Design and synthesis of multifunctional nanostructures for applications in medicine

我们提出的研究计划旨在开发合成方法，以定义明确的纳米结构，该方法与战略合作，“寻找一个普遍的目标，在所需的地方积累，根据当地需求有效地执行任务，并拆卸”。这种智能纳米材料在各种领域都至关重要，更具体地说，在纳米医学中。我们专注于开发一个统一的化学协议，可以适应各种有机和无机结构。它促进了一个收敛的方法，以解决复杂的生物学问题，通过整合从成像与交付的理解。尺寸和形状是设计纳米载体的两个重要关键参数，我们的研究在开发结构-性质关系中实现了这些。在未来五年内，我们将设计，综合，并进行了详细的研究综合铰接功能结构。这些将包括a）大分子（支化的杂臂聚合物;超支化的树枝状聚合物;杂化物，末端树枝状聚合物）;和B）金纳米壳二聚物。纳米结构将通过以下连接实现：i）响应于活性氧物质（硫代缩酮）并被其裂解; ii）在需要时通过在该位点的稳健的硫醇-炔点击化学产生可用于改变形态的末端基团;以及（iii）在完成其任务后分解（酯水解）。携带足够治疗有效载荷的稳定纳米载体将靶向活性氧，这是疾病部位的常见标志物。通过在生物介质中产生颗粒间的连接，积累的载体将被赋予进一步调整其尺寸的能力。这将有助于它们保留在所需部位，并限制非特异性分布。纳米颗粒在通过酸/碱水解完成其预期任务后的降解和分解将有助于其去除。基于金纳米壳二聚体的分子成像探针将为早期检测提供高分辨率图像，并确定纳米制剂在疾病管理中的功效。拟议研究的综合方法将产生基础知识，加快生物医学应用功能纳米结构的翻译，这对加拿大具有重要意义。它将为设计具有综合功能的新型先进材料创造机会。具有多学科技能的HQP将在不同领域为加拿大经济做出贡献。

Our proposed research program is aimed at developing synthetic methodologies to well-defined nanostructures that work with the strategy, “seek a prevalent target to accumulate at the desired place, perform the task efficiently according to local needs, and disassemble”. Such smart nanomaterials are of crucial importance in a diverse range of areas, more specifically in nanomedicine. We focus on developing a unified chemical protocol that could be adapted to a variety of organic and inorganic structures. It facilitates a convergent approach to address complex biological problems by integrating understanding from imaging with delivery. Size and shape are two key parameters of importance in designing nanocarriers, and our research implements these in developing structure-property relationships. During the next five years, we shall design, synthesize, and carry out a detailed study of synthetically articulated functional structures. These will include a) macromolecules (branched, miktoarm polymers; hyperbranched, dendrimers; hybrids, telodendrimers); and b) gold nanoshell dimers. Nanostructures will be enabled with links that i) respond to and are cleaved by reactive oxygen species (thioketal); ii) generate terminal end groups that can be used to change morphology, when needed, through robust thiol-yne click chemistry at the site; and (iii) disassemble upon completion of their undertaking (ester hydrolysis). Stable nanocarriers carrying sufficient therapeutic payloads will target reactive oxygen species, a common marker at disease sites. The accumulating carriers will be empowered with the ability to further tailor their dimensions by generating inter-particle links in a biological medium. It will aid in their retention at the desired site, and limit non-specific distribution. Degradation and disassembly of nanoparticles after they have performed their intended task via acid/base hydrolysis, will assist in their removal. The gold nanoshell dimer based molecular imaging probe will provide high-resolution images for early detection, and determining the efficacy of nanoformulations in disease management. The integrated approach of the proposed research will generate fundamental knowledge that will expedite translation of functional nanostructures for biomedical applications, an area of great significance to Canada. It will create opportunities for the design of new advanced materials with consolidated functions. HQP with multidisciplinary skills will contribute to Canadian economy employed in diverse fields.