The influence of polymer topology on pharmacokinetics: differences between cyclic and linear PEGylated poly(acrylic acid) comb polymers.
The influence of polymer topology on pharmacokinetics: differences between cyclic and linear PEGylated poly(acrylic acid) comb polymers.
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DOI：
10.1016/j.jconrel.2009.05.021
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发表时间：
2009-12-16
影响因子：
10.8
通讯作者：
Szoka, Francis C., Jr.
中科院分区：
文献类型：
--
作者：
Chen, Bo;Jerger, Katherine;Frechet, Jean M. J.;Szoka, Francis C., Jr.
由于肾脏清除率降低以及渗透和滞留（EPR）效应增强，用于输送化疗药物的水溶性聚合物被动靶向实体瘤。由于通过流体动力学直径与聚合物相当的生物纳米孔过滤，肾脏中的聚合物被消除。因此，我们研究了可广泛归为“分子结构”的化学特征，例如：分子量、链柔性、链末端和支化数量，以了解它们如何影响聚合物消除。在本报告中，我们描述了使用 ATRP 和“点击”化学合成四对分子量相似的接枝有聚乙二醇（23、32、65、114 kDa）的具有低多分散性的环状和线性聚丙烯酸聚合物。这些聚合物用 125I 进行放射性标记，并在正常和 C26 腺癌肿瘤 BALB/c 小鼠中测定静脉注射后的药代动力学和组织分布。高于肾阈值 30kDa 的环状聚合物比同类线性聚合物（对于 66 kDa 环状聚合物，t1/2，β= 35 ± 2 h）具有显着更长的消除时间（长 10% 至 33%），并且血清浓度时间曲线下面积更大。这导致环状聚合物比线性聚合物对应物在肿瘤中积累更多。因此，水溶性环状梳形聚合物加入了越来越多的聚合物拓扑中，与线性对应物相比，它们显示出大大延长的循环时间，并提供了用作药物载体的替代聚合物结构。
Water-soluble polymers for the delivery of chemotherapeutic drugs passively target solid tumors as a consequence of reduced renal clearance and the enhanced permeation and retention (EPR) effect. Elimination of the polymers in the kidney occurs due to filtration through biological nanopores with a hydrodynamic diameter comparable to the polymer. Therefore we have investigated chemical features that may broadly be grouped as “molecular architecture” such as: molecular weight, chain flexibility, number of chain ends and branching, to learn how they impact polymer elimination. In this report we describe the synthesis of four pairs of similar molecular weight cyclic and linear polyacrylic acid polymers grafted with polyethylene glycol (23, 32, 65, 114 kDa) with low polydispersities using ATRP and “click” chemistry. The polymers were radiolabeled with 125I and their pharmacokinetics and tissue distribution after intravenous injection were determined in normal and C26 adenocarcinoma tumored BALB/c mice. Cyclic polymers above the renal threshold of 30kDa had a significantly longer elimination time (between 10 to 33 % longer) than did the comparable linear polymer (for the 66 kDa cyclic polymer, t1/2, β= 35 ± 2 h) and a greater area under the serum concentration time curve. This resulted in a greater tumor accumulation of the cyclic polymer than the linear polymer counterpart. Thus water-soluble cyclic comb polymers join a growing list of polymer topologies that show greatly extended circulation times compared to their linear counterparts and provide alternative polymer architecture for use as drug carriers.
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DOI：
10.1073/pnas.50.2.236
发表时间：
1963-01-01
影响因子：
11.1
作者：
DULBECCO, R;VOGT, M
通讯作者：
VOGT, M
影响因子：
15
作者：
Boydston, Andrew J.;Xia, Yan;Kornfield, Julia A.;Gorodetskaya, Irina A.;Grubbs, Robert H.
通讯作者：
Grubbs, Robert H.
影响因子：
4.4
作者：
BLOOMFIE.V;ZIMM, BH
通讯作者：
ZIMM, BH
影响因子：
7.3
作者：
CODY, WL;MAHONEY, M;HADLEY, ME
通讯作者：
HADLEY, ME
影响因子：
15
作者：
Johnson, Jeremiah A.;Lewis, Danielle R.;Turro, Nicholas J.
通讯作者：
Turro, Nicholas J.