，其固有的毒性和缺乏靶向递送能力阻碍了它们的应用。要开发出有效的癌症疫苗，就必须解决这些问题。在这项研究中，我们探讨了树突状细胞膜包被的聚乙烯亚胺/mRNA 纳米颗粒（DPN）能否有效地将 mRNA 运送到树突状细胞并诱导免疫反应。为了进行比较，我们采用了红细胞膜包被聚乙烯亚胺/mRNA（RPN）和普通聚乙烯亚胺/mRNA多聚物（PN）。树突状细胞膜涂层改变了 PN 的 zeta 电位值和表面蛋白形态。与 PN 和 RPN 相比，DPN 在树突状细胞中的吸收率明显更高，在这些细胞中的 mRNA 表达量也更大。携带编码荧光素酶、增强型绿色荧光蛋白或卵清蛋白（OVA）的 mRNA 的 DPN 在树突状细胞中的蛋白表达量高于其他组别。此外，DPN 在内化到树突状细胞后，mRNA 能从溶酶体中逃逸。与其他组相比，小鼠皮下注射含有卵清蛋白 mRNA 的 DPN（DPNOVA）可激发更高滴度的抗卵清蛋白 IgG 抗体和更多的卵清蛋白特异性 CD8+ T 细胞。在 B16F10-OVA 肿瘤模型中，DPNOVA 治疗组的肿瘤生长率最低。此外，DPNOVA治疗组的OVA特异性CD8+ T细胞数量最多。虽然我们在肿瘤模型中证明了 DPN 作为 mRNA 运送系统的可行性，但通过向抗原递呈细胞运送 mRNA，DPN 的潜力可以广泛扩展到各种疾病的免疫治疗中。

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引用次数: 0

Alkyl chain length-regulated in situ intelligent nano-assemblies with AIE-active photosensitizers for photodynamic cancer therapy 具有 AIE 活性光敏剂的烷基链长度调控原位智能纳米组合物，用于光动力癌症治疗

IF 10.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Asian Journal of Pharmaceutical Sciences

Pub Date : 2024-09-21 DOI: 10.1016/j.ajps.2024.100967

Lingyi Shen , Qi-Long Zhang , Yongchao Yao , Ya-Li Huang , Zhichang Zheng , Ming Li , Hong Xu , Lin Tan , Xukun Liao , Binyi Xia , Lin Li , Carl Redshaw , Yang Bai , Chengli Yang

Photodynamic therapy (PDT) brings new hope for the treatment of breast cancer due to few side effects and highly effective cell killing; however, the low bioavailability of traditional photosensitizers (PSs) and their dependence on oxygen severely limits their application. Aggregation-induced emission (AIE) PSs can dramatically facilitate the photosensitization effect, which can have positive impacts on tumor PDT. To-date, most AIE PSs lack tumor targeting capability and possess poor cell delivery, resulting in their use in large quantities that are harmful to healthy tissues. In this study, a series of AIE PSs based on pyridinium-substituted triphenylamine salts ( TTPAs 1–6) with different alkyl chain lengths are synthesized. Results reveal that TTPAs 1–6 promote the generation of type I and II ROS, including ·OH and ¹O₂. In particular, the membrane permeability and targeting of TTPAs 4-6 bearing C8-C10 side-chains are higher than TTPAs 1-3 bearing shorter alkyl chains. Additionally, they can assemble with albumin, thereby forming nanoparticles (TTPA 4–6 NPs) in situ in blood, which significantly facilitates mitochondrial-targeting and strong ROS generation ability. Moreover, the TTPA 4–6 NPs are pH-responsive, allowing for increased accumulation or endocytosis of the tumor and enhancing the imaging or therapeutic effect. Therefore, the in vivo distributions of TTPA 4–6 NPs are visually enriched in tumor sites and exhibited excellent PDT efficacy. This work demonstrates a novel strategy for AIE PDT and has the potential to play an essential role in clinical applications using nano-delivery systems.

光动力疗法（PDT）副作用小、杀灭细胞效果显著，为乳腺癌的治疗带来了新的希望；然而，传统光敏剂（PSs）的生物利用度低以及对氧气的依赖性严重限制了其应用。聚合诱导发射（AIE）光敏剂能显著促进光敏化效应，对肿瘤局部放疗产生积极影响。迄今为止，大多数 AIE PSs 缺乏肿瘤靶向能力，细胞输送能力差，导致大量使用对健康组织有害。本研究以吡啶鎓取代的三苯胺盐（TTPAs 1-6）为基础，合成了一系列具有不同烷基链长的 AIE PSs。结果表明，TTPAs 1-6 可促进 I 型和 II 型 ROS（包括 -OH 和 1O2）的生成。特别是，侧链为 C8-C10 的 TTPAs 4-6 的膜渗透性和靶向性高于侧链为较短烷基链的 TTPAs 1-3。此外，它们还能与白蛋白组装，从而在血液中就地形成纳米颗粒（TTPA 4-6 NPs），这极大地促进了线粒体靶向性和强大的 ROS 生成能力。此外，TTPA 4-6 NPs 还具有 pH 响应性，可增加肿瘤的积累或内吞，增强成像或治疗效果。因此，TTPA 4-6 NPs 在体内可直观地富集于肿瘤部位，并表现出卓越的光动力疗法疗效。这项工作展示了一种新型的 AIE PDT 策略，有望在使用纳米递送系统的临床应用中发挥重要作用。

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引用次数: 0

Structure based release kinetics analysis of doxazosin mesylate sustained-release tablets using micro-computed tomography 利用微计算机断层扫描技术对甲磺酸多沙唑嗪缓释片进行基于结构的释放动力学分析

IF 10.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Asian Journal of Pharmaceutical Sciences

Pub Date : 2024-09-21 DOI: 10.1016/j.ajps.2024.100966

Qian Liu , Mengqing Zan , Hanhan Huang , Hai Su , Wenjing Zhang , Lingyun Ma , Guangchao Zhang , Zunjian Zhang , Jiwen Zhang , Jianzhao Niu , Mingdi Xu

The structures of solid dosage forms determine their release behaviors and are critical attributes for the design and evaluation of the solid dosage forms. Here, the 3D structures of doxazosin mesylate sustained-release tablets were parallelly assessed by micro-computed tomography (micro-CT). There were no significant differences observed in the release profiles between the RLD and the generic formulation in the conventional dissolution, but the generic preparation released slightly faster in media with ethanol during an alcohol-induced dose-dumping test. With their 3D structures obtained via micro-CT determination, the unique release behaviors of both RLD and the generic were investigated to reveal the effects of internal fine structure on the release kinetics. The structural parameters for both preparations were similar in conventional dissolution test, while the dissolutions in ethanol media showed some distinctions between RLD and generic preparations due to their static and dynamic structures. Furthermore, the findings revealed that the presence of ethanol accelerated dissolution and induced changes in internal structure of both RLD and generic preparations. Moreover, structure parameters like volume and area of outer contour, remaining solid volume and cavity volume were not equivalent between the two formulations in 40 % ethanol. In conclusion, the structure data obtained from this study provided valuable insights into the diverse release behaviors observed in various modified-release formulations in drug development and quality control.

固体制剂的结构决定了其释放行为，是设计和评估固体制剂的关键属性。本文采用显微计算机断层扫描（micro-CT）技术同时评估了甲磺酸多沙唑嗪缓释片的三维结构。在常规溶出试验中，RLD与普通制剂的释放曲线无明显差异，但在酒精诱导剂量倾倒试验中，普通制剂在含有乙醇的介质中释放速度稍快。通过显微 CT 检测获得的三维结构，研究了 RLD 和普通制剂的独特释放行为，揭示了内部精细结构对释放动力学的影响。在常规溶出试验中，两种制剂的结构参数相似，而在乙醇介质中，RLD 和普通制剂的溶出由于其静态和动态结构而存在一些差异。此外，研究结果表明，乙醇的存在加速了 RLD 和普通制剂的溶解，并导致其内部结构发生变化。此外，两种制剂在 40% 乙醇中的结构参数，如外廓体积和面积、剩余固体体积和空腔体积并不相同。总之，本研究获得的结构数据为药物开发和质量控制中观察到的各种改良释放制剂的不同释放行为提供了宝贵的见解。

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引用次数: 0

Extracellular vesicles for delivering therapeutic agents in ischemia/reperfusion injury 在缺血再灌注损伤中输送治疗药物的细胞外囊泡

IF 10.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Asian Journal of Pharmaceutical Sciences

Pub Date : 2024-09-04 DOI: 10.1016/j.ajps.2024.100965

Weihang Zhou , Xinchi Jiang , Jianqing Gao

Ischemia/reperfusion (I/R) injury is marked by the restriction and subsequent restoration of blood supply to an organ. This process can exacerbate the initial tissue damage, leading to further disorders, disability, and even death. Extracellular vesicles (EVs) are crucial in cell communication by releasing cargo that regulates the physiological state of recipient cells. The development of EVs presents a novel avenue for delivering therapeutic agents in I/R therapy. The therapeutic potential of EVs derived from stem cells, endothelial cells, and plasma in I/R injury has been actively investigated. Therefore, this review aims to provide an overview of the pathological process of I/R injury and the biophysical properties of EVs. We noted that EVs serve as nontoxic, flexible, and multifunctional carriers for delivering therapeutic agents capable of intervening in I/R injury progression. The therapeutic efficacy of EVs can be enhanced through various engineering strategies. Improving the tropism of EVs via surface modification and modulating their contents via preconditioning are widely investigated in preclinical studies. Finally, we summarize the challenges in the production and delivery of EV-based therapy in I/R injury and discuss how it can advance. This review will encourage further exploration in developing efficient EV-based delivery systems for I/R treatment.

缺血/再灌注（I/R）损伤的特点是限制器官的血液供应，然后再恢复。这一过程会加剧最初的组织损伤，导致进一步的失调、残疾甚至死亡。细胞外囊泡（EVs）通过释放调节受体细胞生理状态的物质，在细胞通讯中起着至关重要的作用。EVs的发展为I/R治疗中递送治疗药物提供了一条新途径。从干细胞、内皮细胞和血浆中提取的EVs在I/R损伤中的治疗潜力已得到积极研究。因此，本综述旨在概述 I/R 损伤的病理过程和 EVs 的生物物理特性。我们注意到，EVs 可作为无毒、灵活和多功能的载体，用于递送能够干预 I/R 损伤进展的治疗药物。EVs的治疗功效可通过各种工程策略得到增强。在临床前研究中，通过表面修饰提高 EVs 的滋养性和通过预处理调节 EVs 的内容物被广泛研究。最后，我们总结了以 EV 为基础的 I/R 损伤治疗在生产和递送方面所面临的挑战，并讨论了如何推进其发展。这篇综述将鼓励人们进一步探索开发基于 EV 的高效传递系统用于 I/R 治疗。

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引用次数: 0

Insights into microscopic fabrication, macroscopic forms and biomedical applications of alginate composite gel containing metal-organic frameworks 对含有金属有机框架的海藻酸盐复合凝胶的微观制造、宏观形态和生物医学应用的深入了解

IF 10.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Asian Journal of Pharmaceutical Sciences

Pub Date : 2024-09-01 DOI: 10.1016/j.ajps.2024.100952

Yuanke Zhang , Lvyao Yang , Min Zhou , Yanhua Mou , Dongmei Wang , Peng Zhang

Overcoming the poor physicochemical properties of pure alginate gel and the inherent shortcomings of pure metal-organic framework (MOF), alginate/MOF composite gel has captured the interest of many researchers as a tunable platform with high stability, controllable pore structure, and enhanced biological activity. Interestingly, different from the traditional organic or inorganic nanofillers physically trapped or chemically linked within neTtworks, MOFs crystals can not only be dispersed by crosslinking polymerization, but also support self-assembly in-situ under the help of chelating cations with alginate. The latter is influenced by multiple factors and may involve some complex mechanisms of action, which is also a topic discussed deeply in this article while summarizing different preparation routes. Furthermore, various physical and chemical levels of improvement strategies and available macroforms are summarized oriented towards obtaining composite gel with ideal performance. Finally, the application status of this composite system in drug delivery, wound healing and other biomedical fields is further discussed. And the current limitations and future development directions are shed light simultaneously, which may provide guidance for the vigorous development of these composite systems.

海藻酸盐/MOF 复合凝胶克服了纯海藻酸盐凝胶理化性质差和纯金属有机框架（MOF）固有的缺点，作为一种具有高稳定性、可控孔结构和增强生物活性的可调平台，引起了许多研究人员的兴趣。有趣的是，不同于传统的有机或无机纳米填料在新结构中的物理截留或化学连接，MOFs 晶体不仅可以通过交联聚合分散，还可以在藻酸盐螯合阳离子的帮助下支持原位自组装。后者受多种因素影响，可能涉及一些复杂的作用机制，这也是本文在总结不同制备路线时深入讨论的一个话题。此外，本文还总结了各种物理和化学层面的改进策略以及可用的宏观形式，以期获得性能理想的复合凝胶。最后，还进一步讨论了这种复合系统在药物输送、伤口愈合和其他生物医学领域的应用现状。同时还阐明了当前的局限性和未来的发展方向，为大力发展这类复合系统提供了指导。

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引用次数: 0

Improving treatment for Parkinson's disease: Harnessing photothermal and phagocytosis-driven delivery of levodopa nanocarriers across the blood-brain barrier 改善帕金森病的治疗：利用光热和吞噬作用驱动左旋多巴纳米载体穿越血脑屏障

IF 10.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Asian Journal of Pharmaceutical Sciences

Pub Date : 2024-08-30 DOI: 10.1016/j.ajps.2024.100963

Kaili Liang, Li Yang, Jiawei Kang, Bo Liu, Ding Zhang, Liyan Wang, Wei Wang, Qing Wang

Parkinson's disease (PD) poses a significant therapeutic challenge, mainly due to the limited ability of drugs to cross the blood-brain barrier (BBB) without undergoing metabolic transformations. Levodopa, a key component of dopamine replacement therapy, effectively enhances dopaminergic activity. However, it encounters obstacles from peripheral decarboxylase, hindering its passage through the BBB. Furthermore, levodopa metabolism generates reactive oxygen species (ROS), exacerbating neuronal damage. Systemic pulsatile dosing further disrupts natural physiological buffering mechanisms. In this investigation, we devised a ROS-responsive levodopa prodrug system capable of releasing the drug and reducing ROS levels in the central nervous system. The prodrug was incorporated within second near-infrared region (NIR-II) gold nanorods (AuNRs) and utilized angiopep-2 (ANG) for targeted delivery across the BBB. The processes of tight junction opening and endocytosis facilitated improved levodopa transport. ROS scavenging helped alleviate neuronal oxidative stress, leading to enhanced behavioral outcomes and reduced oxidative stress levels in a mouse model of PD. Following treatment, the PD mouse model exhibited enhanced flexibility, balance, and spontaneous exploratory activity. This approach successfully alleviated the motor impairments associated with the disease model. Consequently, our strategy, utilizing NIR-II AuNRs and ANG-mediated BBB penetration, coupled with the responsive release of levodopa, offers a promising approach for dopamine supplementation and microenvironmental regulation. This system holds substantial potential as an efficient platform for delivering neuroprotective drugs and advancing PD therapy.

帕金森病（Parkinson's disease，PD）给治疗带来了巨大挑战，主要原因是药物在不发生代谢转化的情况下穿过血脑屏障（BBB）的能力有限。左旋多巴是多巴胺替代疗法的关键成分，能有效增强多巴胺能活性。然而，左旋多巴会遇到外周脱羧酶的阻碍，妨碍其通过 BBB。此外，左旋多巴代谢会产生活性氧（ROS），加剧神经元损伤。全身脉冲式给药进一步破坏了自然生理缓冲机制。在这项研究中，我们设计了一种 ROS 响应型左旋多巴原药系统，该系统能够释放药物并降低中枢神经系统中的 ROS 水平。该原药被整合到第二近红外区（NIR-II）金纳米棒（AuNRs）中，并利用血管内皮抑素-2（ANG）通过 BBB 进行靶向递送。紧密连接开放和内吞过程促进了左旋多巴的转运。清除 ROS 有助于减轻神经元的氧化应激，从而改善行为结果，降低帕金森病小鼠模型的氧化应激水平。治疗后，帕金森病小鼠模型表现出更强的灵活性、平衡性和自发性探索活动。这种方法成功缓解了与该疾病模型相关的运动障碍。因此，我们的策略利用了近红外-Ⅱ AuNRs 和 ANG 介导的 BBB 穿透，再加上左旋多巴的响应性释放，为多巴胺补充和微环境调控提供了一种前景广阔的方法。该系统作为提供神经保护药物和推进帕金森病治疗的高效平台，具有巨大的潜力。

{"title":"Improving treatment for Parkinson's disease: Harnessing photothermal and phagocytosis-driven delivery of levodopa nanocarriers across the blood-brain barrier","authors":"Kaili Liang, Li Yang, Jiawei Kang, Bo Liu, Ding Zhang, Liyan Wang, Wei Wang, Qing Wang","doi":"10.1016/j.ajps.2024.100963","DOIUrl":"10.1016/j.ajps.2024.100963","url":null,"abstract":"<div><div>Parkinson's disease (PD) poses a significant therapeutic challenge, mainly due to the limited ability of drugs to cross the blood-brain barrier (BBB) without undergoing metabolic transformations. Levodopa, a key component of dopamine replacement therapy, effectively enhances dopaminergic activity. However, it encounters obstacles from peripheral decarboxylase, hindering its passage through the BBB. Furthermore, levodopa metabolism generates reactive oxygen species (ROS), exacerbating neuronal damage. Systemic pulsatile dosing further disrupts natural physiological buffering mechanisms. In this investigation, we devised a ROS-responsive levodopa prodrug system capable of releasing the drug and reducing ROS levels in the central nervous system. The prodrug was incorporated within second near-infrared region (NIR-II) gold nanorods (AuNRs) and utilized angiopep-2 (ANG) for targeted delivery across the BBB. The processes of tight junction opening and endocytosis facilitated improved levodopa transport. ROS scavenging helped alleviate neuronal oxidative stress, leading to enhanced behavioral outcomes and reduced oxidative stress levels in a mouse model of PD. Following treatment, the PD mouse model exhibited enhanced flexibility, balance, and spontaneous exploratory activity. This approach successfully alleviated the motor impairments associated with the disease model. Consequently, our strategy, utilizing NIR-II AuNRs and ANG-mediated BBB penetration, coupled with the responsive release of levodopa, offers a promising approach for dopamine supplementation and microenvironmental regulation. This system holds substantial potential as an efficient platform for delivering neuroprotective drugs and advancing PD therapy.</div></div>","PeriodicalId":8539,"journal":{"name":"Asian Journal of Pharmaceutical Sciences","volume":"19 6","pages":"Article 100963"},"PeriodicalIF":10.7,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142191681","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A natural compound-empowered podophyllotoxin prodrug nanoassembly magnifies efficacy-toxicity benefits in cancer chemotherapy 一种由天然化合物赋能的荚叶毒素原药纳米组合可放大癌症化疗的疗效和毒性优势

IF 10.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Asian Journal of Pharmaceutical Sciences

Pub Date : 2024-08-01 DOI: 10.1016/j.ajps.2024.100892

Small-molecule prodrug nanoassembly technology with a unique advantage in off-target toxicity reduction has been widely used for antitumor drug delivery. However, prodrug activation remains a rate-limiting step for exerting therapeutic actions, which requires to quickly reach the minimum valid concentrations of free drugs. Fortunately, we find that a natural compound (BL-193) selectively improves the chemotherapy sensitivity of breast cancer cells to podophyllotoxin (PPT) at ineffective dose concentrations. Based on this, we propose to combine prodrug nanoassembly with chemotherapy sensitization to fully unleash the chemotherapeutic potential of PPT. Specifically, a redox-sensitive prodrug (PSSF) of PPT is synthesized by coupling 9-fluorenyl-methanol (Fmoc-OH) with PPT linked via disulfide bond. Intriguingly, PSSF with a π-conjugated structure readily co-assembles with BL-193 into stable nanoassembly. Significantly, BL-193 serves as an excellent chemosensitizer that creates an ultra-low-dose chemotherapeutic window for PPT. Moreover, prodrug design and precise hybrid nanoassembly well manage off-target toxicity. As expected, such a BL-193-empowered prodrug nanoassembly elicits potent antitumor responses. This study offers a novel paradigm to magnify chemotherapy efficacy-toxicity benefits.

小分子原药纳米组装技术在减少脱靶毒性方面具有独特优势，已被广泛应用于抗肿瘤给药。然而，原药活化仍然是发挥治疗作用的一个限制性步骤，需要快速达到游离药物的最低有效浓度。幸运的是，我们发现一种天然化合物（BL-193）能在无效剂量浓度下选择性地提高乳腺癌细胞对豆荚毒素（PPT）的化疗敏感性。在此基础上，我们提出将原药纳米组装与化疗增敏相结合，以充分释放 PPT 的化疗潜力。具体来说，我们将 9-芴基甲醇（Fmoc-OH）与通过二硫键连接的 PPT 结合在一起，合成了 PPT 的氧化还原敏感原药（PSSF）。有趣的是，具有 π 共轭结构的 PSSF 很容易与 BL-193 共同组装成稳定的纳米组件。值得注意的是，BL-193 是一种出色的化疗增敏剂，为 PPT 创造了一个超低剂量化疗窗口。此外，原药设计和精确的混合纳米组装可以很好地控制脱靶毒性。正如预期的那样，这种由 BL-193 赋能的原药纳米组合能激发有效的抗肿瘤反应。这项研究为放大化疗疗效-毒性效益提供了一种新的范例。

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引用次数: 0