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首页> 外文学位 >Dendrimer based nanotherapeutics for ocular drug delivery.
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Dendrimer based nanotherapeutics for ocular drug delivery.

机译：基于树状大分子的纳米药物，用于眼部药物递送。

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摘要

PAMAM dendrimers are a class of well-defined, hyperbranched polymeric nanocarriers that are being investigated for ocular drug and gene delivery. Their favorable properties such as small size, multivalency and water solubility can provide significant opportunities for many biologically unstable drugs and allows potentially favorable ocular biodistribution. This work exploits hydroxyl terminated dendrimers (G4-OH) as drug/gene delivery vehicles that can target retinal microglia and pigment epithelium via systemic delivery with improved efficacy at much lower concentrations without any side effects.;Two different drugs Triamcinolone acetonide (TA) and N-Acetyl Cysteine (NAC) conjugated to G4-OH dendrimers showed tailorable sustained release in physiological relevant solutions and were evaluated in-vitro and in-vivo. Dendrimer-TA conjugates enhanced the solubility of TA and were 100 fold more effective at lower concentrations than free TA in its anti-inflammatory activity in activated microglia and in suppressing VEGF production in hypoxic RPE cells. Dendrimers targeted activated microglia/macrophages and RPE and retained for a period of 21 days in I/R mice model. The relative retention of intravitreal and intravenous dendrimers was comparable, if a 30-fold intravenous dose is used; suggesting intravenous route targeting retinal diseases are possible with dendrimers. D-NAC when injected intravenously attenuated retinal and choroidal inflammation, significantly reduced (∼73%) CNV growth at early stage of AMD in rat model of CNV. A combination therapy of D-NAC + D-TA significantly suppressed microglial activation and promoted CNV regression in late stages of AMD without causing side-effects.;G4-OH was modified with linker having minimal amine groups and incorporation of TA as a nuclear localization enhancer resulted in compact gene vectors with favorable safety profile and achieved high levels of transgene expression in hard to transfect human retinal pigment epithelial cells (hRPE). Prepared dendrimer-gene complexes were non-toxic and achieved significant cell uptake and safe delivery of gene in to the nucleus. Further, polyethylene glycol (PEG) surface coating enhanced colloidal stability in physiological relevant solutions without affecting its transfection efficacy.
机译：PAMAM树状聚合物是一类定义明确的，超支化的聚合物纳米载体，正在研究其眼药和基因传递的方法。它们的良好特性（例如小尺寸，多价和水溶性）可以为许多生物不稳定的药物提供重要的机会，并可以潜在地促进眼部生物分布。这项工作利用羟基封端的树枝状大分子（G4-OH）作为药物/基因递送载体，可以通过全身递送靶向视网膜小胶质细胞和色素上皮，并且在低得多的浓度下具有更高的功效，而没有任何副作用。与G4-OH树状大分子缀合的N-乙酰半胱氨酸（NAC）在生理相关溶液中显示出可调节的持续释放，并进行了体外和体内评估。树枝状大分子-TA缀合物增强了TA的溶解性，并且在较低的浓度下比游离TA在活化小胶质细胞中的抗炎活性和在低氧RPE细胞中抑制VEGF产生的效力高100倍。树状聚合物靶向活化的小胶质细胞/巨噬细胞和RPE，并在I / R小鼠模型中保留21天。如果使用30倍的静脉注射剂量，玻璃体内和静脉内树状聚合物的相对保留率是可比的。提示树状大分子可能通过静脉途径靶向视网膜疾病。静脉注射D-NAC可减轻视网膜和脉络膜炎症，在CNV大鼠模型的AMD早期显着减少（〜73％）CNV生长。 D-NAC + D-TA的联合疗法可在AMD晚期显着抑制小胶质细胞活化并促进CNV消退，而不会引起副作用。; G4-OH被具有最小胺基团和TA掺入作为核定位的连接基修饰增强子产生了紧凑的基因载体，具有良好的安全性，并在难以转染的人类视网膜色素上皮细胞（hRPE）中实现了高水平的转基因表达。制备的树状聚合物-基因复合物是无毒的，并实现了显着的细胞摄取和安全地将基因传递到细胞核中。此外，聚乙二醇（PEG）表面涂层在生理相关溶液中增强了胶体稳定性，而不会影响其转染效率。

著录项

  • 作者

    Kambhampati, Siva Pramodh.;

  • 作者单位

    Wayne State University.;

  • 授予单位 Wayne State University.;
  • 学科 Engineering Biomedical.;Nanotechnology.;Health Sciences Ophthalmology.
  • 学位 Ph.D.
  • 年度 2014
  • 页码 166 p.
  • 总页数 166
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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