A New Dimension in Renal Clearance Design Criteria for Dendrimer Nanostructures

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清除率的设计标准的理解增加一个新的维度。我们通过了解树枝状聚合物上的表面电荷（SC）如何用于调节其药理学性质来实现这一目标。存在关于尺寸如何影响树枝状聚合物在体内的行为的报告，但没有广泛的药理学研究，即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但恒定大小的树枝状聚合物;合成不同流体动力学半径（rh）和恒定SC的树枝状聚合物;并确定其药代动力学、生物分布和清除途径。树枝状聚合物具有带有重复单元的核心。这些重复单元从核心上的臂生长。臂数是核心多重数（CM）。重复单元锚定到核心的一个点，分支从该点生长。这些分支的数目是分支接合多重性（BM），并且重复单元的数目定义了代（G）。表面基团的数目（NSQ）为：NSG = CM*（BM）G。我们使用标准的肽化学制备树枝状聚合物的收敛方法。通过将不同的重复单元从表面（双官能Gd（III）-螯合物）向下连接到连接点来制备树枝状突起。通过使用CM不同的核和连接由BM不同的重复单元制备的树枝状分子，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NMR方法测量rh。我们用MRI和直接采血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值与临床上批准的低分子量Gd（III）-螯合物造影剂的值。肾清除率与肾小球滤过率比较，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在t ~“功能无限”后尿中发现的剂量，并将其除以AUC。使用ADAPT II，通过多房室和非房室模型拟合[Tr]P（t）曲线，分析药代动力学数据。我们使用最大似然估计和线性模型的方差的加性误差。我们还使用Akaike的信息准则，Schwartz准则，模型参数的估计误差和残差分析来选择模型结构，使拟合精度最大化，参数数量最小化。这提供了用于诊断和治疗的树枝状聚合物的肾清除率设计标准的理解。这项研究从字面上增加了一个新的层面，我们的理解所需的设计标准，控制和优化基于树枝状聚合物的纳米结构肾脏清除。所获得的知识是制造用于治疗和诊断的低毒性和低全身保留的树枝状聚合物的基础。

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.