A New Dimension in Renal Clearance Design Criteria for Dendrimer Nanostructures

树枝状聚合物纳米结构肾清除率设计标准的新维度

• 批准号: 7279608
• 负责人: ERIK C WIENER
• 金额: $ 59.61万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7279608
• 关键词: Address; Affect; Animals; Anions; Area Under Curve; Attention; Behavior; Biodistribution; Biological Process; Biology; Blood specimen; Charge; Charts and Tables; Chemistry; Contrast Media; Data; Dendrimers; Development; Diagnosis; Diagnostic; Diffusion; Dimensions; Dose; Drug Delivery Systems; Drug Kinetics; Generations; Glomerular Capillary; Glomerular Filtration Rate; Goals; Graph; Kidney; Knowledge; Linear Models; Link; Literature; Magnetic Resonance Imaging; Manuscripts; Measures; Medicine; Membrane; Metabolic Clearance Rate; Methods; Modeling; Molecular Weight; Nanostructures; Nanotechnology; Numbers; Pathway interactions; Peptides; Plasma; Polymers; Probenecid; Property; Publishing; Renal clearance function; Reporting; Research; Residual state; Role; Scheme; Standards of Weights and Measures; Structure; Surface; System; Therapeutic; Toxic effect; Tubular formation; Upper arm; Urine; base; design; improved; in vivo; inhibitor/antagonist; light scattering; nanoparticle; nanoscale; radius bone structure; size; tumor; uptake

DESCRIPTION (provided by applicant): The goal of our research is to add a new dimension to our understanding of the design criteria for renal clearance of dendrimer based nanostructures. We achieve this by gaining an understanding of how surface charge (SC) on dendrimers can be used to tune their pharmacological properties. Reports exist on how size affects the behavior of dendrimers in vivo, yet no extensive pharmacological study that keeps SC constant while varying the size and size constant while varying the SC exists. We aim to: Synthesize dendrimers of varying SC but constant size; Synthesize dendrimers of varying hydrodynamic radii (rh) and constant SC; and Determine their pharmacokinetics, biodistribution, and clearance pathway. Dendrimers have a core with repeat units. These repeat units grow from arms on the core. The number of arms is the core multiplicity (CM). The repeat unit anchors to the core at a point, and branches grow from that point. The number of these branches is the branch juncture multiplicity (BM), and the number of repeat units defines a generation (G). The number of surface groups (NSQ) is: NSG = CM* (BM)G. We use standard peptide chemistry to prepare dendrimers by convergent methods. Dendrons are prepared by linking the different repeat units from the surface (bifunctional Gd(lll)-Chelates) down to the attachment point. By using cores differing in CM and attaching dendrons prepared from repeat units differing in BM we prepared dendrimers with differing NSG but the same rh and differing rh but the same NSG. The rh is measured using light scattering and diffusion ordered NMR methods. We obtain the plasma clearance curves, [Tr]P(t), with MRI and direct blood sampling methods. From [Tr]P(t) we calculate the pharmacokinetic parameters and area under the curve (AUC). We will compare dendrimer values with those of a low molecular weight clinically approved Gd(lll)-chelate contrast agent. Renal clearance is compared to glomerular filtration rate by taking the dose found in the urine after t ~ "functional infinity" from normal animals and those treated with the anion tubular secretion inhibitor probenecid and dividing it by the AUC. Pharmacokinetic data is analyzed by fitting the [Tr]P(t) profiles with multicompartmental and non-compartmental models using ADAPT II. We use the maximum likelihood estimation and linear models for the variance of the additive errors. We also use Akaike's Information Criteria, Schwartz Criteria, estimated error of the model parameters, and residual analysis to select the model structure maximizing the fit accuracy and minimizing the number of parameters. This provides an understanding of the renal clearance design criteria for dendrimers used in diagnosis and therapy. This research literally adds a new dimension to our understanding of the design criteria needed for controlling and optimizing dendrimer based nanostructure kidney clearance. The knowledge gained is fundamental in making dendrimers for therapy and diagnosis with low toxicity and low whole body retention.

描述（由申请人提供）：我们的研究的目的是为我们对基于树枝状聚合物的纳米结构的肾脏清除的设计标准添加新的维度。我们通过了解如何使用树状聚合物的表面电荷（SC）来调整其药理特性来实现这一目标。有关于大小如何影响体内树枝状聚合物行为的报告，但是没有广泛的药理学研究可以使SC保持恒定，同时在改变SC的同时改变大小和尺寸恒定。我们的目标是：合成不同SC的树枝状聚合物，但尺寸恒定；合成的水动力半径（RH）和常数SC的树状聚合物；并确定其药代动力学，生物分布和清除途径。树枝状聚合物具有重复单位的核心。这些重复单元从核心上的手臂上生长。武器的数量是核心多重性（CM）。重复单元在一个点锚定在核心上，分支从那一点生长。这些分支的数量是分支连接多重性（BM），重复单元的数量定义了一代（G）。表面组（NSQ）的数量为：NSG = CM*（BM）G。我们使用标准肽化学来通过收敛方法制备树枝状聚合物。树木是通过将表面（双功能GD（LLL）chelates）向下连接到附着点的不同重复单元来制备的。通过使用CM不同的核心并附着在BM不同的重复单元中制备的树突，我们制备了具有不同NSG但相同RH和不同rh但相同NSG的树枝状聚合物。使用光散射和扩散有序的NMR方法测量RH。我们使用MRI和直接取样方法获得了血浆清除曲线[TR] P（T）。从[TR] P（t）中，我们计算曲线下的药代动力学参数和面积（AUC）。我们将将树枝状大分子的值与低分子量临床批准的GD（LLL） - 螯合对比剂的值进行比较。将肾脏清除率与肾小球过滤率进行比较，通过服用正常动物的T〜“功能无穷大”和用阴离子管状分泌抑制剂探针治疗的剂量，并将其除以AUC。通过使用Adapt II拟合[TR] P（T）曲线与多室和非门室模型，可以分析药代动力学数据。我们将最大似然估计和线性模型用于添加误差的方差。我们还使用Akaike的信息标准，Schwartz标准，模型参数的估计误差以及残差分析来选择最大化拟合精度并最大程度地降低参数数量的模型结构。这提供了对用于诊断和治疗中使用的树枝状聚合物的肾脏清除设计标准。这项研究从字面上增加了我们对控制和优化基于树突的纳米结构肾脏所需的设计标准的理解。获得的知识对于制造患有低毒性和低毒性的治疗和诊断的树枝状聚合物至关重要。