A New Dimension in Renal Clearance Design Criteria for Dendrimer Nanostructures

描述（由申请人提供）：我们的研究目标是为我们对基于树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。我们通过了解树状大分子上的表面电荷（SC）如何用于调整其药理学特性来实现这一目标。关于树突分子大小如何影响体内树突分子的行为已有报道，但没有广泛的药理学研究表明，在改变树突分子大小的同时保持树突分子大小不变，在改变树突分子存在的同时保持树突分子大小不变。我们的目标是：合成不同SC但尺寸不变的树状大分子；合成变流体动力半径（rh）和恒定SC的树状大分子确定其药代动力学、生物分布和清除途径。树状大分子有一个带有重复单元的核心。这些重复单位从核心上的手臂生长。兵种的数量是核心多重性（CM）。重复单元在某一点锚定在核心，分支从该点开始生长。这些分支的数量称为分支接点多重性（BM），重复单元的数量定义为一代(G)。表面基团数（NSQ）为：NSG = CM* (BM)G。我们使用标准的肽化学方法通过收敛方法制备树突状分子。树突是通过将不同的重复单元从表面（双功能Gd(ll)-螯合物）连接到附着点来制备的。利用CM不同的核和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的树突。rh是用光散射和扩散有序核磁共振方法测量的。我们通过MRI和直接采血方法获得血浆清除率曲线[Tr]P(t)。由[Tr]P(t)计算药代动力学参数和曲线下面积（AUC）。我们将比较树状分子值与临床批准的低分子量Gd（ll）螯合造影剂的值。用正常动物和用阴离子小管分泌抑制剂probenecid治疗的动物在t ~“功能无限”后尿液中的剂量除以AUC，比较肾清除率与肾小球滤过率。采用ADAPT II多室和非室室模型拟合[Tr]P(t)谱，分析药代动力学数据。我们使用极大似然估计和线性模型来描述加性误差的方差。利用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拟合精度最大、参数数量最少的模型结构。这提供了用于诊断和治疗树突状分子的肾脏清除设计标准的理解。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。所获得的知识是基础，使树状大分子治疗和诊断具有低毒性和低全身潴留。

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.