Rational Design of a Tumor Targeting and Penetrating Nanoparticle for Drug Delivery

用于药物输送的肿瘤靶向和穿透纳米颗粒的合理设计

• 批准号: RGPIN-2016-03755
• 负责人: Li, ShyhDar
• 金额: $ 2.04万
• 依托单位: University of British Columbia
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=614606
• 关键词: Rational; Design; Tumor; Targeting; Penetrating

My research program focuses on engineering innovative nanoparticles (NPs) for use if targeting drugs to tumors. NPs preferentially accumulate in tumors via the enlarged vascular gap but do not leak out through the tightly sealed capillary presented in most normal tissues. After traveling through the circulatory system and reaching the tumor tissue, the NPs need to move from the blood vessels to interact with tumor cells, where they must release their cargo drug for biological activity. NPs can be chemically engineered to control their properties such as particle size, charge, the presentation of a targeting ligand, and drug release kinetics. These physical properties affect the penetration of NPs in tumors, the intracellular uptake of NPs by tumor cells, and the biological activity. For example, smaller NPs exhibit improved tumor penetration compared to their larger counterparts. Ligand-conjugated NPs display increased uptake by the tumor cells; however, the effect of ligand on tumor penetration requires better understanding. Additionally, NPs that exhibit triggered-release mechanisms (i.e., burst release in tumors) show enhanced activity, but certain cell-cycle dependent drugs, such as anti-tubulin agents, may prefer sustained release. The fundamental knowledge of this field needs to be strengthened to fully understand how physical properties of various types of NPs impact their drug delivery, and the knowledge will eventually lead to rational design of an improved NP system. My lab has engineered a proprietary polysaccharide-based NP system to target a water insoluble anti-tubulin drug to tumors. In the next five years, my research program will focus on controlling the physical properties of this NP system by chemical engineering, and examining how these properties affect the drug delivery. Particularly, we will focus on how the density of a targeting ligand at the NP surface impacts the tumor penetration and cellular internalization. We will study how drug release kinetics influences the drug delivery of this NP system. We will engineer the NP constructs that contain various combinations of ligand density and release kinetics, and examine how these two factors interact to impact the drug delivery. The short term goal of this program is to gain new knowledge about chemical engineering of this new NP system to control the physical properties and to identify the major NP designing factors that affect the drug delivery. The knowledge gain from this type of mechanistic study might be applied to other NP systems and is highly appreciated by the drug delivery and NP engineering fields, as it will eventually lead to rational design of an improved NP system for drug targeting to tumors, which is the long term goal of this program. This hypothesis driven research program focusing on mechanistic studies will offer comprehensive training opportunities in the junction of chemical engineering and biology.

我的研究项目主要集中在工程创新的纳米粒子（NP）的使用，如果靶向药物的肿瘤。纳米颗粒优先通过扩大的血管间隙在肿瘤中积聚，但不会通过大多数正常组织中存在的紧密密封的毛细血管泄漏。在穿过循环系统并到达肿瘤组织后，NP需要从血管中移动以与肿瘤细胞相互作用，在那里它们必须释放其货物药物以进行生物活性。纳米颗粒可以被化学工程化以控制它们的性质，如粒度、电荷、靶向配体的呈递和药物释放动力学。这些物理性质影响NPs在肿瘤中的渗透、肿瘤细胞对NPs的细胞内摄取以及生物活性。例如，与其较大的对应物相比，较小的NP表现出改善的肿瘤渗透。配体缀合的纳米颗粒显示增加的肿瘤细胞的摄取;然而，配体对肿瘤渗透的影响需要更好的理解。此外，表现出触发释放机制的NP（即，肿瘤中的突释）显示增强的活性，但某些细胞周期依赖性药物，如抗微管蛋白剂，可能更喜欢持续释放。这一领域的基础知识需要加强，以充分了解各种类型的NP的物理性质如何影响其药物递送，这些知识最终将导致改进的NP系统的合理设计。我的实验室设计了一种基于多糖的专有NP系统，将一种水不溶性抗微管蛋白药物靶向肿瘤。在接下来的五年里，我的研究计划将集中在通过化学工程控制这种NP系统的物理性质，并研究这些性质如何影响药物递送。特别地，我们将关注NP表面的靶向配体的密度如何影响肿瘤渗透和细胞内化。我们将研究药物释放动力学如何影响该NP系统的药物递送。我们将设计含有配体密度和释放动力学的各种组合的NP结构，并研究这两个因素如何相互作用以影响药物递送。该计划的短期目标是获得有关这种新NP系统的化学工程的新知识，以控制物理性质并确定影响药物递送的主要NP设计因素。从这种类型的机制研究中获得的知识可能会应用于其他NP系统，并受到药物递送和NP工程领域的高度赞赏，因为它最终将导致合理设计改进的NP系统，用于药物靶向肿瘤，这是该计划的长期目标。这个假设驱动的研究计划，侧重于机械研究将提供全面的培训机会，在化学工程和生物学的交界处。