Multiscale approaches to engineering living cells for nanotherapeutic delivery

用于纳米治疗递送的活细胞工程多尺度方法

• 批准号: 10711015
• 负责人: Zongmin Zhao
• 金额: $ 39.34万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10711015
• 关键词: Active Biological Transport; Address; Area; Biodistribution; Biological; Biological Products; Biology; Breathing; Cells; Clinical; Disease; Drug Delivery Systems; Drug Kinetics; Encapsulated; Engineering; Erythrocytes; Face; Goals; Inflammation; Macrophage; Methods; Modality; Modeling; Outcome; Pathologic; Pharmaceutical Preparations; Pharmacodynamics; Property; Public Health; Research; Signal Transduction; Site; Surface; System; Therapeutic; Tissues; cell motility; cellular engineering; design; improved; macromolecule; migration; nanoparticle; nanoparticle delivery; nanoscale; nanotherapeutic; novel; particle; programs; small molecule; therapeutic nanoparticles

PROJECT SUMMARY Nanoparticle therapeutics (NTs) that encapsulate drugs in a nanoscale particle has emerged as a primising therapeutic modality for treating many diseases. NTs encompass a diverse array of nanoparticle types and can easily incorporate a wide-array of drugs, ranging from small molecules, to macromolecules, to biologics. The diversity of nanoparticles and encapsulated drugs renders NTs a versatile therapeutic modality that is being clincally investigated to treat many dieseases in various tissues. Like any other therapetic modality, the successful application of NTs requires their specific delivery to target sites while avoiding off-target accumulation. However, owing to their distinct features (e.g. large-size), NTs face unique biological barriers which lead to their unfavorable pharmacokinetics (PK), biodistribution, and pharmacodynamics (PD) profiles. As such, a pressing and unaddressed challenge is to better understand the biological barriers for NTs and to develop effective strategies to guide the precise delivery of NTs to unleash their full therapeutic potential. Toward this end, the overarching goal of my research program is to identify ideal delivery parameters for NTs and to develop novel strategeis for precise delivery of NTs. One strategy we are focusing on is to utilize inspirations from the intrinsic biology, living cells in particular. Indeed, living cells such as circulatory cells can be leveraged as ideal delivery systems. Circulatory cells can navigate the body, sense pathological signals, and reach diseased tissues via an active transport mechanism. NTs can be loaded inside or onto the surface of circulatory cells to be delivered to target sites. My research has made significant strides in this area where we have developed novel methods to incorporate NTs with diverse living cells and demonstrated that two circulatory cells (erythrocytes and macrophages) could modulate the PK, biodistribution, and efficacy of NTs. The rapid progression in advancing cells towards NTs delivery highlights the urgent need for mechanistic studies to i) elucidate how the interface between living cell carriers and NTs impacts the transport of NTs and migration of carrier cells and ii) to identify principles for utilizing living cells for precise delivery of NTs. We aim to capitalize our expertise in nanoparticle design and cell engineering to address this unmet need. Specifically, over the next five years, using inflammation that occurs in various tissues as a model, we will focus on i) understanding how cell-based carriers impact the outcomes of NTs delivery, ii) studying how the loading and physicochemical properties of NTs influence the carrier cells’ migration, and iii) developing multiscale strategies to achieve cell-specific delivery of NTs. These studies will enable us to establish a set of design rules that govern the delivery efficacy and interactions of NTs with living cells, which will ultimately improve the capability and broaden the spectrum of NTs for treating various diseases. Successful realization of our program will not only contribute to understanding the key features for a NTs to interact with the living cells but also develop a set of principles for rational engineering living cells to improve the biological outcomes of NTs and other therapeutics.

项目概要 将药物封装在纳米级颗粒中的纳米颗粒疗法（NT）已成为一种启动剂 治疗许多疾病的治疗方式涵盖多种纳米颗粒类型，并且可以。 轻松整合各种药物，从小分子到大分子，再到生物制剂。 纳米颗粒和封装药物的多样性提供了一种正在开发的多功能治疗方式 与任何其他治疗方式一样，经临床研究可治疗多种组织疾病。 NT 的成功应用需要将其特异性递送至靶位点，同时避免脱靶积累。 然而，由于其独特的特征（例如大尺寸），NT面临着独特的生物屏障，这导致它们 不利的药代动力学（PK）、生物分布和药效学（PD）特征因此迫切需要解决。 尚未解决的挑战是更好地了解 NT 的生物屏障并开发有效的 指导 NT 精确递送以充分发挥其治疗潜力的策略。 我的研究计划的总体目标是确定 NT 的理想递送参数并开发新颖的 策略是NT的精确传递，我们关注的一个策略是利用内在的灵感。 生物学，尤其是活细胞，例如循环细胞等活细胞可以用作理想的递送。 循环细胞可以在身体中导航、感知病理信号并通过这些途径到达患病组织。 NT 可以装载到循环细胞内部或表面。 我的研究在这个领域取得了重大进展，我们开发了新颖的技术。 将 NT 与多种活细胞结合的方法，并证明两种循环细胞（红细胞 和巨噬细胞）可以调节 NT 的 PK、生物分布和功效。 推进细胞向 NT 递送强调了迫切需要进行机制研究，以 i) 阐明如何 活细胞载体和 NT 之间的界面影响 NT 的运输和载体细胞的迁移，ii) 确定利用活细胞精确递送 NT 的原理。我们的目标是利用我们在这方面的专业知识。 具体来说，在未来五年内，使用纳米颗粒设计和细胞工程来解决这一未满足的需求。 以各种组织中发生的炎症作为模型，我们将重点关注 i) 了解细胞载体如何 影响 NT 递送的结果，ii) 研究 NT 的负载和理化特性 影响载体细胞的迁移，以及iii）开发多尺度策略以实现细胞特异性递送 这些研究将使我们能够建立一套设计规则来管理交付效率和 NT与活细胞的相互作用，最终将提高NT的能力并拓宽NT的谱系 治疗各种疾病的成功实施不仅有助于理解 NT 与活细胞相互作用的关键特征，同时也制定了一套合理工程的原则 活细胞可改善 NT 和其他疗法的生物学效果。