Yousef Shaimaa, Alsaab Hashem O, Sau Samaresh, Iyer Arun K
Use-inspired Biomaterials & Integrated Nano Delivery (U-BiND) Systems Laboratory Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA.
Molecular Imaging Program, Barbara Ann Karmanos Cancer Institute, Wayne State University, School of Medicine, Detroit, MI 48201, USA.
Heliyon. 2018 Dec 22;4(12):e01071. doi: 10.1016/j.heliyon.2018.e01071. eCollection 2018 Dec.
Hepatocellular cellular carcinoma (HCC) is one of the most challenging liver cancer subtypes. Due to lack of cell surface biomarkers and highly metastatic nature, early detection and targeted therapy of HCC is an unmet need. Galactosamine (Gal) is among the few selective ligands used for targeting HCCs due to its high binding affinity to asialoglycoprotein receptors (ASGPRs) overexpressed in HCC. In the present work, we engineered nanoscale G4 polyamidoamine (PAMAM) dendrimers anchored to galactosamine and loaded with the potent anticancer curcumin derivative (CDF) as a platform for targeted drug delivery to HCC. targeting ability and bio-distribution of PAMAM-Gal were assessed via its labeling with the clinically used, highly contrast, near infrared (NIR) dye: S0456, with testing of the obtained conjugate in aggressive HCC xenograft model. Our results highlighted the targeted dendrimer PAMAM-Gal ability to achieve selective high cellular uptake via ASGPR mediated endocytosis and significantly enhance the delivery of CDF into the studied HCC cell lines. Cytotoxicity MTT assays in HCC cell lines, interestingly highlighted, the comparative high potency of CDF, where CDF was more potent as a chemotherapeutic anticancer small molecule than the currently in use Doxorubicin, Sorafenib and Cisplatin chemotherapeutic agents. In conclusion the proof-of-concept study using nanoscale PAMAM-Gal dendrimer has demonstrated its competency as an efficient delivery system for selective delivery of potent CDF for HCC anticancer therapy as well as HCC diagnosis via NIR imaging.
肝细胞癌(HCC)是最具挑战性的肝癌亚型之一。由于缺乏细胞表面生物标志物以及具有高度转移性,HCC的早期检测和靶向治疗仍是未满足的需求。半乳糖胺(Gal)因其对HCC中过表达的去唾液酸糖蛋白受体(ASGPR)具有高结合亲和力,是用于靶向HCC的少数选择性配体之一。在本研究中,我们设计了锚定半乳糖胺并负载强效抗癌姜黄素衍生物(CDF)的纳米级G4聚酰胺胺(PAMAM)树枝状大分子,作为向HCC靶向给药的平台。通过用临床使用的、高对比度的近红外(NIR)染料S0456标记PAMAM-Gal来评估其靶向能力和生物分布,并在侵袭性HCC异种移植模型中测试所得的缀合物。我们的结果突出了靶向树枝状大分子PAMAM-Gal通过ASGPR介导的内吞作用实现选择性高细胞摄取的能力,并显著增强了CDF向所研究的HCC细胞系中的递送。在HCC细胞系中进行的细胞毒性MTT试验有趣地突出了CDF相对较高的效力,其中CDF作为化疗抗癌小分子比目前使用的阿霉素、索拉非尼和顺铂化疗药物更有效。总之,使用纳米级PAMAM-Gal树枝状大分子的概念验证研究已证明其作为一种有效递送系统的能力,可用于将强效CDF选择性递送至HCC进行抗癌治疗以及通过NIR成像进行HCC诊断。