pH敏感双层型苦参结肠靶向微丸在大鼠体内的药代动力学研究

目的:比较苦参结肠靶向微丸与苦参溶液中苦参碱的药动学行为差异,以明确该靶向制剂在体内的药动学特征。方法:采用反相高效液相法,检测给药后血浆、结肠内容物中苦参碱含量;用DAS药动学软件统计程序处理,提取PK参数。结果:微丸与溶液中苦参碱在血浆及结肠内容物中tmax,Cmax,AUC等参数均有明显差异,微丸中苦参碱吸收存在明显的迟滞效应,且大部分未被吸收进入体循环,而在结肠中显示出高浓度分布。结论:制备的苦参微丸具有良好结肠靶向分布特征,达到了预期设计目标。     

The use of pH-triggered leaky heterogeneities on rigid lipid bilayers to improve intracellular trafficking and therapeutic potential of targeted liposomal immunochemotherapy

During endocytosis, pH-triggered release of encapsulated therapeutics from delivery carriers may accelerate their intracellular trafficking increasing therapeutic efficacy. To improve the therapeutic potential of targeted immunochemotherapy using anti-HER2/neu liposomal doxorubicin, we exploit the formation of leaky heterogeneities on rigid lipid bilayers to extensively release doxorubicin during endocytosis. We have previously demonstrated that pH-dependent formation of phase-separated lipid heterogeneities on the plane of a bilayer membrane increases the permeability of bilayers when they are composed of lipid pairs with rigid non-matching acyl chain lengths. This was suggested to be due to defective packing among lipids residing at the interfaces of lipid domains. Here we design nanometer-size antiHER2/neu-labeled PEGylated vesicles composed of lipid pairs with longer non-matching acyl chain lengths (n = 18 and 21). These vesicles exhibit superior killing efficacy of cancer cells compared to established liposome formulations, and their killing efficacy is similar to the effect of combined free doxorubicin and free antiHER2/neu antibody. Other transport-related properties such as liposome blood circulation times, and specific binding and internalization by cancer cells are unaffected. These results demonstrate the potential of vesicles with pH-triggered leaky heterogeneities to increase the therapeutic potential of targeted immunochemotherapy.     

pH敏感型盐酸左氧氟沙星眼用即型凝胶的制备及其体外释放考察

目的研制具有缓释作用的pH敏感型盐酸左氧氟沙星眼用即型凝胶。方法以卡波普为凝胶基质,以羟丙甲基纤维素为增稠剂,以溶液的粘度、即型凝胶形成能力及盐酸左氧氟沙星含量为评价指标,确定制备处方和工艺,并以优选处方进行体外释放考察。结果经实验,其优选处方为盐酸左氧氟沙星0.1 g,羟丙甲基纤维素E 50 LV 2.0 g,卡波普9 400.3g,磷酸氢二钠0.35 g,磷酸二氢钠0.45 g,氯化钠0.50 g,尼泊金乙酯0.03 g,加水共制成100 ml。体外释放结果显示其释药平缓,具有较好的缓释特征。结论优选处方工艺稳定,质量控制方法可靠,适用于pH敏感型盐酸左氧氟沙星眼用即型凝胶的制备和评价。     

Endogenous H2O2-Sensitive and Weak Acidic pH-Triggered Nitrogen-Doped Graphene Nanoparticles (N-GNMs) in the Tumor Microenvironment Serve as Peroxidase-Mimicking Nanozymes for Tumor-Specific Treatment

Nanozymes are emerging as a promising strategy for the treatment of tumors. Herein, to cope with the tumor microenvironment (TME), weak acidity (pH 5.6 to 6.8) and trace amounts of overexpressed hydrogen peroxide (H₂O₂) (100 µM–1 mM), we report nitrogen-doped graphene nanomaterials (N-GNMs), which act as highly efficient catalytic peroxidase (POD)-mimicking nanozymes in the TME for tumor-specific treatment. N-GNMs exhibit POD catalytic properties triggered by a weakly acidic TME and convert H₂O₂ into highly toxic hydroxyl radicals (•OH) thus causing the death of tumor cells while in the neutral pH surroundings of normal tissues, such catalysis is restrained and leaves normal cells undamaged thereby achieving a tumor-specific treatment. N-GNMs also display a high catalytic activity and can respond to the trace endogenous H₂O₂ in the TME resulting in a high efficiency of tumor therapy. Our in vitro chemical and cell experiments illustrated the POD-like activity of N-GNMs and in vivo tumor model experiments confirmed the significant inhibitory effect of N-GNMs on tumor growth.     

pH敏感型苦参结肠靶向微丸的处方筛选及其释药性能评价

目的:筛选确定pH敏感型苦参结肠靶向微丸的制剂处方,评价其释药性能。方法:采用挤出-滚圆法制备丸芯,以圆整度、脆碎度、得率、粒度分布、溶出度为评价指标,对丸芯处方进行筛选。采用流化床包衣技术,以释药性能为评价指标,对pH敏感包衣处方进行筛选,以浆法对包衣微丸的体外释药性能进行评价。结果:以主药4倍量的微晶纤维素为稀释剂,加入6%羧甲基淀粉钠混匀,加入28%水润湿,制软材,挤出滚圆得丸芯;以Eudragit S100为膜控材料,加入25%滑石粉,20%柠檬酸三乙酯,以95%乙醇为溶剂,配制包衣液,包衣使丸芯增重30%,得包衣微丸。该微丸在人工胃液、小肠液中苦参碱、氧化苦参碱的累积泄漏率为21.6%,结肠液中累积释放率达95.3%。结论:拟定了苦参结肠靶向微丸的制剂处方,制备得微丸质量稳定,具有良好结肠靶向释药性能。     

pH敏感双层型苦参结肠靶向微丸的体内外释药性能评价

目的:评价pH敏感双层型苦参结肠靶向微丸的体内外结肠靶向性能。方法:采用桨法对微丸的体外释药性能进行评价,采用多层螺旋CT扫描技术,实时监测微丸在人体消化道内的运转情况。结果:该微丸在人工胃液2 h、小肠液4 h共累积释药26.18%,而在人工结肠液中2 h后,累积释药达99.52%,基本释放完全。微丸口服后1 h,完全自胃部排空,5 h后所有微丸均到达结肠。在胃、小肠各部均未检测到微丸的崩解,进入结肠后开始检测到崩解溶散现象,10 h后检测到明显崩解,24 h后微丸在结肠完全崩解溶散。结论:该微丸在体内外均具有良好的结肠靶向释药性能。     

Responsive Polyphenol-Crosslinked Supramacromolecular Microgels with pH-Triggered Disassembly in Aqueous Solution

This work focuses on the pH-triggered disassembly of supramacromolecular microgels, which are composed of the temperature-responsive poly(N-vinylcaprolactam) (PVCL) and the natural polyphenol tannic acid (TA). A systematic investigation of the microgel formation demonstrates that a retarded addition of tannic acid during semi-batch precipitation polymerization influences the yield, chemical composition, and properties of the microgels to a great extent. Microgel properties, such as size, deformability, and chemical stability, can be easily tuned by varying the ratio between both building blocks PVCL and TA. Finally, the pH-triggered disassembly of supramacromolecular microgels at different pH and temperatures demonstrates that their chemical structure can precisely control the degradation profile. Temperatures lower than the volume phase transition temperature (VPTT) of PVCL (T < 32 °C) and a pH > 10 result in a complete disassembly of the microgels into PVCL chains and TA due to the destruction of the hydrogen bonds responsible for the formation of a colloidal microgel. Interestingly, at temperatures above VPTT, the microgels keep their integrity due to enhanced hydrophobic interactions between the polymer chains of the microgel and are no longer affected by pH changes.