Starch nanoparticles for delivery of the histone deacetylase inhibitor CG-1521 in breast cancer treatment
Starch nanoparticles for delivery of the histone deacetylase inhibitor CG-1521 in breast cancer treatment
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DOI：
10.2147/ijn.s191837
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发表时间：
2019-01-01
影响因子：
8
通讯作者：
Tenniswood, Martin
中科院分区：
文献类型：
--
作者：
Alp, Esma;Damkaci, Fehmi;Tenniswood, Martin
背景：表观遗传药物（例如组蛋白脱乙酰酶抑制剂）的功效常常因水溶性差而降低，导致生物利用度有限和治疗指数低。为了克服治疗指数不理想的问题，我们开发了 CG-1521 的生物相容性淀粉纳米颗粒制剂，CG-1521 是一种针对难以治疗的乳腺癌的临床前开发的组蛋白脱乙酰酶抑制剂，可提高其生物利用度和半衰期。方法：这些纳米颗粒 (CG-NP) 的理化参数（尺寸、zeta 电位、形态、负载和释放动力学）已得到优化，并在 MCF-7 中测量其细胞毒性和细胞凋亡能力乳腺癌细胞系。在分子水平上比较了封装药物与游离药物的作用机制。结果：我们表明，与同等剂量的游离CG-1521相比，CG-1521的封装显着降低了药物的释放速率，并显着增强了纳米颗粒的细胞毒能力。 CG-NPs 在体外诱导 MCF-7 细胞的细胞周期停滞和显着的细胞凋亡。封装药物的生物作用与游离药物对基因表达的影响相似。结论：研究结果表明，将CG-1521封装到淀粉纳米颗粒中可以改善乳腺癌治疗中组蛋白脱乙酰酶抑制剂的药物递送，而不干扰药物的作用机制。
Background: The efficacy of epigenetic drugs, such as histone deacetylase inhibitors, is often diminished by poor aqueous solubility resulting in limited bioavailability and a low therapeutic index. To overcome the suboptimal therapeutic index, we have developed a biocompatible starch nanoparticle formulation of CG-1521, a histone deacetylase inhibitor in preclinical development for hard-to-treat breast cancers, which improves its bioavailability and half-life.Methods: The physicochemical parameters (size, zeta potential, morphology, loading, and release kinetics) of these nanoparticles (CG-NPs) have been optimized and their cytotoxic and apoptotic capacities measured in MCF-7 breast cancer cell line. The mechanism of action of the encapsulated drug was compared with the free drug at molecular level.Results: We show that encapsulation of CG-1521 substantially reduces the release rate of drug and provides a significantly enhanced cytotoxic ability of nanoparticles compared with equivalent dose of free CG-1521. CG-NPs induced cell cycle arrest and significant apoptosis in MCF-7 cells in vitro. The biological action of encapsulated drug has the similar impact with free drug on gene expression.Conclusion: The findings suggest that encapsulation of CG-1521 into starch nanoparticles can improve drug delivery of histone deacetylase inhibitors for breast cancer therapy without interfering with the mechanism of action of the drug.