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首页> 外文学位 >Polysaccharide-based polyion complex micelles as new delivery systems for hydrophilic cationic drugs.
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Polysaccharide-based polyion complex micelles as new delivery systems for hydrophilic cationic drugs.

机译：基于多糖的聚离子复合胶束作为亲水性阳离子药物的新递送系统。

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摘要

Polyion complex (PIC) micelles have emerged as promising delivery systems of ionic hydrophilic drugs. It was the aim of this study to develop dextran-based PIC micelles for the delivery of hydrophilic cationic drugs using a new family of carboxymethyldextran-block-poly(ethylene glycol) (CMD-PEG) copolymers. Four CMD-PEG copolymers were prepared: (i) two copolymers identical in terms of the length of CMD and PEG blocks, but different in terms of the charge density of the CMD block; and (ii) two copolymers in which the charged block is the same, but the PEG block is of different molecular weight. The micellization of CMD-PEG copolymers and drug delivery aspects of the resulting micelles were evaluated using different cationic drugs: diminazene (DIM), a model cationic drug, minocycline hydrochloride (MH), a semisynthetic tetracycline antibiotic with promising neuroprotective properties and different aminoglycoside antibiotics. The cytotoxicity of CMD-PEG copolymers was evaluated in different cell lines using MTT and Alamar blue assays. CMD-PEG micelles encapsulating different drugs were characterized using different techniques, such as 1H NMR spectroscopy, dynamic light scattering (DLS), and isothermal titration calorimetry (ITC). The pattern of drug release and pharmacological activity of micelles-encapsulated drugs were also evaluated. The CMD-PEG copolymers did not induce cytotoxicity in human hepatocytes and murine microglia (N9) in concentrations as high as 15 mg/mL after incubation for 24 h. Electrostatic interactions between CMD-PEG copolymers and different cationic drugs triggered the formation of PIC micelles with a CMD/drug core and a PEG corona. The properties of DIM/CMD-PEG micelles were strongly dependent on the degree of carboxymethylation of the CMD block. Micelles of CMD-PEG copolymers having degree of carboxymethylation ≥ 60%, incorporated up to 64 wt% DIM, resisted salt-induced disintegration in solutions up to 400 mM NaCl and sustained DIM release under physiological conditions (pH 7.4, 150 mM NaCl). In contrast, micelles of CMD-PEG of degree of carboxymethylation ∼30% had lower drug content (∼40 wt% DIM) and disintegrated at lower salt concentration (∼100 mM NaCl). The CMD-PEG copolymer that showed the most satisfactory micellar properties, in terms of high drug loading capacity, sustained drug release and micelles stability was selected as a potential delivery system of minocycline hydrochloride (MH) and different aminoglycosides. CMD-PEG micelles encapsulating either MH or aminoglycosides had small size ( 200 nm in diameter), high drug loading capacity (≥ 50 wt% drug) and sustained drug release. These micelles were stable in aqueous solution for up to one month, after freeze drying and in the presence of bovine serum albumin. Furthermore, the micelles protected MH against degradation in aqueous solutions. Micelles-encapsulated drugs maintained their pharmacological activity where MH micelles reduced lipopolysaccharides-induced inflammation in murine microglia (N9) cells. And aminoglycosides micelles were able to kill a test micro-organism (E. coli X-1 blue strain) in culture. Aminoglycosides/CMD-PEG micelles were unstable under physiological conditions. Micelle properties were greatly enhanced by hydrophobic modification of CMD-PEG. Thus, aminoglycosides/dodecyl-CMD-PEG micelles showed smaller size and better stability under physiological conditions. The results obtained in this study show that CMD-PEG copolymers are promising delivery systems for cationic hydrophilic drugs.;Keywords: Dextran, Polyion complex micelles, Diminazene, Hydrophilic drugs, Minocycline, Neuroinflammation, Aminoglycosides, Micelles stability.
机译：聚离子复合物（PIC）胶束已经成为有希望的离子亲水药物的递送系统。这项研究的目的是开发一种基于葡聚糖的PIC胶束，以使用新型的羧甲基葡聚糖-嵌段-聚（乙二醇）（CMD-PEG）共聚物家族来提供亲水性阳离子药物。制备了四种CMD-PEG共聚物：（i）两种共聚物，其CMD和PEG嵌段的长度相同，但是其CMD嵌段的电荷密度不同； （ii）带电荷的嵌段相同但PEG嵌段的分子量不同的两种共聚物。使用不同的阳离子药物评估了CMD-PEG共聚物的胶束化作用和所得胶束的药物递送方面：地美那嗪（DIM），模型阳离子药物，盐酸米诺环素（MH），具有良好神经保护特性的半合成四环素抗生素和不同的氨基糖苷抗生素。使用MTT和Alamar蓝分析法评估了不同细胞系中CMD-PEG共聚物的细胞毒性。使用不同的技术（例如1H NMR光谱，动态光散射（DLS）和等温滴定量热法（ITC））对封装不同药物的CMD-PEG胶束进行表征。还评估了胶束包封的药物的释放模式和药理活性。温育24小时后，CMD-PEG共聚物不会以高达15 mg / mL的浓度诱导人肝细胞和鼠小胶质细胞（N9）的细胞毒性。 CMD-PEG共聚物与不同阳离子药物之间的静电相互作用触发了具有CMD /药物核心和PEG电晕的PIC胶束的形成。 DIM / CMD-PEG胶束的性质强烈取决于CMD嵌段的羧甲基化程度。羧甲基化度≥60％，掺入高达64 wt％DIM的CMD-PEG共聚物胶束，在高达400 mM NaCl的溶液中抵抗盐诱导的崩解，并在生理条件（pH 7.4，150 mM NaCl）下持续释放DIM。相比之下，羧甲基化程度约为30％的CMD-PEG胶束具有较低的药物含量（约40 wt％DIM），并且在较低的盐浓度（约100 mM NaCl）下会崩解。在高载药量，持续药物释放和胶束稳定性方面表现出最令人满意的胶束特性的CMD-PEG共聚物被选作盐酸米诺环素和不同氨基糖苷的潜在传递系统。封装了MH或氨基糖苷的CMD-PEG胶束体积小（直径<200 nm），高载药量（≥50 wt％药物）和持续释放药物。冷冻干燥后，在牛血清白蛋白存在下，这些胶束在水溶液中可稳定长达一个月。此外，胶束保护MH避免在水溶液中降解。胶束包裹的药物保持了其药理活性，其中MH胶束减少了脂多糖诱导的鼠小神经胶质（N9）细胞的炎症。氨基糖苷类胶束能够杀死培养物中的测试微生物（大肠杆菌X-1蓝色菌株）。氨基糖苷/ CMD-PEG胶束在生理条件下不稳定。通过对CMD-PEG进行疏水改性，胶束特性得到了极大的增强。因此，氨基糖苷/十二烷基-CMD-PEG胶束在生理条件下显示出较小的尺寸和更好的稳定性。这项研究获得的结果表明，CMD-PEG共聚物是阳离子亲水性药物的有希望的传递系统。

著录项

  • 作者

    Soliman, Ghareb Mohamed.;

  • 作者单位

    Universite de Montreal (Canada).;

  • 授予单位 Universite de Montreal (Canada).;
  • 学科 Health Sciences Pharmacy.
  • 学位 Ph.D.
  • 年度 2010
  • 页码 258 p.
  • 总页数 258
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 肿瘤学;
  • 关键词

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