Design and synthesis of multifunctional nanostructures for applications in medicine

我们提出的研究计划旨在开发明确纳米结构的合成方法，该方法与“寻找普遍目标在所需位置积累，根据当地需求有效执行任务，然后分解”的策略相结合。这种智能纳米材料在各个领域都至关重要，特别是在纳米医学领域。我们专注于开发可适用于各种有机和无机结构的统一化学方案。它通过整合成像与交付的理解，促进了解决复杂生物学问题的聚合方法。尺寸和形状是设计纳米载体的两个重要的关键参数，我们的研究在开发结构-性能关系中实现了这些参数。未来五年，我们将设计、综合并进行综合铰接功能结构的详细研究。这些将包括a)大分子（支化的miktoarm聚合物；超支化的树枝状聚合物；杂化物，末端树枝状聚合物）； b) 金纳米壳二聚体。纳米结构将通过以下链接实现：i) 响应活性氧（缩酮硫醇）并被其裂解； ii) 在需要时，通过在位点上强大的硫醇-炔点击化学生成可用于改变形态的末端基团； (iii) 完成任务后拆卸（酯水解）。携带足够治疗有效负载的稳定纳米载体将靶向活性氧，这是疾病部位的常见标记。通过在生物介质中产生颗粒间链接，积累的载体将能够进一步调整其尺寸。它将有助于将它们保留在所需的位置，并限制非特定分布。纳米粒子通过酸/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，从而加快功能纳米结构在生物医学应用中的转化，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 将为加拿大经济在各个领域的发展做出贡献。

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.