Journal of Materials Chemistry B
·
2020
·Vol. 8
·期 47
·10854-10866
·
IF 5.344
Cuifu Fang,Zhiwei Zhong,Teng Zhang,Shuang Jia,Xingwei Ding,Weimin Zhou,Xiaolei Wang
Problems such as massive hemorrhage caused by uncontrolled drug dosage are the main significant obstacles in clinical thrombolytic therapy, which are prominently due to the lack of targeting and controlled release ability of efficient thrombolytic drug systems. In recent years, our team demonstrated that the photothermal effect can facilitate the thrombolytic effect of urokinase plasminogen activator (uPA). However, conventional photothermal agents are relatively expensive or contain heavy metals. If drug delivery systems with low toxicity, minimized heavy metal elements and easy accessibility (preferably provided by human self) can be developed, they will be of value in the future related applications. Herein, uPA-loaded human black hair derived nanoparticles with gelatin capsules (uPA@HBHNP@GNCs) were applied for the first time as a thrombolytic system. Upon irradiation by near-infrared I window (NIR-I) laser or II window (NIR-II) laser, the photothermal effect of HBHNP was triggered to promote the melting of the gelatin encapsulated around the outer layer, thereby realizing the targeted release of uPA. The in vitro and in vivo experiments demonstrated that the deep response to NIR (especially II window) of this system exhibited a satisfactory thrombolytic effect with ideal biosafety. Briefly, the proposed hair derived drug delivery system has the characteristics of human source, low cost, minimum heavy metal components, deep response to NIR (II window) laser, and good biocompatibility, which is expected to be expanded to the treatment for some diseases, even in deep tissue areas.
研究领域:
药学
·
生物医学工程
·
治疗学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY
·
2020
·Vol. 84
·期 6
·1153-1159
·
IF 1.516
Xue Guangpu,Xie Xie,Zhou Yang,Yuan Cai,Huang Mingdong,Jiang Longguang
Peptidic inhibitors of proteases are attracting increasing interest not only as drug candidates but also for studying the function and regulation mechanisms of these enzymes. Previously, we screened out a cyclic peptide inhibitor of human uPA and found that Ala substitution of P2 residue turns upain-1 to a substrate. To further investigate the effect of P2 residue on the peptide behavior transformation, we constructed upain-1-W3F, which has Phe replacement in the P2 position. We determined KD and Ki of upain-1-W3F and found that upain-1-W3F might still exist as an inhibitor. Furthermore, the high-resolution crystal structure of upain-1-W3F·uPA reveals that upain-1-W3F indeed stays as an intact inhibitor bind to uPA. We thus propose that the P2 residue plays a nonnegligible role in the conversion of upain-1 to a substrate. These results also proposed a strategy to optimize the pharmacological properties of peptide-based drug candidates by hydrophobicity and steric hindrance.Abbreviations : uPA: urokinase-type plasminogen activator; SPD: serine protease domain; S1 pocket: specific substrate-binding pocket
研究领域:
药理学
·
生物化学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2024
·
IF 10.5
Mengjuan Sun,Chang Liu,Ji Liu,Jing Wen,Tianjiao Hao,Daquan Chen,Yan Shen
Thrombus-induced cardiovascular diseases threaten human health. Current treatment strategies often rely on urokinase plasminogen activator (uPA) for its efficacy, yet it has such limiting factors as short half-life, lack of thrombus targeting, and systemic side effects leading to unintended bleeding. In addition, thrombolytic interventions can trigger inflammation-induced damage at thrombus sites, which affects endothelial function. To address these challenges, Fer-1/uPA@pep-CREKA-Lipo (Fu@pep-CLipo) has been developed. This system achieves precise and efficient thrombolysis while enhancing the thrombus microenvironment and mitigating ischemia-reperfusion injury, with exceptional thrombus targeting ability via the strong affinity of the Cys-Arg-Glu-Lys-Ala (CREKA) peptide for fibrin. The Cys-Nle-TPRSFL-DSPE (pep) could respond to the thrombus microenvironment and fixed-point cleavage. The uPA component linked to the liposome surface is strategically cleaved upon exposure to abundant thrombin at thrombus sites. Importantly, the inclusion of Fer-1 within Fu@pep-CLipo contributes to reactive oxygen species (ROS) scavenging and significantly improves the thrombus microenvironment. This innovative approach not only achieves highly efficient and precise thrombolysis but also positively influences the expression of eNOS protein while suppressing inflammatory factors like TNF-α and IL-6. This dual action contributes to improved thrombus inflammatory microenvironment and mitigated ischemia-reperfusion injury.
研究领域:
心血管疾病
·
药学
·
纳米技术
·
治疗学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CARBOHYDRATE POLYMERS
·
2024
·
IF 10.7
Caijie Yuan,Yaxin Ye,Enling Hu,Ruiqi Xie,Bitao Lu,Kun Yu,Weiwei Ding,Wenyi Wang,Guangqian Lan,Fei Lu
Global public health is seriously threatened by thrombotic disorders because of their high rates of mortality and disability. Most thrombolytic agents, especially protein-based pharmaceuticals, have a short half-life in circulation, reducing their effectiveness in thrombolysis. The creation of an intelligent drug delivery system that delivers medication precisely and releases it under regulated conditions at nearby thrombus sites is essential for effective thrombolysis. In this article, we present a unique medication delivery system (MCRUA) that selectively targets platelets and releases drugs by stimulation from the thrombus' microenvironment. The thrombolytic enzyme urokinase-type plasminogen-activator (uPA) and the anti-inflammatory medication Aspirin (acetylsalicylic acid, ASA) are both loaded onto pH-sensitive CaCO 3 /cyclodextrin crosslinking metal-organic frameworks (MC) that make up the MCRUA system. c(RGD) is functionalized on the surface of MC, which is functionalized by RGD to an esterification reaction. Additionally, the thrombus site's acidic microenvironment causes MCRUA to disintegrate to release uPA for thrombolysis and aiding in vessel recanalization. Moreover, cyclodextrin-encapsulated ASA enables the treatment of the inflammatory environment within the thrombus, enhancing the antiplatelet aggregation effects and promoting cooperative thrombolysis therapy. When used for thrombotic disorders, our drug delivery system (MCRUA) promotes thrombolysis, suppresses rethrombosis, and enhances biosafety with fewer hemorrhagic side effects.
研究领域:
药学
·
纳米技术
·
药物递送系统
·
血栓
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）