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pH- and GSH-Sensitive Hyaluronic Acid-MP Conjugate Micelles for Intracellular Delivery of Doxorubicin to Colon Cancer Cells and Cancer Stem Cells
Biomacromolecules ( IF 5.5 ) Pub Date : 2018-07-25 00:00:00 , DOI: 10.1021/acs.biomac.8b00856
Tilahun Ayane Debele,Lu-Yi Yu,Cheng-Sheng Yang,Yao-An Shen,Chun-Liang Lo

A dual-sensitive polymeric drug conjugate (HA-SS-MP) was synthesized by conjugating hydrophobic 6-mercaptopurine (MP) to thiolated hyaluronic acid (HA) as the carrier and ligand to deliver doxorubicin (Dox) to parental colon cancer and colon cancer stem cells. Because of the amphiphilic nature of HA-SS-MP, it was self-assembled in the aqueous media, and Dox was physically encapsulated in the core of the micelles. The particle size and the zeta potential of the micelle were analyzed by dynamic light scattering (DLS), and the morphology of the micelle was investigated using transmission electron microscopy (TEM). Drug release study results revealed more drug release at pH 5.0 in the presence of GSH than that at the physiological pH value. The cytotoxicity of free Dox was slightly greater than that of Dox-loaded HA-SS-MP micelles. In vitro cytotoxicity of HA-SS-MP and Dox-loaded HA-SS-MP micelles was greater for cancer stem cells (HCT116-CSCs) than for parental HCT116 colon cancer cells and L929 normal fibroblast cells. The MTT and flow cytometry results confirmed that free HA competitively inhibited Dox-loaded HA-SS-MP uptake. Similarly, flow cytometry results revealed anti-CD44 antibody competitively inhibited cellular uptake of Rhodamine B isothiocyanate conjugated micelles, which confirms that the synthesized micelle is uptaken via CD44 receptor. Cell cycle analysis revealed that free drugs and Dox-loaded HA-SS-MP arrested parental HCT116 colon cancer cells at the S phase, while cell arrest was observed at the G0G1 phase in HCT116-CSCs. In addition, ex vivo biodistribution study showed that Dox-loaded HA-SS-MP micelles were accumulated more in the tumor region than in any other organ. Furthermore, the in vivo results revealed that Dox-loaded HA-SS-MP micelles exhibited more therapeutic efficacy than the free drugs in inhibiting tumor growth in BALB/C nude mice. Overall, the results suggested that the synthesized micelles could be promising as a stimuli carrier and ligand for delivering Dox to colon cancer cells and also to eradicate colon cancer stem cells.

中文翻译:

pH和GSH敏感的透明质酸-MP结合胶束,将阿霉素向结肠癌细胞和癌干细胞进行细胞内递送。

通过将疏水性6-巯基嘌呤(MP)与巯基化透明质酸(HA)结合为载体和配体,从而将阿霉素(Dox)递送给亲代结肠癌和结肠癌,合成了双敏感性聚合物药物偶联物(HA-SS-MP)干细胞。由于HA-SS-MP的两亲性质,它可以在水性介质中自组装,而Dox则被物理包封在胶束的核心中。通过动态光散射(DLS)分析胶束的粒径和ζ电位,并使用透射电子显微镜(TEM)研究胶束的形态。药物释放研究结果表明,在存在GSH的情况下,pH 5.0时的药物释放要比生理pH值时的释放更多。游离Dox的细胞毒性略大于载有Dox的HA-SS-MP胶束。癌症干细胞(HCT116-CSC)的HA-SS-MP和Dox加载的HA-SS-MP胶束的体外细胞毒性比亲代HCT116结肠癌细胞和L929正常成纤维细胞更大。MTT和流式细胞仪结果证实游离的HA竞争性抑制Dox加载的HA-SS-MP摄取。类似地,流式细胞仪结果显示抗CD44抗体竞争性抑制罗丹明B异硫氰酸酯共轭胶束的细胞摄取,这证实了合成的胶束是通过CD44受体摄取的。细胞周期分析显示,游离药物和载有Dox的HA-SS-MP在S期阻滞了亲本HCT116结肠癌细胞,而在HCT116-CSC中在G0G1期观察到了细胞阻滞。另外,离体生物分布研究表明,载有Dox的HA-SS-MP胶束在肿瘤区域的蓄积量高于任何其他器官。此外,体内结果显示,载有Dox的HA-SS-MP胶束在抑制BALB / C裸鼠中的肿瘤生长方面比游离药物显示出更高的治疗功效。总体而言,结果表明,合成的胶束有望作为刺激载体和配体用于将Dox递送至结肠癌细胞并根除结肠癌干细胞。
更新日期:2018-07-25
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