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Biodegradable branched polycationic polymers as non-viral gene delivery vectors for bone tissue engineering.

机译:可生物降解的支链聚阳离子聚合物,作为骨组织工程的非病毒基因递送载体。

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摘要

In this work, biodegradable branched triacrylate/amine polycationic polymers (TAPPs) were synthesized from different amine and triacrylate monomers by Michael addition polymerization and incorporated into a composite scaffold to evaluate these polymers in a bone tissue engineering system. The effects of the hydrophilic spacer lengths in the polymer on characteristics which are important for gene delivery were evaluated by varying the triacrylate monomer used in the synthesis. The results demonstrated that hydrophilic spacers can be incorporated into polycationic polymers to reduce their cytotoxicity and enhance the degradability. The effects of amine basicities in the polymer on characteristics which are important for gene delivery were also evaluated by varying the amine monomers used in the synthesis. The results indicated that polycationic polymers with amines that dissociate above pH 7.4, which are available as positively charged groups for plasmid DNA (pDNA) complexation at pH 7.4, can be synthesized to produce stable polyplexes with increased zeta potential and decreased hydrodynamic size that efficiently transfect cells. TAPP/pDNA polyplexes were then incorporated into a composite containing gelatin microparticles (GMPs) and a porous poly(propylene fumarate) scaffold. The release of pDNA in vitro was not affected by the crosslinking density of the GMPs but depended, instead, on the degradation rates of the TAPPs. Besides the initial burst release of polyplexes not bounded to the GMPs and the minimal release of pDNA through diffusion and dissociation from the GMPs, the pDNA was likely released as naked pDNA or in an incomplete polyplex as fragments of the polymer had to degrade to release the pDNA. The results indicated that polymeric vectors with a lower degradation rate can prolong the release of pDNA from the composite scaffold. Composite scaffolds loaded with TAPP/pDNA polyplexes may not have delivered enough intact polyplexes, as enhanced bone formation was not observed in a critical-size rat cranial defect at 12 weeks postimplantation compared to those loaded with naked pDNA. A gene delivery system consisting of biodegradable polycationic polymers should be designed to release the pDNA in an intact polyplex form.
机译:在这项工作中,通过迈克尔加成聚合反应从不同的胺和三丙烯酸酯单体合成了可生物降解的支链三丙烯酸酯/胺聚阳离子聚合物(TAPPs),并将其掺入复合支架中以在骨组织工程系统中评估这些聚合物。通过改变合成中使用的三丙烯酸酯单体,评估了聚合物中亲水间隔基长度对基因传递重要特性的影响。结果表明,可以将亲水性间隔基引入聚阳离子聚合物中以降低其细胞毒性并增强降解性。还通过改变合成中使用的胺单体来评估聚合物中胺碱性对基因传递重要特性的影响。结果表明,可以合成具有在pH 7.4以上解离的胺的聚阳离子聚合物,可在pH 7.4时作为带正电荷的基团用于质粒DNA(pDNA)络合,可合成稳定的多链体,增加Zeta电位并减小流体动力学尺寸,从而有效地进行转染细胞。然后将TAPP / pDNA复合物掺入包含明胶微粒(GMP)和多孔聚(富马酸丙二酯)支架的复合物中。 pDNA的体外释放不受GMP交联密度的影响,而是取决于TAPPs的降解速率。除了不与GMP结合的多聚体的初始爆发释放和通过从GMP扩散和解离而使pDNA的释放最小外,pDNA可能以裸露的pDNA或不完整的多聚体形式释放,因为聚合物的片段必须降解才能释放出GMP。 pDNA。结果表明具有较低降解速率的聚合物载体可以延长pDNA从复合支架的释放。载有TAPP / pDNA复合物的复合支架可能未递送足够的完整复合物,因为与植入裸pDNA的复合物相比,在植入后12周的临界尺寸大鼠颅骨缺损中未观察到骨形成增强。应设计一个由可生物降解的聚阳离子聚合物组成的基因传递系统,以完整的多链体形式释放pDNA。

著录项

  • 作者

    Chew, Sue Anne.;

  • 作者单位

    Rice University.;

  • 授予单位 Rice University.;
  • 学科 Chemistry Polymer.;Engineering Biomedical.
  • 学位 Ph.D.
  • 年度 2010
  • 页码 150 p.
  • 总页数 150
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

  • 入库时间 2022-08-17 11:36:52

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