Fang Xiao-Bin, Xu Ying-Qi, Chan Hon-Fai, Wang Chun-Ming, Zheng Qing, Xiao Fei, Chen Mei-Wan
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau , Macau 999078, China.
Department of Biomedical Engineering, Columbia University , New York, New York 10027, United States.
Mol Pharm. 2016 Nov 7;13(11):3613-3625. doi: 10.1021/acs.molpharmaceut.6b00116. Epub 2016 Oct 21.
Hepatocellular carcinoma (HCC) is an aggressive malignancy and the second leading cause of cancer death worldwide. Most current therapeutic agents lack the tumor-targeting efficiency and result in a nonselective biodistribution in the body. In our previous study, we identified a peptide Ala-Pro-Asp-Thr-Lys-Thr-Gln (APDTKTQ) that can selectively bind to the receptor of advanced glycation end-products (RAGE), an immunoglobulin superfamily cell surface molecule overexpressed during HCC malignant progression. Here, we report the design of a mixed micelles system modified with this peptide to target HCC cells. Specifically, we modified Pluronic F68 (F68) with APDTKTQ (F68-APDTKTQ), and we conjugated d-α-tocopheryl polyethylene glycol succinate (TPGS) with poly(lactic-co-glycolic acid) (PLGA) by a disulfide linker (TPGS-S-S-PLGA). We mixed TPGS-S-S-PLGA and F68-APDTKTQ (TSP/FP) to form a micelle, followed by the loading of oridonin (ORI). The prepared micelles showed a homogeneously spherical shape without aggregation, triggered an increased cellular uptake, and induced apoptosis in more cells than did the free ORI. Taken together, these results demonstrate the potential of this APDTKTQ-modified ORI-loaded TSP/FP mixed micelle system as a promising strategy for HCC-targeting therapy.
肝细胞癌（HCC）是一种侵袭性恶性肿瘤，是全球癌症死亡的第二大主要原因。目前大多数治疗药物缺乏肿瘤靶向效率，导致在体内的生物分布无选择性。在我们之前的研究中，我们鉴定出一种肽Ala-Pro-Asp-Thr-Lys-Thr-Gln（APDTKTQ），它可以选择性地结合晚期糖基化终产物受体（RAGE），RAGE是一种免疫球蛋白超家族细胞表面分子，在HCC恶性进展过程中过度表达。在此，我们报告了一种用该肽修饰的混合胶束系统的设计，用于靶向HCC细胞。具体而言，我们用APDTKTQ修饰了普朗尼克F68（F68）（F68-APDTKTQ），并且通过二硫键连接子将d-α-生育酚聚乙二醇琥珀酸酯（TPGS）与聚乳酸-羟基乙酸共聚物（PLGA）偶联（TPGS-S-S-PLGA）。我们将TPGS-S-S-PLGA和F68-APDTKTQ（TSP/FP）混合以形成胶束，随后负载冬凌草甲素（ORI）。所制备的胶束呈现均匀的球形且无聚集，引发细胞摄取增加，并且与游离ORI相比，诱导更多细胞凋亡。综上所述，这些结果证明了这种载有APDTKTQ修饰的ORI的TSP/FP混合胶束系统作为一种有前景的HCC靶向治疗策略的潜力。
