Programming Pharmacokinetics in Vivo via In Situ Switching of Nanoscale Particle

描述（由申请人提供） 摘要：控制小分子药物和诊断的药代动力学和靶向是药物化学、制药科学和生物医学成像的核心。对设计用于体内靶向递送和检测的纳米级载体的强烈兴趣是基于这样的想法，即这些材料可以推断它们对小分子和其他货物（包括生物分子）的药代动力学、生物利用度和靶向性质。这种纳米级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性副作用方面具有关键作用，这些化疗药物在癌症治疗中表现出主要障碍。此外，将诊断有效地和选择性地靶向给定组织，同时避免非特异性积累，大大增强了体内成像应用中的信噪比。 生物疾病载体（特别是病毒）的天然有效靶向和感染特性使它们成为设计和开发用于靶向药物递送的合成和半合成纳米级载体的模型。因此，研究集中在各种尺寸的适当修饰的球形颗粒的开发、降解性概况、表面化学和材料构成上。最近，病毒形态的非凡多样性和合成复杂纳米结构的能力不断提高，激发了对形状如何影响合成纳米颗粒与细胞的相互作用及其体内行为的研究。特别地，丝状（或棒状）形态已经显示出相对于它们的球形类似物具有显著不同的性质，包括更长的血液循环时间和延长的细胞摄取速率。递送载体的这些关键性质的有趣的形状和大小依赖性激发了我们开发具有可切换、可变换形态的纳米级颗粒的提议。我们提出了一类新型材料，其能够在体内进行可切换的、程序化的药代动力学特征，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）、刺激体循环中的肾清除以及与选择性靶向相结合的巨噬细胞摄取的逃避。 该研究计划的目标是开发能够响应特定生化刺激而切换其药代动力学和组织靶向特征的材料。这将利用一种新的机制-刺激响应纳米颗粒形态转变来实现。我们提出了一些实验，探索的可行性和验证这种方法载体定向靶向。我们的初步药代动力学数据将在健康小鼠和体外巨噬细胞中进一步验证，以检查我们控制和转换几个因素的能力，包括：组织蓄积、清除模式、循环半衰期、免疫应答和降解。研究将包括靶向药物递送，以及以荧光标记和MRI试剂的形式将诊断靶向体外人类癌细胞系和体内小鼠癌症模型。 公共卫生相关性：准确检测、诊断和靶向病变组织的能力是治疗患者的关键挑战。该研究计划旨在发现新的方法，用于特异性掩蔽和靶向肿瘤细胞的毒性抗癌药物，并标记它们用于诊断。这是一种新的方法，以制药和生物医学成像科学与广泛的，一般意义上的程序化，“智能”治疗，以解决尚未解决的问题，在治疗人类疾病，包括减轻化疗副作用和早期，准确的诊断。

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.