Bogdanov Alexei A, Mazzanti Mary, Castillo Gerardo, Bolotin Elijah
1. University of Massahcusetts Medical School, Worcester MA;
Theranostics. 2012;2(6):553-76. doi: 10.7150/thno.4070. Epub 2012 Jun 4.
Initially developed in 1992 as an MR imaging agent, the family of protected graft copolymers (PGC) is based on a conjugate of polylysine backbone to which methoxypoly(ethylene glycol) (MPEG) chains are covalently linked in a random fasion via N-ε-amino groups. While PGC is relatively simple in terms of its chemcial composition and structure, it has proved to be a versatile platform for in vivo drug delivery. The advantages of poly amino acid backbone grafting include multiple available linking sites for drug and adaptor molecules. The grafting of PEG chains to PGC does not compromise biodegradability and does not result in measurable toxicity or immunogenicity. In fact, the biocompatablility of PGC has resulted in its being one of the few 100% synthetic non-proteinaceous macromolecules that has suceeded in passing the initial safety phase of clinical trials. PGC is capable of long circulation times after injection into the blood stream and as such found use early on as a carrier system for delivery of paramagnetic imaging compounds for angiography. Other PGC types were later developed for use in nuclear medicine and optical imaging applications in vivo. Recent developments in PGC-based drug carrier formulations include the use of zinc as a bridge between the PGC carrier and zinc-binding proteins and re-engineering of the PGC carrier as a covalent amphiphile that is capabe of binding to hydrophobic residues of small proteins and peptides. At present, PGC-based formulations have been developed and tested in various disease models for: 1) MR imaging local blood circulation in stroke, cancer and diabetes; 2) MR and nuclear imaging of blood volume and vascular permeability in inflammation; 3) optical imaging of proteolytic activity in cancer and inflammation; 4) delivery of platinum(II) compounds for treating cancer; 5) delivery of small proteins and peptides for treating diabetes, obesity and myocardial infarction. This review summarizes the experience accumulated by various research groups that chose to use PGC as a drug delivery platform.
受保护接枝共聚物（PGC）家族最初于1992年作为一种磁共振成像剂开发，它基于聚赖氨酸主链的共轭物，甲氧基聚（乙二醇）（MPEG）链通过N-ε-氨基以随机方式与之共价连接。虽然PGC在化学成分和结构方面相对简单，但已被证明是一种用于体内药物递送的通用平台。聚氨基酸主链接枝的优点包括药物和适配分子有多个可用的连接位点。PEG链接枝到PGC上不会损害生物降解性，也不会导致可测量的毒性或免疫原性。事实上，PGC的生物相容性使其成为少数几种成功通过临床试验初始安全阶段的100%合成非蛋白质大分子之一。PGC注入血流后能够实现长时间循环，因此早期被用作递送用于血管造影的顺磁性成像化合物的载体系统。后来又开发了其他类型的PGC用于体内核医学和光学成像应用。基于PGC的药物载体配方的最新进展包括使用锌作为PGC载体与锌结合蛋白之间的桥梁，以及将PGC载体重新设计为一种共价两亲物，它能够与小蛋白质和肽的疏水残基结合。目前，基于PGC的配方已在各种疾病模型中进行了开发和测试，用于：1）中风、癌症和糖尿病中磁共振成像局部血液循环；2）炎症中血容量和血管通透性的磁共振和核成像；3）癌症和炎症中蛋白水解活性的光学成像；4）递送铂（II）化合物治疗癌症；5）递送小蛋白质和肽治疗糖尿病、肥胖症和心肌梗死。本综述总结了各个选择使用PGC作为药物递送平台的研究小组积累的经验。
