Liu Kai, Wang Zhi-qi, Wang Shi-jiang, Liu Ping, Qin Yue-hong, Ma Yan, Li Xiao-Chen, Huo Zhi-Jun
Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, People's Republic of China.
Department of Head and Neck Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, People's Republic of China.
Int J Nanomedicine. 2015 Oct 12;10:6445-54. doi: 10.2147/IJN.S89476. eCollection 2015.
Colon cancer is one of the leading causes of cancer-related death worldwide, and the therapeutic application of 5-fluorouracil (5-FU) is limited due to its nonspecificity, low bioavailability, and overdose. The present study is an attempt to improve the chemotherapeutic efficacy of 5-FU in colon cancers. Therefore, we have prepared 5-FU-loaded hyaluronic acid (HA)-conjugated silica nanoparticles (SiNPs) to target to colon cancer cells. In this study, we have showed the specific binding and intracellular accumulation of targeted nanoparticles based on HA surface modifications in colon carcinoma cells. The particles had spherical shapes with sizes of approximately 130 nm. HA-conjugated nanoparticles showed a sustained release pattern for 5-FU and continuously released for 120 hours. We have further investigated the cytotoxicity potential of targeted and nontargeted nanoparticles in colo-205 cancer cells. IC50 value of 5-FU/hyaluronic acid-conjugated silica nanoparticles (HSNP) was 0.65 µg/mL compared with ~2.8 µg/mL for 5-FU/SNP after 24 hours of incubation. The result clearly showed that HA-conjugated NP was more effective in inducing apoptosis in cancer cells than nontargeted NP. The 5-FU/HSNP showed ~45% of cell apoptosis (early and late apoptosis stage) compared with only 20% for 5-FU/silica nanoparticles (SNP)-treated group. The HA-conjugated nanoparticles provide the possibility of efficient drug transport into tumors that could effectively reduce the side effects in the normal tissues. 5-FU/HSNP was highly efficient in suppressing the tumor growth in xenograft tumor model. The proportion of Ki67 in 5-FU/HSNP-treated group was significantly lower than that of either free drug or nontargeted SiNPs. Altogether, we have showed that conjugation of HA to SiNPs could result in enhanced uptake of 5-FU through CD44-mediated endocytosis uptake and could result in significant antitumor efficacy. Thus, 5-FU/HSNP could be a promising drug delivery system for colon cancer therapy.
结肠癌是全球癌症相关死亡的主要原因之一，由于5-氟尿嘧啶（5-FU）的非特异性、低生物利用度和过量使用，其治疗应用受到限制。本研究旨在提高5-FU在结肠癌治疗中的疗效。因此，我们制备了负载5-FU的透明质酸（HA）共轭二氧化硅纳米颗粒（SiNPs），以靶向结肠癌细胞。在本研究中，我们展示了基于HA表面修饰的靶向纳米颗粒在结肠癌细胞中的特异性结合和细胞内积累。这些颗粒呈球形，大小约为130nm。HA共轭纳米颗粒显示出5-FU的持续释放模式，并持续释放120小时。我们进一步研究了靶向和非靶向纳米颗粒对colo-205癌细胞的细胞毒性潜力。孵育24小时后，5-FU/透明质酸共轭二氧化硅纳米颗粒（HSNP）的IC50值为0.65μg/mL，而5-FU/SNP的IC50值约为2.8μg/mL。结果清楚地表明，HA共轭纳米颗粒在诱导癌细胞凋亡方面比非靶向纳米颗粒更有效。与5-FU/二氧化硅纳米颗粒（SNP）处理组仅20%相比，5-FU/HSNP显示约45%的细胞凋亡（早期和晚期凋亡阶段）。HA共轭纳米颗粒为将药物有效输送到肿瘤中提供了可能性，这可以有效减少正常组织中的副作用。5-FU/HSNP在异种移植肿瘤模型中高效抑制肿瘤生长。5-FU/HSNP处理组中Ki67的比例显著低于游离药物或非靶向SiNPs组。总之，我们表明将HA与SiNPs共轭可通过CD44介导的内吞摄取增强5-FU的摄取，并可产生显著的抗肿瘤疗效。因此，5-FU/HSNP可能是一种有前途的结肠癌治疗药物递送系统。
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