Programming Pharmacokinetics in Vivo via In Situ Switching of Nanoscale Particle

通过纳米级颗粒的原位切换对体内药代动力学进行编程

• 批准号: 8146821
• 负责人: Nathan Claude Gianneschi
• 金额: $ 232.38万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8146821
• 关键词: Adverse effects; Affect; Antineoplastic Agents; Behavior; Biochemical; Biological; Biological Availability; Blood Circulation; Blood Circulation Time; Cancer Model; Cancer cell line; Cells; Chemistry; Complex; Constitution; Coupled; Data; Dependence; Detection; Development; Diagnosis; Diagnostic; Disease Vectors; Dose-Limiting; Drug Delivery Systems; Drug Kinetics; Goals; Half-Life; Histocompatibility Testing; Human; Image; Immune response; In Situ; In Vitro; Investigation; Label; Liver; Magnetic Resonance Imaging; Masks; Methods; Modeling; Morphology; Mus; Noise; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Property; Relative (related person); Renal clearance function; Research; Science; Shapes; Signal Transduction; Stimulus; Structure; Surface; Therapeutic; Tissues; Virus; abstracting; analog; bioimaging; cancer therapy; chemotherapy; design; human disease; in vivo; interest; macrophage; nanoparticle; nanoscale; neoplastic cell; novel; novel strategies; particle; programs; public health relevance; research study; response; retinal rods; small molecule; targeted delivery; tumor; uptake; vector; virus morphology

DESCRIPTION (Provided by the applicant) Abstract: Controlling the pharmacokinetics and targeting of small molecule drugs and diagnostics is at the core of medicinal chemistry, pharmaceutical science and biomedical imaging. The intense interest in nanoscale vehicles designed for targeted delivery and detection in vivo is predicated on the idea that such materials may infer their pharmacokinetic, bioavailability and targeting properties on small molecules and other cargo including biomolecules. Such nanoscale packaging strategies have a key role in alleviating dose-limiting side effects associated with many otherwise clinically effective chemotherapeutic drugs presenting a major hurdle in the treatment of cancer. In addition, targeting diagnostics efficiently and selectively to given tissues while avoiding non-specific accumulation greatly enhances signal to noise in in vivo imaging applications. The naturally efficient targeting and infectious properties of biological disease vectors, in particular viruses, has made them models in efforts to design and develop synthetic and semisynthetic nanoscale vectors for targeted drug delivery. Therefore, research has focused on the development of appropriately decorated spherical particles of various sizes, degradability profiles, surface chemistry and material constitution. More recently, the extraordinary diversity of virus morphologies and an increasing ability to synthesize complex nanoscale structures, has inspired investigations into how shape can affect synthetic nanoscale particle interactions with cells and their behavior in vivo. In particular filamentous (or rod shaped) morphologies have been shown to have significantly different properties relative to their spherical analogues including longer blood circulation times and extended cell-uptake rates. The intriguing shape and size dependence of these key properties of delivery vectors inspires our proposal to develop nanoscale particles with switchable, transformable morphologies. We propose a novel class of materials capable of switchable, programmed pharmacokinetic profiles in vivo with utility in a range of functions including differential uptake into particular tissue types (e.g. tumor targeting vs liver uptake), stimulated renal clearance from systemic circulation, and evasion of macrophage uptake coupled with selective targeting. The goal of this research program is to develop materials capable of switching their pharmacokinetic and tissue targeting profiles in response to specific biochemical stimuli. This will be achieved utilizing a novel mechanism - stimuli-responsive nanoparticle morphology transitions. We propose a number of experiments for exploring the viability and validating this approach to vector directed targeting. Our preliminary pharmacokinetic data will be further validated in healthy mice and in vitro with macrophages, to examine our ability to control and switch several factors including: tissue accumulation, mode of clearance, circulation half-life, immune- response and degradation. Investigations will include targeted drug delivery, and targeting of diagnostics in the form of fluorescent labels and MRI-agents to human cancer cell lines in vitro and mouse cancer models in vivo. Public Health Relevance: The ability to accurately detect, diagnose and target diseased tissue is a key challenge in treating patients. This research program aims to discover new methods for specifically masking and targeting toxic anticancer drugs specifically to tumor cells and for labeling them for diagnosis. This is a novel approach to pharmaceutical and biomedical imaging science with broad, general implications for programmed, "smart" therapeutics for tackling as yet unsolved problems in the treatment of human disease including allevation of chemotherapy side-effects and early, accurate diagnoses.

描述(由申请人提供) 摘要：控制小分子药物的药代动力学和靶向性是药物化学、药学和生物医学成像的核心。人们对用于体内靶向传递和检测的纳米级载体的浓厚兴趣是基于这样的想法，即这种材料可以推断出它们的药代动力学、生物利用度和在小分子和其他货物(包括生物分子)上的靶向特性。这种纳米尺度的包装策略在减轻与许多其他临床有效的化疗药物相关的剂量限制副作用方面发挥了关键作用，这些副作用是癌症治疗的主要障碍。此外，有效和选择性地针对特定组织进行诊断，同时避免非特异性积累，大大提高了活体成像应用中的信噪比。生物疾病载体，特别是病毒的天然有效的靶向性和感染性，使它们成为设计和开发合成和半合成纳米载体用于靶向药物输送的典范。因此，研究的重点是开发各种大小、可降解性、表面化学和材料组成的适当修饰的球形颗粒。最近，病毒形态的非凡多样性和合成复杂纳米结构的能力日益增强，促使人们研究形状如何影响合成的纳米粒子与细胞的相互作用及其在体内的行为。特别是，丝状(或棒状)形态与球形类似物相比具有显着不同的特性，包括更长的血液循环时间和延长的细胞摄取率。输送载体的这些关键性质对形状和大小的有趣依赖激发了我们开发具有可切换、可变形形态的纳米粒子的建议。我们提出了一类新的材料，能够在体内切换、程序化的药代动力学曲线，具有一系列功能，包括对特定组织类型的差异摄取(例如，肿瘤靶向与肝脏摄取)，刺激肾脏从体循环中清除，以及逃避巨噬细胞摄取与选择性靶向。这项研究计划的目标是开发能够改变其药代动力学和组织靶向特征的材料，以响应特定的生化刺激。这将利用一种新的机制--刺激响应型纳米颗粒形态转变来实现。我们提出了一些实验来探索这种方法的可行性，并验证这种方法在载体定向打靶中的有效性。我们的初步药代动力学数据将在健康小鼠和巨噬细胞体外进一步验证，以检验我们控制和切换几个因素的能力，包括：组织积累、清除模式、循环半衰期、免疫反应和降解。研究将包括靶向药物输送，以及以荧光标记和核磁共振试剂的形式将诊断靶向体外的人类癌细胞系和体内的小鼠癌症模型。 公共卫生相关性：准确检测、诊断和定位病变组织的能力是治疗患者的关键挑战。这项研究计划旨在发现新的方法，专门掩蔽和靶向有毒的抗癌药物，特别是针对肿瘤细胞，并标记它们以供诊断。这是一种药物和生物医学成像科学的新方法，对程序化的“智能”疗法具有广泛的普遍意义，用于解决人类疾病治疗中尚未解决的问题，包括减轻化疗副作用和早期准确诊断。