Metal Chelate Conjugated Dendrimer Constructs for Diagnosis and Therapy

以树状大分子为基础的磁共振造影剂消除了血清白蛋白或线性聚合物为基础的磁共振造影剂的许多缺陷。这是由于他们通过迭代合成方法的制备，促进了树突分子的大小和形状的控制，同时产生了可重复的化学手段，对临床翻译至关重要。为了制造具有树状大分子的MRI造影剂，用化学部分开发的螯合Gd（III）技术修饰树状大分子的末端伯胺。从历史上看，这些试剂的摩尔弛度是Magnevist的6倍，Magnevist是目前批准的MRI造影剂，在化学部分的开创性合作出版物中报道。基于大分子螯合物缀合树突状聚合物的Gd(III) MR造影剂已被证明可以通过调整基本标准来调节：生成（分子量和物理尺寸）、核心元素（亲脂性和电荷）、PEG偶联（延长循环，最大限度地减少非特异性器官摄取）、赖氨酸共给药（协助肾脏清除）和偶联靶向载体（分子靶向）。将靶向载体附加到基于树突分子的显像剂上提供分子靶向显像剂。结合近红外光学成像染料，发射放射性核素的SPECT或PET，提供了多模态树突基显像剂的创建。但是，由于缺乏相关人员，加上Brechbiel博士预期退休和化学科的关闭，这个项目的任何研究都没有现成的结果，因此这个项目将于今年终止。

Macromolecular MRI contrast agents based upon dendrimers obviate many deficiencies of serum albumin or linear polymer based MRI contrast agents. This is due to their preparation through an iterative synthesis methodology that promotes controlled size and shape of the dendrimer concomitantly generating the means for reproducible chemistry key to clinical translation. To create MRI contrast agents with dendrimers, the terminal primary amines of dendrimers are modified with chelated Gd(III) technology developed in the Chemistry Section. Historically, these reagents demonstrated a molar relaxivity 6 times that of Magnevist, the currently approved MRI contrast agent as reported in a seminal collaborative publication from the Chemistry Section. Macromolecular chelate conjugated dendrimer based Gd(III) MR contrast agents have been shown to be tunable by adjusting fundamental criteria: generation (MW & physical size), core elements (lipophilicity & charge), PEG conjugation (prolonging circulation minimizing non-specific organ uptake), lysine co-administration (assisting in renal clearance), and conjugation to targeting vectors (molecular targeting). Appending targeting vectors to dendrimer based agents provides molecularly targeted imaging agents. Incorporation of NIR optical imaging dye, SPECT or PET emitting radionuclides, provides for the creation of multi-modality dendrimer based imaging agents. However, no results are readily available on any studies from this project due to a lack of involved personnel combined with the anticipated retirement of Dr. Brechbiel and closure of the Chemistry Section, and as such this project will be terminated this year.