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（申请人提供） 摘要：控制小分子药物和诊断的药代动力学和靶向靶向是药物化学，药物科学和生物医学成像的核心。对旨在靶向递送和在体内检测的纳米级车辆的强烈兴趣是基于这样的想法，即这种材料可以推断出其药代动力学，生物利用度以及对小分子和其他货物（包括生物分子）的靶向性能。这种纳米级包装策略在减轻与许多其他临床上有效的化学治疗药物相关的剂量副作用方面具有关键作用，这在癌症治疗方面具有重大障碍。此外，在避免非特异性积累的同时，有效，有选择地将诊断靶向诊断，从而大大提高了体内成像应用中噪声的信号。 生物学疾病载体的自然有效靶向和感染性能，特别是病毒，使它们成为设计和开发合成和半合成纳米级向量的模型，以靶向药物递送。因此，研究集中在开发各种大小，降解性曲线，表面化学和材料构成的适当装饰的球形颗粒。最近，病毒形态的非凡多样性以及综合复杂纳米级结构的越来越多的能力，激发了对形状如何影响合成纳米级粒子与细胞的相互作用及其在体内行为的研究。特别是丝状（或杆状）形态学的形态相对于其球形类似物的特性显着不同，包括更长的血液循环时间和延长的细胞摄取率。这些递送向量的这些关键特性的有趣形状和尺寸依赖性激发了我们开发具有可切换，可转换形态的纳米级颗粒的建议。我们提出了一类新型的材料，能够在体内切换，程序化的药代动力学特征，并在一系列功能中使用效用，包括对特定组织类型的差异吸收（例如，靶向肿瘤靶向肝脏的摄取），从全身循环中刺激的肾脏清除率，以及对巨噬细胞的逃避巨噬细胞的选择。 该研究计划的目的是开发能够响应特定的生化刺激来切换其药代动力学和组织靶向谱的材料。利用一种新型机制 - 刺激响应性纳米颗粒形态过渡将实现这一目标。我们提出了许多实验，以探索生存能力并验证对向量定向的方法。我们的初步药代动力学数据将在健康小鼠和体外与巨噬细胞进行进一步验证，以检查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，免疫反应和降解。研究将包括针对性的药物输送，以及以荧光标签和MRI-Agent形式靶向诊断，并在体外对人类癌细胞系的MRI-Agent靶向。 公共卫生相关性：准确检测，诊断和靶向患病组织的能力是治疗患者的关键挑战。该研究计划旨在发现专门掩盖和靶向专门针对肿瘤细胞的有毒抗癌药物并将其标记诊断的新方法。这是一种新型的药物和生物医学成像科学的方法，对程序的“智能”疗法具有广泛的，一般的影响，以解决人类疾病的治疗中尚未解决的问题，包括减轻化学疗法副作用和早期，准确的诊断。