Ostadhossein Fatemeh, Misra Santosh K, Mukherjee Prabuddha, Ostadhossein Alireza, Daza Enrique, Tiwari Saumya, Mittal Shachi, Gryka Mark C, Bhargava Rohit, Pan Dipanjan
Department of Bioengineering, University of Illinois at Urbana-Champaign, 1304 W. Springfield Ave., Urbana, IL, 61801, USA.
Department of Engineering Science and Mechanics, Pennsylvania State University, University Park, PA, 16802, USA.
Small. 2016 Nov;12(42):5845-5861. doi: 10.1002/smll.201601161. Epub 2016 Aug 22.
Signal transducer and activator of transcription factor 3 (STAT-3) is known to be overexpressed in cancer stem cells. Poor solubility and variable drug absorption are linked to low bioavailability and decreased efficacy. Many of the drugs regulating STAT-3 expression lack aqueous solubility; hence hindering efficient bioavailability. A theranostics nanoplatform based on luminescent carbon particles decorated with cucurbit[6]uril is introduced for enhancing the solubility of niclosamide, a STAT-3 inhibitor. The host-guest chemistry between cucurbit[6]uril and niclosamide makes the delivery of the hydrophobic drug feasible while carbon nanoparticles enhance cellular internalization. Extensive physicochemical characterizations confirm successful synthesis. Subsequently, the host-guest chemistry of niclosamide and cucurbit[6]uril is studied experimentally and computationally. In vitro assessments in human breast cancer cells indicate approximately twofold enhancement in IC of drug. Fourier transform infrared and fluorescence imaging demonstrate efficient cellular internalization. Furthermore, the catalytic biodegradation of the nanoplatforms occur upon exposure to human myeloperoxidase in short time. In vivo studies on athymic mice with MCF-7 xenograft indicate the size of tumor in the treatment group is half of the controls after 40 d. Immunohistochemistry corroborates the downregulation of STAT-3 phosphorylation. Overall, the host-guest chemistry on nanocarbon acts as a novel arsenal for STAT-3 inhibition.
已知信号转导和转录激活因子3（STAT-3）在癌症干细胞中过表达。溶解度差和药物吸收可变与生物利用度低和疗效降低有关。许多调节STAT-3表达的药物缺乏水溶性，因此阻碍了有效的生物利用度。引入了一种基于用葫芦[6]脲修饰的发光碳颗粒的诊疗纳米平台，以提高STAT-3抑制剂氯硝柳胺的溶解度。葫芦[6]脲与氯硝柳胺之间的主客体化学使得疏水性药物的递送成为可能，而碳纳米颗粒增强了细胞内化。广泛的物理化学表征证实了成功合成。随后，通过实验和计算研究了氯硝柳胺与葫芦[6]脲的主客体化学。在人乳腺癌细胞中的体外评估表明药物的半数抑制浓度（IC）提高了约两倍。傅里叶变换红外光谱和荧光成像证明了有效的细胞内化。此外，纳米平台在短时间内暴露于人类髓过氧化物酶后会发生催化生物降解。对携带MCF-7异种移植瘤的无胸腺小鼠的体内研究表明，40天后治疗组肿瘤大小是对照组的一半。免疫组织化学证实了STAT-3磷酸化的下调。总体而言，纳米碳上的主客体化学作为抑制STAT-3的一种新型手段。
