RAFT-synthesized graft copolymers that enhance pH-dependent membrane destabilization and protein circulation times.
RAFT-synthesized graft copolymers that enhance pH-dependent membrane destabilization and protein circulation times.
复制标题
DOI：
10.1016/j.jconrel.2011.06.013
复制
发表时间：
2011-10-30
期刊：
影响因子：
--
通讯作者：
Stayton PS
中科院分区：
文献类型：
--
作者：
Crownover E;Duvall CL;Convertine A;Hoffman AS;Stayton PS
在这里，我们描述了一种新的聚丙基丙烯酸(PolyPAA)接枝共聚物结构，它显示出强大的pH依赖的、膜不稳定的活性，并被证明增强了蛋白质的血液循环动力学。通过与炔官能性链转移剂(CTA)的可逆加成-断裂链转移(RAFT)聚合，合成了含有单一遥螺炔官能团的聚聚丙烯酸酯(PAA)，并通过叠氮-炔基[3+2]惠氏环加成反应偶联到RAFT聚合的聚甲基丙烯酸叠氮丙酯(PolyAPMA)上。接枝共聚物在内质体的pH值下变得不稳定，并且在显著低于线性聚PAA的浓度时表现出活性。将PAA接枝到用生物素功能支链CTA聚合的聚APMA上，制备了生物素封端的聚PAA接枝共聚物。研究了氚标记的亲和素在聚PAA接枝共聚物上的血液循环时间和生物分布，以及临床上使用的具有生物素功能化的40 kDa支化聚乙二醇(PEG)。线状和接枝的聚PAA分别比单独的亲和素增加了9倍和12倍的曲线下面积(AUC)。此外，聚PAA接枝共聚物结合物在肿瘤组织中的积聚明显多于线型聚PAA和支化的聚乙二醇偶联物。本报告提供的所有数据表明，聚PAA接枝共聚物具有强大的pH依赖性、膜不稳定活性、低细胞毒性，并显著增加血液循环时间和肿瘤聚集。
Here we describe a new graft copolymer architecture of poly(propylacrylic acid) (polyPAA) that displays potent pH-dependent, membrane-destabilizing activity and in addition is shown to enhance protein blood circulation kinetics. PolyPAA containing a single telechelic alkyne functionality was prepared via reversible addition-fragmentation chain transfer (RAFT) polymerization with an alkyne-functional chain transfer agent (CTA) and coupled to RAFT polymerized poly(azidopropyl methacrylate) (polyAPMA) through azide-alkyne [3+2] Huisgen cycloaddition. The graft copolymers become membrane destabilizing at endosomal pH values and are active at significantly lower concentrations than the linear polyPAA. A biotin terminated polyPAA graft copolymer was prepared by grafting PAA onto polyAPMA polymerized with a biotin functional RAFT CTA. The blood circulation time and biodistribution of tritium labeled avidin conjugated to the polyPAA graft copolymer was characterized along with a clinically utilized 40 kDa branched polyethylene glycol (PEG) also possessing biotin functionalization. The linear and graft polyPAA increase the area under the curve (AUC) over avidin alone by 9 and 12 times, respectively. Furthermore, polyPAA graft copolymer conjugates accumulated in tumor tissue significantly more than the linear polyPAA and the branched PEG conjugates. The collective data presented in this report indicate that the polyPAA graft copolymers exhibit robust pH-dependent, membrane-destabilizing activity, low cytotoxicity and significantly enhance blood circulation time and tumor accumulation.
登录
查看更多内容
DOI：
10.1016/j.jconrel.2008.10.004
发表时间：
2009-02-10
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
--
作者：
Convertine AJ;Benoit DS;Duvall CL;Hoffman AS;Stayton PS
通讯作者：
Stayton PS
影响因子：
10.8
作者：
Caliceti, P;Chinol, M;Paganelli, G
通讯作者：
Paganelli, G
影响因子：
10.8
作者：
Murthy, N;Robichaud, JR;Hoffman, AS
通讯作者：
Hoffman, AS
影响因子：
4.7
作者：
Foster, Suzanne;Duvall, Craig L.;Crownover, Emily F.;Hoffman, Allan S.;Stayton, Patrick S.
通讯作者：
Stayton, Patrick S.
影响因子：
4.1
作者：
Jones, RA;Cheung, CY;Wilson, MR
通讯作者：
Wilson, MR