The targeted transduction of MMP-overexpressing tumor cells by ACPP-HPMA copolymer-coated adenovirus conjugates.
The targeted transduction of MMP-overexpressing tumor cells by ACPP-HPMA copolymer-coated adenovirus conjugates.
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ACPP-HPMA 共聚物包被的腺病毒缀合物对 MMP 过表达肿瘤细胞的靶向转导
DOI：
10.1371/journal.pone.0100670
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Zhang Y
中科院分区：
文献类型：
--
作者：
Li S;Chen J;Xu H;Long J;Xie X;Zhang Y
我们设计并测试了一种新的方法，选择性地将HPMA聚合物包被的5型腺病毒（Ad 5）颗粒递送到基质金属蛋白酶（MMP）过表达的肿瘤细胞中。设计了一种可激活的细胞穿透肽（ACPP），并通过C-末端氨基酸（天冬酰胺，N）连接到HPMA聚合物的反应性4-硝基苯氧基基团。ACPP是可活化的细胞穿透肽（CPP），在聚阳离子和聚阴离子结构域之间具有接头，MMP介导的切割释放CPP部分及其附着的货物以使细胞进入。我们的数据表明，这些HPMA聚合物共轭物的运输由一个单一的ACPP分子的细胞质发生通过一个nonendocytotic和浓度无关的过程。通过倒置荧光显微镜观察到摄取在20分钟内完成。相比之下，HPMA聚合物包被的Ad 5没有ACPP的内化仅通过内吞作用。在转导过程中，Ad 5中和抗体的存在不影响最佳制剂，并且ACPP/聚合物包被的Ad 5也保留了对几种MMP过表达肿瘤细胞类型的高靶向能力。首次证实了ACPP介导的聚合物结合的Ad 5向MMP过表达的肿瘤细胞的胞质递送。这些发现是重要的，因为它们证明了基于聚合物的系统用于靶向递送到MMP过表达的实体瘤中的用途，并强调了如何克服主要的细胞障碍以实现细胞内大分子递送。
We have designed and tested a new way to selectively deliver HPMA polymer-coated adenovirus type 5 (Ad5) particles into matrix metalloproteinase (MMP)-overexpressing tumor cells. An activatable cell penetrating peptide (ACPP) was designed and attached to the reactive 4-nitrophenoxy groups of HPMA polymers by the C-terminal amino acid (asparagine, N). ACPPs are activatable cell penetrating peptides (CPPs) with a linker between polycationic and polyanionic domains, and MMP-mediated cleavage releases the CPP portion and its attached cargo to enable cell entry. Our data indicate that the transport of these HPMA polymer conjugates by a single ACPP molecule to the cytoplasm occurs via a nonendocytotic and concentration-independent process. The uptake was observed to finish within 20 minutes by inverted fluorescence microscopy. In contrast, HPMA polymer-coated Ad5 without ACPPs was internalized solely by endocytosis. The optimal formulation was not affected by the presence of Ad5 neutralizing antibodies during transduction, and ACPP/polymer-coated Ad5 also retained high targeting capability to several MMP-overexpressing tumor cell types. For the first time, ACPP-mediated cytoplasmic delivery of polymer-bound Ad5 to MMP-overexpressing tumor cells was demonstrated. These findings are significant, as they demonstrate the use of a polymer-based system for the targeted delivery into MMP-overexpressing solid tumors and highlight how to overcome major cellular obstacles to achieve intracellular macromolecular delivery.
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影响因子：
4.9
作者：
Kasman LM;Barua S;Lu P;Rege K;Voelkel-Johnson C
通讯作者：
Voelkel-Johnson C
影响因子：
82.9
作者：
Bremer, C;Tung, CH;Weissleder, R
通讯作者：
Weissleder, R
DOI：
10.1073/pnas.88.5.1864
发表时间：
1991-03-01
影响因子：
11.1
作者：
JOLIOT, A;PERNELLE, C;PROCHIANTZ, A
通讯作者：
PROCHIANTZ, A
影响因子：
4.2
作者：
Croyle, MA;Yu, QC;Wilson, JM
通讯作者：
Wilson, JM
影响因子：
4.5
作者：
Fisher, Kerry D.;Green, Nicola K.;Seymour, Leonard W.
通讯作者：
Seymour, Leonard W.