"OA02" peptide facilitates the precise targeting of paclitaxel-loaded micellar nanoparticles to ovarian cancer in vivo.
"OA02" peptide facilitates the precise targeting of paclitaxel-loaded micellar nanoparticles to ovarian cancer in vivo.
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DOI：
10.1158/0008-5472.can-11-3883
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发表时间：
2012-04-15
期刊：
影响因子：
11.2
通讯作者：
Lam KS
中科院分区：
文献类型：
--
作者：
Xiao K;Li Y;Lee JS;Gonik AM;Dong T;Fung G;Sanchez E;Xing L;Cheng HR;Luo J;Lam KS
报道了基于线性聚乙二醇（PEG）-嵌段-树枝状胆酸（CA）共聚物（末端树枝状聚合物）的胶束纳米颗粒（NP），用于在癌症治疗中靶向递送化疗药物。胶束纳米颗粒已经用针对α-3整联蛋白受体的高亲和力“OA 02”肽修饰，以提高在卵巢癌细胞表面过表达的肿瘤靶向特异性。使用“点击化学”将含炔的0A 02肽缀合至代表性PEG 5 k-CA 8末端树枝状聚合物（胶束形成单元）中PEG链远端的叠氮基。OA 02肽的缀合对PEG 5 k-CA 8 NPs的物理化学性质具有可忽略的影响，并且如所假设的，OA 02肽通过受体介导的内吞作用显著增强SKOV-3和ES-2卵巢癌细胞中PEG 5 k-CA 8 NPs的摄取效率，但在α-3整联蛋白阴性K562白血病细胞中没有。当负载紫杉醇（PTX）时，OA 02-NPs与非靶向NPs相比对SKOV-3和ES-2卵巢癌细胞具有显著更高的体外细胞毒性。此外，体内生物分布研究表明，OA 02肽极大地促进了肿瘤定位和PEG 5 k-CA 8 NP进入卵巢癌细胞的细胞内摄取，如在SKOV 3-luc荷瘤小鼠中验证的。最后，当与等效剂量的非靶向PTX-NP以及临床PTX制剂（Taxol®）相比时，负载PTX的OA 02-NP在携带SKOV-3肿瘤异种移植物的裸鼠中表现出上级抗肿瘤功效和较低的全身毒性特征。因此，OA 02靶向末端树枝状聚合物负载PTX作为卵巢癌患者的新治疗方法具有很大的潜力。
Micellar nanoparticles (NPs) based on linear polyethylene glycol (PEG)-block-dendritic cholic acids (CA) copolymers (telodendrimers), for the targeted delivery of chemotherapeutic drugs in the treatment of cancers, are reported. The micellar NPs have been decorated with a high-affinity “OA02” peptide against alpha-3 integrin receptor to improve the tumor targeting specificity which is overexpressed on the surface of ovarian cancer cells. “Click chemistry” was used to conjugate alkyne-containing OA02 peptide to the azide group at the distal terminus of the PEG chain in a representative PEG5k-CA8 telodendrimer (micelle forming unit). The conjugation of OA02 peptide had negligible influence on the physicochemical properties of PEG5k-CA8 NPs and as hypothesized, OA02 peptide dramatically enhanced the uptake efficiency of PEG5k-CA8 NPs in SKOV-3 and ES-2 ovarian cancer cells via receptor-mediated endocytosis, but not in alpha-3 integrin negative K562 leukemia cells. When loaded with paclitaxel (PTX), OA02-NPs had significantly higher in vitro cytotoxicity against both SKOV-3 and ES-2 ovarian cancer cells as compared with non-targeted NPs. Furthermore, the in vivo biodistribution study demonstrated OA02 peptide greatly facilitated tumor localization and the intracellular uptake of PEG5k-CA8 NPs into ovarian cancer cells as validated in SKOV3-luc tumor bearing mice. Finally, PTX-loaded OA02-NPs exhibited superior anti-tumor efficacy and lower systemic toxicity profile in nude mice bearing SKOV-3 tumor xenografts, when compared with equivalent doses of non-targeted PTX-NPs as well as clinical PTX formulation (Taxol®). Therefore, OA02 targeted telodendrimers loaded with PTX have great potential as a new therapeutic approach for ovarian cancer patients.