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）：我们研究的目标是为我们对基于树枝状聚合物的纳米结构的肾脏清除设计标准的理解增加一个新的维度。我们通过了解如何使用树枝状聚合物上的表面电荷（SC）来调整其药理学特性来实现这一目标。关于尺寸如何影响树枝状聚合物在体内的行为已有报道，但还没有广泛的药理学研究可以在改变尺寸的同时保持 SC 恒定，以及在改变 SC 的同时保持尺寸恒定。我们的目标是： 合成不同 SC 但大小恒定的树枝状聚合物；合成不同流体动力学半径 (rh) 和恒定 SC 的树枝状聚合物；确定它们的药代动力学、生物分布和清除途径。树枝状聚合物有一个带有重复单元的核心。这些重复单元从核心上的臂生长出来。臂的数量就是核心重数（CM）。重复单元锚定在核心的某个点上，分支从该点开始生长。这些分支的数量是分支接合点多重性（BM），重复单元的数量定义了一代（G）。表面基团数 (NSQ) 为：NSG = CM* (BM)G。我们使用标准的肽化学通过收敛方法制备树枝状聚合物。通过将不同的重复单元从表面（双功能 Gd(III)-螯合物）向下连接到附着点来制备树突。通过使用CM不同的核心和由BM不同的重复单元制备的附着树突，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。 rh 使用光散射和扩散有序 NMR 方法测量。我们通过 MRI 和直接血液采样方法获得血浆清除率曲线 [Tr]P(t)。根据 [Tr]P(t)，我们计算药代动力学参数和曲线下面积 (AUC)。我们将比较树枝状聚合物的值与临床批准的低分子量 Gd(III)-螯合物造影剂的值。通过取正常动物和用阴离子肾小管分泌抑制剂丙磺舒治疗的动物的“功能无限”后尿液中发现的剂量并将其除以AUC，将肾清除率与肾小球滤过率进行比较。使用 ADAPT II 通过将 [Tr]P(t) 曲线与多房室和非房室模型进行拟合来分析药代动力学数据。我们使用最大似然估计和线性模型来计算加性误差的方差。我们还使用 Akaike 信息准则、Schwartz 准则、模型参数的估计误差和残差分析来选择模型结构，以最大化拟合精度并最小化参数数量。这提供了对用于诊断和治疗的树枝状聚合物的肾脏清除率设计标准的理解。这项研究确实为我们对控制和优化基于树枝状聚合物的纳米结构肾脏清除所需的设计标准的理解增加了一个新的维度。所获得的知识对于制造低毒性和低全身保留的用于治疗和诊断的树枝状聚合物至关重要。