Design and synthesis of multifunctional nanostructures for applications in medicine

我们建议的研究计划旨在开发合成方法，以明确定义的纳米结构与该战略合作，“寻找一个普遍存在的目标，在所需的地方积累，根据当地的需要有效地执行任务，并拆解”。这种智能纳米材料在不同的领域至关重要，更具体地说是在纳米医学领域。我们专注于开发一种统一的化学协议，可以适用于各种有机和无机结构。它促进了一种融合的方法，通过将成像的理解与交付相结合来解决复杂的生物学问题。尺寸和形状是设计纳米载体的两个重要参数，我们的研究在发展结构-性质关系时实现了这两个参数。在接下来的五年里，我们将对合成关节功能结构进行设计、合成和详细的研究。这将包括a)大分子(支化的、单臂聚合物；超支化的树状大分子；杂化的、端枝状大分子)；以及b)金纳米壳二聚体。纳米结构将能够连接：i)反应并被活性氧物种(硫代缩酮)切割；ii)产生末端基团，这些末端基团可在需要时通过现场强大的硫醇-炔点击化学作用来改变形态；以及(Iii)在完成其工作(酯水解)后拆解。稳定的纳米载体携带足够的治疗有效载荷，将靶向活性氧物种，这是疾病部位的常见标志。累积的载体将被赋予通过在生物介质中产生颗粒间连接来进一步定制其尺寸的能力。它将有助于它们保留在所需的位置，并限制非特定的分布。纳米粒子通过酸/碱水解完成预定任务后的降解和拆解将有助于它们的去除。基于金纳米壳二聚体的分子成像探测器将提供高分辨率图像，用于早期检测，并确定纳米制剂在疾病管理中的有效性。拟议研究的综合方法将产生基础知识，将加快将功能纳米结构转化为生物医学应用，这对加拿大具有重要意义。它将为设计具有统一功能的新的先进材料创造机会。拥有多学科技能的HQP将为加拿大经济在不同领域的就业做出贡献。

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.