Department of Fiber Science and Apparel Design, Cornell University, Ithaca, NY 14853-4401, United States.
Biomedical Engineering Field, Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853-4401, United States.
Acta Biomater. 2017 Oct 15;62:234-245. doi: 10.1016/j.actbio.2017.08.036. Epub 2017 Aug 30.
β-Cyclodextrin can form inclusion complex with a series of guest molecules including phenyl moieties, and has gained considerable popularity in the study of supramolecular nanostructure. In this study, a biodegradable nanocomplex (HA(CD)-4Phe4 nanocomplex) was developed from β-cyclodextrin grafted hyaluronic acid (HA) and phenylalanine based poly(ester amide). The phenylalanine based poly(ester amide) is a biodegradable pseudo protein which provides the encapsulation capacity for gambogic acid (GA), a naturally-derived chemotherapeutic which has been effectively employed to treat multidrug resistant tumor. The therapeutic potency of free GA is limited due to its poor solubility in water and the lack of tumor-selective toxicity. The nanocomplex carrier enhanced the solubility and availability of GA in aqueous media, and the HA component enabled the targeted delivery to tumor cells with overexpression of CD44 receptors. In the presence of hyaluronidase, the release of GA from the nanocomplex was significantly accelerated, due to the enzymatic biodegradation of the carrier. Compared to free GA, GA-loaded nanocomplex exhibited improved cytotoxicity in MDA-MB-435/MDR multidrug resistant melanoma cells, and induced enhanced level of apoptosis and mitochondrial depolarization, at low concentration of GA (1-2µM). The nanocomplex enhanced the therapeutic potency of GA, especially when diluted in physiological environment. In addition, suppressed matrix metalloproteinase activity was also detected in MDA-MB-435/MDR cells treated by GA-loaded nanocomplex, which demonstrated its potency in the inhibition of tumor metastasis. The in vitro data suggested that HA(CD)-4Phe4 nanocomplex could provide a promising alternative in the treatment of multidrug resistant tumor cells.
Gambogic acid (GA), naturally derived from genus Garcinia trees, exhibited significant cytotoxic activity against multiple types of tumors with resistance to traditional chemotherapeutics. Unfortunately, the poor solubility of GA in conventional pharmaceutical solvents and non-targeted distribution in normal tissues greatly limited its therapeutic potency. To overcome the challenges, we develop a nanoplatform from the supramolecular assembly of β-cyclodextrin grafted hyaluronic acid (HA) and phenylalanine based pseudo protein. The pseudo protein in the nanocomplex provided the hydrophobic interaction and loading capacity for GA, while the HA component targeted the overexpressed CD44 receptor and improved the selective endocytosis in multidrug resistant melanoma cells. The supramolecular nanocomplex provide a promising platform for the delivery of hydrophobic chemotherapeutics to improve the bioavailability and efficiency.
β-环糊精可以与一系列包括苯部分的客体分子形成包合复合物，并且在超分子纳米结构的研究中已经得到了相当大的关注。在这项研究中，由β-环糊精接枝透明质酸（HA）和基于苯丙氨酸的聚酯酰胺制备了可生物降解的纳米复合物（HA（CD）-4Phe4 纳米复合物）。基于苯丙氨酸的聚酯酰胺是一种可生物降解的伪蛋白，可为藤黄酸（GA）提供包封能力，藤黄酸是一种天然衍生的化疗药物，已有效用于治疗多药耐药肿瘤。游离 GA 的治疗效力受到其在水中的溶解度差和缺乏肿瘤选择性毒性的限制。纳米复合物载体增强了 GA 在水性介质中的溶解度和可用性，并且 HA 成分能够使具有过表达 CD44 受体的肿瘤细胞靶向递送。在透明质酸酶存在下，由于载体的酶促生物降解，GA 从纳米复合物中的释放明显加速。与游离 GA 相比，GA 负载的纳米复合物在 MDA-MB-435/MDR 多药耐药黑色素瘤细胞中显示出改善的细胞毒性，并且在低浓度 GA（1-2μM）下诱导增强的凋亡和线粒体去极化水平。纳米复合物增强了 GA 的治疗效力，尤其是在生理环境中稀释时。此外，还检测到用 GA 负载的纳米复合物处理的 MDA-MB-435/MDR 细胞中基质金属蛋白酶活性受到抑制，表明其在抑制肿瘤转移方面具有潜力。体外数据表明，HA（CD）-4Phe4 纳米复合物可为多药耐药肿瘤细胞的治疗提供有前途的替代方法。
藤黄酸（GA）天然来源于藤黄属植物，对多种对传统化疗药物有耐药性的肿瘤具有显著的细胞毒性活性。不幸的是，GA 在常规药物溶剂中的溶解度差和在正常组织中的非靶向分布极大地限制了其治疗效力。为了克服这些挑战，我们从β-环糊精接枝透明质酸（HA）和基于苯丙氨酸的伪蛋白的超分子组装中开发了一种纳米平台。纳米复合物中的伪蛋白提供了 GA 的疏水相互作用和负载能力，而 HA 成分靶向过表达的 CD44 受体，并提高了多药耐药黑色素瘤细胞中的选择性内吞作用。超分子纳米复合物为递送疏水性化疗药物提供了有前途的平台，以提高生物利用度和效率。
