Metal-polyphenol-network coated CaCO3 as pH-responsive nanocarriers to enable effective intratumoral penetration and reversal of multidrug resistance for augmented cancer treatments

Construction of multifunctional stimuli-responsive nanotherapeutics enabling improved intratumoral penetration of therapeutics and reversal of multiple-drug resistance (MDR) is potent to achieve effective cancer treatment. Herein, we report a general method to synthesize pH-dissociable calcium carbonate (CaCO₃) hollow nanoparticles with amorphous CaCO₃ as the template, gallic acid (GA) as the organic ligand, and ferrous ions as the metallic center via a one-pot coordination reaction. The obtained GA–Fe@CaCO₃ exhibits high loading efficiencies to both oxidized cisplatin prodrug and doxorubicin, yielding drug loaded GA–Fe@CaCO₃ nanotherapeutics featured in pH-responsive size shrinkage, drug release, and Fenton catalytic activity. Compared to nonresponsive GA–Fe@silica nanoparticles prepared with silica nanoparticles as the template, such GA–Fe@CaCO₃ confers significantly improved intratumoral penetration capacity. Moreover, both types of drug-loaded GA–Fe@CaCO₃ nanotherapeutics exhibit synergistic therapeutic efficacies to corresponding MDR cancer cells because of the GA–Fe mediated intracellular oxidative stress amplification that could reduce the efflux of engulfed drugs by impairing the mitochondrial-mediated production of adenosine triphosphate (ATP). As a result, it is found that the doxorubicin loaded GA–Fe@CaCO₃ exhibits superior therapeutic effect towards doxorubicin-resistant 4T1 breast tumors via combined chemodynamic and chemo-therapies. This work highlights the preparation of pH-dissociable CaCO₃-based nanotherapeutics to enable effective tumor penetration for enhanced treatment of drug-resistant tumors.

     

用无粘结预应力技术加固吊车梁

论述了用无粘结预应力技术改造加固吊车梁的升级设计与施工。     

操作器力和位置混合控制——算法与系统行为分析

本文首先回顾了力控制技术的发展,对在操作空间一级实现力和位置混合控制的算法做了说明。着重分析了在约束空间中系统的动、静态行为。指出了环境刚度对主动力控制系统动态行为的影响,以及关节摩擦对力控制精度的影响。     

操作器力和位置混合控制:数学模型和实验研究中的几个问题

本文是文[1]的续篇.首先讨论了为实现力和位置混合控制算法的数学模型中的几个问题,然后介绍并讨论了几个典型力和位置混合控制的实验内容和实验结果,该实验是在 KD-1控制器支持下完成的.最后对力控制技术的进一步发展进行了初步的分析.     

Ni-Alginate Hydrogel Microspheres with Sustained Interleukin 2 Release to Boost Cytokine-Based Cancer Immunotherapy

Interleukin 2 (IL2) is the first approved immunotherapeutic agent in cancer treatment. However, high-dose IL2 administrated through intratumoral injection still spreads all over the body, causing serious systemic toxicity. Herein, an injectable nickel-alginate hydrogel microsphere (Ni-ALGMS) to allow effective loading of IL2 and its sustained release after intratumoral administration is reported. In this design, histidine (his)-tagged IL2 is assembled into the Ni-ALGMS via the coordination bonds between his-tag and Ni²⁺. After injecting IL2-loaded Ni-ALGMSs (IL2@Ni-ALGMSs) into the tumor, IL2 slowly releases over long periods, thereby avoiding the risk of cytokine storm happening in IL2 systemic administration. Applying such IL2@Ni-ALGMSs for tumor model treatment can significantly increase the tumor infiltration of T lymphocytes, and effectively inhibit tumor growth, especially in combination with immune checkpoint inhibitors. This study presents a novel IL2 sustained-releasing platform for tumor immunotherapy, which can also be conveniently applied in other cytokines-based immunotherapies.