Multivalent display of pendant pro-apoptotic peptides increases cytotoxic activity.
Multivalent display of pendant pro-apoptotic peptides increases cytotoxic activity.
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吊坠促凋亡肽的多价显示会增加细胞毒性活性。
DOI：
10.1016/j.jconrel.2015.01.013
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发表时间：
2015-05-10
影响因子：
10.8
通讯作者：
Pun, Suzie H.
中科院分区：
文献类型：
--
作者：
Chu, David S. H.;Bocek, Michael J.;Shi, Julie;Ta, Anh;Ngambenjawong, Chayanon;Rostomily, Robert C.;Pun, Suzie H.
几种阳离子抗微生物肽已被研究作为潜在的抗癌药物，由于它们相对于正常细胞表现出对癌细胞的选择性毒性。例如，KLA（一种促凋亡肽）的细胞内递送导致对多种癌细胞系的毒性;然而，相对低的活性和小的尺寸导致当在体内应用时快速的肾排泄，限制了其治疗潜力。在这项工作中，凋亡肽-聚合物杂化材料的开发，以增加凋亡肽的活性，通过多价展示。通过肽大分子单体与N-（2-羟丙基）甲基丙烯酰胺（HPMA）的RAFT共聚反应，制备了具有梳状结构的多价肽材料。聚合物展示了用于靶向p32的GKRK肽序列，p32是一种经常在癌细胞表面过表达的蛋白质，与KLA大分子单体融合或作为其共聚单体。在三种测试的癌细胞系中，凋亡聚合物的细胞毒性显著高于游离肽，如通过与游离肽相比聚合物的IC 50值降低一个数量级所证明的。通过放射性标记和亚细胞分级分离测定一种聚合物构建体的摄取效率和细胞内运输。尽管它们具有更强的细胞毒性特征，但聚合KLA构建体具有差的细胞摄取效率（<1%）。一个显着的分数（20%）的内化结构与完整的线粒体部分本地化。为了增加细胞摄取，通过与O-甲基异脲反应将聚合物胺转化为胍。胍基化聚合物破坏分离的线粒体的功能超过其基于赖氨酸的类似物，但总体毒性降低，可能是由于线粒体运输效率低下。因此，虽然多价KLA聚合物比KLA肽更有效，但这些材料可以通过设计具有改善的细胞内化和线粒体靶向效率的下一代材料来显著改善。
Several cationic antimicrobial peptides have been investigated as potential anti-cancer drugs due to their demonstrated selective toxicity towards cancer cells relative to normal cells. For example, intracellular delivery of KLA, a pro-apoptotic peptide, results in toxicity against a variety of cancer cell lines; however, the relatively low activity and small size leads to rapid renal excretion when applied in vivo, limiting its therapeutic potential. In this work, apoptotic peptide-polymer hybrid materials were developed to increase apoptotic peptide activity via multivalent display. Multivalent peptide materials were prepared with comb-like structure by RAFT copolymerization of peptide macromonomers with N-(2-hydroxypropyl) methacrylamide (HPMA). Polymers displayed a GKRK peptide sequence for targeting p32, a protein often overexpressed on the surface of cancer cells, either fused with or as a comonomer to a KLA macromonomer. In three tested cancer cell lines, apoptotic polymers were significantly more cytotoxic than free peptides as evidenced by an order of magnitude decrease in IC50 values for the polymers compared to free peptide. The uptake efficiency and intracellular trafficking of one polymer construct was determined by radiolabeling and subcellular fractionation. Despite their more potent cytotoxic profile, polymeric KLA constructs have poor cellular uptake efficiency (<1%). A significant fraction (20%) of internalized constructs localize with intact mitochondrial fractions. In an effort to increase cellular uptake, polymer amines were converted to guanidines by reaction with O-methylisourea. Guanidinylated polymers disrupted function of isolated mitochondria more than their lysine-based analogs, but overall toxicity was decreased, likely due to inefficient mitochondrial trafficking. Thus, while multivalent KLA polymers are more potent than KLA peptides, these materials can be substantially improved by designing next generation materials with improved cellular internalization and mitochondrial targeting efficiency.
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影响因子：
17.1
作者：
Ren Y;Cheung HW;von Maltzhan G;Agrawal A;Cowley GS;Weir BA;Boehm JS;Tamayo P;Karst AM;Liu JF;Hirsch MS;Mesirov JP;Drapkin R;Root DE;Lo J;Fogal V;Ruoslahti E;Hahn WC;Bhatia SN
通讯作者：
Bhatia SN
影响因子：
8
作者：
Fröhlich E
通讯作者：
Fröhlich E
影响因子：
4.3
作者：
Richter, Martin;Chakrabarti, Alokta;Rademann, Joerg
通讯作者：
Rademann, Joerg
影响因子：
8
作者：
Papo, N;Shai, Y
通讯作者：
Shai, Y
影响因子：
12.4
作者：
Agemy, Lilach;Kotamraju, Venkata R.;Ruoslahti, Erkki
通讯作者：
Ruoslahti, Erkki