Engineered Macromolecular and Nanostructured Materials for Biomedical Relevance

在过去的二十年中，基因疗法在治疗遗传性和获得性疾病方面引起了极大的关注。尽管对基因治疗有相当大的兴趣，但将基因传递到靶细胞仍然是一个巨大的挑战。目前主要的研究工作集中在设计合适的载体载体，紧凑和保护基因治疗的寡核苷酸。DNA或RNA是大的、亲水的、带负电荷的大分子，在生理环境中非常不稳定，不能有效地穿过生物膜。由于基因和细胞表面都带负电荷，因此不受保护的基因很难自发进入细胞内。研究最初集中在病毒上，因为这些载体在向许多细胞系传递DNA和RNA方面表现出高效率。然而，与病毒载体系统相关的一些问题，如毒性、免疫原性和规模化操作的局限性，鼓励了对其他潜在的DNA或RNA载体进入目标组织的探索。非病毒载体系统是压缩DNA以进行全身递送的另一种手段，但是，与病毒类似物不同，非病毒基因载体由于许多细胞外和细胞内障碍，始终表现出显著降低的转染效率。它们的生物相容性和易于生产使它们在基因治疗中具有潜在的用途和吸引力。由于碳水化合物在细胞表面非常重要，它们参与了许多细胞过程并调节了许多细胞相互作用。因此，开发基于碳水化合物的纳米系统用于基因治疗并非不合理，因为这些材料的勤奋工程可以将其转化为高度创新的治疗方法。我们建立了可逆加成-破碎链转移过程（RAFT），主要基于水溶性聚合物的易合成性来设计定义良好的聚合物。RAFT工艺使我们能够设计和制造先进的阳离子糖共聚物和低毒性的纳米凝胶，用于DNA/siRNA递送。这种对生物材料设计的显著控制对其物理化学和生物特性都产生了重大影响。我们在这个研究项目的动机是为了评估新的碳水化合物为基础的宏观/纳米结构的基因体外递送。这些碳水化合物载体系统基本上是基于半乳糖的聚合物和纳米凝胶，具有生物相关的基序，用于靶向和安全的递送

Gene therapy has drawn significant attention over the past two decades for the treatment of inherited and acquired diseases. Despite the considerable interest in gene therapy, delivery of genes to the target cells remains a huge challenge. Major research efforts are currently focused on designing suitable carrier vectors that compact and protect oligonucleotides for gene therapy. DNA or RNA is large, hydrophilic, negatively charged macromolecule, very unstable in the physiological environment and does not cross biological membranes effectively. Since both the genes and cell surfaces are negatively charged, spontaneous entry of unprotected genes inside cells is difficult. Research was initially focused on viruses as these vectors exhibited high efficiency at delivering both DNA and RNA to numerous cell lines. However, several problems associated with viral vector systems, such as toxicity, immunogenicity and limitations with respect to scale-up procedures encouraged the exploration of other potential DNA or RNA carriers into targeted tissue. Non-viral vector systems are other means for compacting DNA for systemic delivery, but, unlike viral analogues, non-viral gene carriers consistently demonstrate significant reduced transfection efficiency due to numerous extra- and intracellular obstacles. Their biocompatibility and facilitated production make them potentially useful and attractive for gene therapy. As carbohydrates are prominent on cell surfaces, they are involved in a number of cellular processes and modulate many cellular interactions. Therefore, it is not unreasonable to develop carbohydrate-based nano-systems for gene therapy since diligent engineering of these materials can transform them into highly innovative therapeutics. We have established the reversible addition-fragmentation chain transfer process (RAFT) for designing well-defined polymers mainly based on the ease of synthesizing water-soluble polymers. The RAFT process has enabled us to design and fabricate advanced cationic glycopolymers and nanogels with low toxicity for DNA/siRNA delivery. This remarkable control on the design of biomaterials has had significant impact on both their physicochemical and biological properties. Our motivation in this research program is towards the evaluation of novel carbohydrate-based macro/nano-structures for the delivery of genes in vitro. Those carbohydrate vector systems will be essentially galactose based polymers and nanogels with biologically relevant motifs for targeted and safe delivery.**