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RGD 修饰的聚（D，L-乳酸）纳米粒增强冬凌草甲素的肿瘤靶向性。

RGD-modified poly(D,L-lactic acid) nanoparticles enhance tumor targeting of oridonin.

机构信息

School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China.

出版信息

Int J Nanomedicine. 2012;7:211-9. doi: 10.2147/IJN.S27581. Epub 2012 Jan 9.

DOI:10.2147/IJN.S27581
PMID:22275836
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3263413/
Abstract

OBJECTIVE: The purpose of this study was to develop an active targeting strategy to improve the therapeutic antitumor efficacy of oridonin (ORI), the main active ingredient in the medicinal herb Rabdosia rubescens. METHODS: A modified spontaneous emulsification solvent diffusion method was used to prepare the ORI-loaded atactic poly(D,L-lactic acid) nanoparticles (ORI-PLA-NPs). Surface cross-linking with the peptide Arg-Gly-Asp (RGD) further modified the ORI-PLA-NPs, generating ORI-PLA-RGD-NPs. The NPs were characterized and release experiments were performed in vitro. The pharmacokinetics, tissue distribution, and antitumor activity of the NPs were studied in mice bearing hepatocarcinoma 22 (H22)-derived tumors. RESULTS: The ORI-PLA-NPs and ORI-PLA-RGD-NPs were smooth, sphere-like, and relatively uniform in size. The RGD surface modification slightly increased the mean particle size (95.8 nm for ORI-PLA-NPs versus 105.2 nm for ORI-PLA-RGD-NPs) and considerably altered the surface electrical property (-10.19 mV for ORI-PLA-NPs versus -21.95 mV for ORI-PLA-RGD-NPs), but it had no obvious influence on ORI loading (8.23% ± 0.35% for ORI-PLA-NPs versus 8.02% ± 0.38% for ORI-PLA-RGD-NPs), entrapment efficiency (28.86% ± 0.93% for ORI-PLA-NPs versus 28.24% ± 0.81% for ORI-PLA-RGD-NPs), or the release of ORI. The pharmacokinetic properties of free ORI were improved by encapsulation in NPs, as shown by increased area under the concentration-time curve (11.89 ± 0.35 μg·mL(-1) · h for ORI solution versus 22.03 ± 0.01 μg · mL(-1) · h for ORI-PLA-RGD-NPs) and prolonged mean retention time (2.03 ± 0.09 hours for ORI solution versus 8.68 ± 0.66 hours for ORI-PLA-RGD-NPs). In the tissue distribution study, more ORI targeted tumor tissue in the mice treated with ORI-PLA-RGD-NPs than with ORI-PLA-NPs or ORI solution. Consistent with these observations, ORI-PLA-RGD-NPs showed greater antitumor efficacy than ORI-PLA-RGD-NPs or ORI solution, as reflected by the decreased tumor growth and the prolonged survival time of mice bearing H22 tumors. CONCLUSION: The tumor-targeting efficiency and subsequent antitumor efficacy of ORI is increased by incorporation into ORI-PLA-RGD-NPs.

摘要

目的：本研究旨在开发一种主动靶向策略，以提高来源于草药冬凌草的主要活性成分冬凌草甲素（ORI）的治疗抗肿瘤疗效。

方法：采用改良的自发乳化溶剂扩散法制备 ORI 载无规聚（D，L-乳酸）纳米粒（ORI-PLA-NPs）。用肽 Arg-Gly-Asp（RGD）进行表面交联进一步修饰 ORI-PLA-NPs，生成 ORI-PLA-RGD-NPs。对 NPs 进行了表征，并进行了体外释放实验。研究了载药纳米粒在荷肝癌 22（H22）肿瘤小鼠中的药代动力学、组织分布和抗肿瘤活性。

结果：ORI-PLA-NPs 和 ORI-PLA-RGD-NPs 呈光滑、球形且大小相对均匀。RGD 表面修饰略微增加了平均粒径（ORI-PLA-NPs 为 95.8nm，ORI-PLA-RGD-NPs 为 105.2nm），并显著改变了表面电荷性质（ORI-PLA-NPs 为-10.19mV，ORI-PLA-RGD-NPs 为-21.95mV），但对 ORI 载药量（ORI-PLA-NPs 为 8.23%±0.35%，ORI-PLA-RGD-NPs 为 8.02%±0.38%）、包封率（ORI-PLA-NPs 为 28.86%±0.93%，ORI-PLA-RGD-NPs 为 28.24%±0.81%）或 ORI 的释放没有明显影响。ORI 被包封在 NPs 中后，其药代动力学性质得到改善，表现为曲线下面积增加（ORI 溶液为 11.89±0.35μg·mL（-1）·h，ORI-PLA-RGD-NPs 为 22.03±0.01μg·mL（-1）·h）和平均滞留时间延长（ORI 溶液为 2.03±0.09 小时，ORI-PLA-RGD-NPs 为 8.68±0.66 小时）。在组织分布研究中，与 ORI-PLA-NPs 或 ORI 溶液相比，荷瘤小鼠用 ORI-PLA-RGD-NPs 治疗后，更多的 ORI 靶向肿瘤组织。与这些观察结果一致，与 ORI-PLA-RGD-NPs 或 ORI 溶液相比，ORI-PLA-RGD-NPs 显示出更高的抗肿瘤疗效，表现为肿瘤生长减少和荷 H22 肿瘤小鼠的生存时间延长。

结论：将 ORI 包封入 ORI-PLA-RGD-NPs 可提高 ORI 的肿瘤靶向效率和随后的抗肿瘤疗效。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c70/3263413/46c73040a98e/ijn-7-211f9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c70/3263413/5c1a9567ab2d/ijn-7-211f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c70/3263413/b0bd3d394840/ijn-7-211f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c70/3263413/a2929782bc0a/ijn-7-211f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c70/3263413/24c1ce311930/ijn-7-211f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c70/3263413/0e7d54e2a329/ijn-7-211f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c70/3263413/8881f94fb6e6/ijn-7-211f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c70/3263413/2d86255c4e74/ijn-7-211f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c70/3263413/8572572252db/ijn-7-211f8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c70/3263413/46c73040a98e/ijn-7-211f9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c70/3263413/5c1a9567ab2d/ijn-7-211f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c70/3263413/b0bd3d394840/ijn-7-211f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c70/3263413/a2929782bc0a/ijn-7-211f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c70/3263413/24c1ce311930/ijn-7-211f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c70/3263413/0e7d54e2a329/ijn-7-211f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c70/3263413/8881f94fb6e6/ijn-7-211f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c70/3263413/2d86255c4e74/ijn-7-211f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c70/3263413/8572572252db/ijn-7-211f8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c70/3263413/46c73040a98e/ijn-7-211f9.jpg

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本文引用的文献

[1]
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Int J Nanomedicine. 2011-5-27

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J Drug Target. 2008-7

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Int J Pharm. 2008-5-1

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Int J Pharm. 2008-5-1

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