Multivalent Presentation of Peptide Targeting Groups Alters Polymer Biodistribution to Target Tissues,Biomacromolecules

当前位置： X-MOL 学术 › Biomacromolecules › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Multivalent Presentation of Peptide Targeting Groups Alters Polymer Biodistribution to Target Tissues
Biomacromolecules ( IF 5.5 ) Pub Date : 2017-12-28 00:00:00 , DOI: 10.1021/acs.biomac.7b01193
Maureen R. Newman _{1,

2} , Steven G. Russell _{1,

2} , Christopher S. Schmitt _{1,

2} , Ian A. Marozas _{1,

2} , Tzong-Jen Sheu _{1,

2} , J. Edward Puzas _{1,

2} , Danielle S. W. Benoit _{1,

2}

Affiliation

Drug delivery to bone is challenging, whereby drug distribution is commonly <1% of injected dose, despite development of several bone-targeted drug delivery systems specific to hydroxyapatite. These bone-targeted drug delivery systems still suffer from poor target cell localization within bone, as at any given time overall bone volume is far greater than acutely remodeling bone volume, which harbors relevant cell targets (osteoclasts or osteoblasts). Thus, there exists a need to target bone-acting drugs specifically to sites of bone remodeling. To address this need, this study synthesized oligo(ethylene glycol) copolymers based on a peptide with high affinity to tartrate-resistant acid phosphatase (TRAP), an enzyme deposited by osteoclasts during the bone resorption phase of bone remodeling, which provides greater specificity relevant for bone cell drugging. Gradient and random peptide orientations, as well as polymer molecular weights, were investigated. TRAP-targeted, high molecular weight (M_n) random copolymers exhibited superior accumulation in remodeling bone, where fracture accumulation was observed for at least 1 week and accounted for 14% of tissue distribution. Intermediate and low M_n random copolymer accumulation was lower, indicating residence time depends on M_n. High M_n gradient polymers were cleared, with only 2% persisting at fractures after 1 week, suggesting TRAP binding depends on peptide density. Peptide density and M_n are easily modified in this versatile targeting platform, which can be applied to a range of bone drug delivery applications.

中文翻译：

肽靶向基团的多价呈现改变了聚合物对靶组织的生物分布。

药物向骨骼的递送具有挑战性，尽管开发了几种针对羟基磷灰石的骨靶向药物递送系统，但药物分布通常小于注射剂量的1％。这些以骨为靶标的药物输送系统仍然在骨内靶细胞定位不良，因为在任何给定时间，总骨量远大于具有相关细胞靶标（破骨细胞或成骨细胞）的急性重塑骨量。因此，需要将骨作用药物特异性地靶向骨重塑的部位。为了满足这一需求，本研究基于一种肽合成了一种低聚（乙二醇）共聚物，该肽与抗酒石酸酸性磷酸酶（TRAP）具有高亲和力，该酶是破骨细胞在骨重塑的骨吸收阶段沉积的酶，它提供了与骨细胞药物相关的更高的特异性。研究了梯度和随机肽的方向，以及聚合物的分子量。靶向TRAP的高分子量（M _n）无规共聚物在重塑骨骼中表现出优异的蓄积性，其中观察到骨折蓄积至少1周，占组织分布的14％。M _n和低M _n的无规共聚物的累积量较低，表明停留时间取决于M _n。清除了高M _n梯度聚合物，只有1％的化合物在1周后仍然存在于骨折处，这表明TRAP结合取决于肽的密度。在这个多功能的靶向平台上，肽密度和M _n易于修饰，可应用于一系列骨药物递送应用。

更新日期：2017-12-28

点击分享查看原文

点击收藏

公开下载

阅读更多本刊最新论文本刊介绍/投稿指南11