Anticancer Platelet-Mimicking Nanovehicles.
Anticancer Platelet-Mimicking Nanovehicles.
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抗癌血小板模拟纳米颗粒。
DOI：
10.1002/adma.201503323
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发表时间：
2015-11-25
期刊：
影响因子：
--
通讯作者：
Gu Z
中科院分区：
文献类型：
--
作者：
Hu Q;Sun W;Qian C;Wang C;Bomba HN;Gu Z
DOI：10.1002/adma. 201503323单乳液法，并通过酸可降解交联剂交联。[10]血小板膜来源于血小板并纯化以涂覆NV的表面。PM-NV具有大量的“自我识别”蛋白，有望最大限度地降低体内免疫原性并延长循环时间。[11]更重要的是，PM上过表达的P-选择素可以特异性结合癌细胞表面上调的CD 44受体。综上所述，我们假设PM-NV可以主动靶向肿瘤部位，并将抗癌治疗剂依次递送至其最活跃的目的地。为了证明我们的假设，我们将两种抗癌治疗剂-肿瘤坏死因子（TNF）相关的凋亡诱导配体（TRAIL）和阿霉素（Dox）-装入PM-NV（命名为TRAIL-Dox-PM-NV）。作为最重要的细胞外凋亡激活剂之一，TRAIL通过与细胞表面的死亡受体（DR 4，DR 5）结合诱导肿瘤细胞凋亡[12];而Dox可以嵌入癌细胞的核DNA，触发内在的凋亡信号通路。[13]在静脉内（iv）注射后，预计PM-NV通过被动增强渗透性和滞留（EPR）效应[14]和基于PM与癌细胞上过表达的CD 44受体之间的亲和力的主动靶向作用的组合在肿瘤部位积聚（图1 B）。同时，P-Selectin的捕获能力使PM-NV在癌细胞表面聚集，促进TRAIL与细胞膜的相互作用，从而启动外源性凋亡信号。此外，P-选择素和CD 44的亲和力也预期容易消除CTC（图1 B），这在肿瘤转移中起着至关重要的作用。[15]在细胞内化后，预期内溶酶体中的酸性消化PM-NV中的酸响应模态，伴随着囊封的Dox的释放，其将在癌细胞的核中积累以协同诱导细胞凋亡。
DOI: 10.1002/adma. 201503323 single emulsion method and cross-linked by an acid-degradable cross-linker.[10] The platelet membranes are derived from platelets and purified to coat the surface of NV. Equipped with large numbers of “self-recognized” proteins, PM-NV is expected to minimize the in vivo immunogenicity and prolong the circulation time.[11] More importantly, the overexpressed P-Selectin on the PM can specifically bind to CD44 receptors upregulated on the surface of cancer cells. Taken together, we hypothesized that the PM-NV could actively target at tumor site and sequentially deliver anticancer therapeutics to their most active destinations. To demonstrate our hypothesis, we loaded two anticancer therapeutics––tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) and doxorubicin (Dox)—into PM-NV (designated TRAIL-Dox-PM-NV). As one of the most important extracellular activators of apoptosis, TRAIL induces apoptosis of tumor cells by binding to the death receptors (DR4, DR5) on the cell surface;[12] while Dox can intercalate the nuclear DNA of cancer cells to trigger the intrinsic apoptosis signaling pathway.[13]After intravenous (iv) injection, the PM-NVs are expected to accumulate in the tumor site by combination of the passive enhanced permeability and retention (EPR) effect [14] and active targeting based on the affinity between PM and overexpressed CD44 receptors on the cancer cells (Figure 1 b). Meanwhile, the aggregation of PM-NV on the surface of cancer cells enabled by capture ability of P-Selectin could facilitate the interaction between TRAIL and cell membranes, and subsequently initiation of extrinsic apoptosis signaling. Additionally, the affinity of P-Selectin and CD44 is also expected to readily eliminate CTCs (Figure 1 b), which plays a vital role in tumor metastasis.[15] After cellular internalization, the acidity in the endolysosome is expected to digest the acid-responsive modality in the PM-NV, accompanied by the release of encapsulated Dox, which will accumulate in the nuclei of cancer cells for synergistically inducing apoptosis.