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采用 CD44 靶向壳聚糖纳米粒将 PLXDC1 小干扰 RNA 选择性递送至内皮细胞用于上皮性卵巢癌的抗血管生成肿瘤治疗。

Selective delivery of PLXDC1 small interfering RNA to endothelial cells for anti-angiogenesis tumor therapy using CD44-targeted chitosan nanoparticles for epithelial ovarian cancer.

机构信息

a Department of Immunology School of Medicine , Konkuk University , Chungju , South Korea.

b Asan Institute for Life Sciences, Asan Medical Center , University of Ulsan College of Medicine , Seoul , Republic of Korea.

出版信息

Drug Deliv. 2018 Nov;25(1):1394-1402. doi: 10.1080/10717544.2018.1480672.

DOI:10.1080/10717544.2018.1480672
PMID:29890852
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6096458/
Abstract

Angiogenesis plays an essential role in the growth and metastasis of tumor cells, and the modulation of angiogenesis can be an effective approach for cancer therapy. We focused on silencing the angiogenic gene PLXDC1 as an important factor for anti-angiogenesis tumor therapy. Herein, we developed PLXDC1 small interfering siRNA (siRNA)-incorporated chitosan nanoparticle (CH-NP/siRNA) coated with hyaluronic acid (HA) to target the CD44 receptor on tumor endothelial cells. This study aimed to improve targeted delivery and enhance therapeutic efficacy for tumor anti-angiogenesis. The HA-CH-NP/siRNA was 200 ± 10 nm in size with a zeta potential of 26.4 mV. The loading efficiency of siRNA to the HA-CH-NP/siRNA was up to 60%. The selective binding of HA-CH-NP/siRNA to CD44-positive tumor endothelial cells increased by 2.1-fold compared with that of the CD44 nontargeted CH-NP/siRNA. PLXDC1 silencing by the HA-CH-NP/siRNA significantly inhibited tumor growth in A2780 tumor-bearing mice compared with that in the control group (p < .01), and mRNA expression of PLXDC1 was significantly reduced in the HA-CH-NP/siRNA-treated group. Furthermore, treatment with HA-CH-NP/siRNA resulted in significant inhibition of cell proliferation (p < .001), reduced microvessel density (p < .001), and increased cell apoptosis (p < .001). This study demonstrates that HA-CH-NP/siRNA is a highly selective delivery platform for siRNA, and has broad potential to be used in anti-angiogenesis tumor therapy.

摘要

血管生成在肿瘤细胞的生长和转移中起着至关重要的作用，调节血管生成可以成为癌症治疗的有效方法。我们专注于沉默血管生成基因 PLXDC1，作为抗血管生成肿瘤治疗的重要因素。在此，我们开发了一种 PLXDC1 小干扰 RNA（siRNA）包封在壳聚糖纳米颗粒（CH-NP/siRNA）上并涂覆透明质酸（HA）的方法，以针对肿瘤内皮细胞上的 CD44 受体。本研究旨在提高靶向递送并增强肿瘤抗血管生成的治疗效果。HA-CH-NP/siRNA 的大小为 200±10nm，zeta 电位为 26.4mV。siRNA 对 HA-CH-NP/siRNA 的负载效率高达 60%。与非靶向 CD44 的 CH-NP/siRNA 相比，HA-CH-NP/siRNA 对 CD44 阳性肿瘤内皮细胞的选择性结合增加了 2.1 倍。与对照组相比，HA-CH-NP/siRNA 对 PLXDC1 的沉默显著抑制了 A2780 荷瘤小鼠的肿瘤生长（p<.01），并且 HA-CH-NP/siRNA 处理组中 PLXDC1 的 mRNA 表达显著降低。此外，HA-CH-NP/siRNA 的治疗导致细胞增殖显著抑制（p<.001），微血管密度降低（p<.001），细胞凋亡增加（p<.001）。本研究表明，HA-CH-NP/siRNA 是一种高效的 siRNA 递药平台，具有广泛的应用于抗血管生成肿瘤治疗的潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b732/6096458/9d59e21f6c0c/IDRD_A_1480672_F0006_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b732/6096458/200eda787345/IDRD_A_1480672_F0001_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b732/6096458/eb502bf7cc97/IDRD_A_1480672_F0002_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b732/6096458/2f4bb70c1adb/IDRD_A_1480672_F0003_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b732/6096458/8c6d9c045da7/IDRD_A_1480672_F0004_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b732/6096458/9f2992afa38b/IDRD_A_1480672_F0005_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b732/6096458/9d59e21f6c0c/IDRD_A_1480672_F0006_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b732/6096458/200eda787345/IDRD_A_1480672_F0001_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b732/6096458/eb502bf7cc97/IDRD_A_1480672_F0002_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b732/6096458/2f4bb70c1adb/IDRD_A_1480672_F0003_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b732/6096458/8c6d9c045da7/IDRD_A_1480672_F0004_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b732/6096458/9f2992afa38b/IDRD_A_1480672_F0005_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b732/6096458/9d59e21f6c0c/IDRD_A_1480672_F0006_C.jpg

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