Kesharwani Prashant, Xie Lingxiao, Banerjee Sanjeev, Mao Guangzhao, Padhye Subhash, Sarkar Fazlul H, 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, 259 Mack Ave, Detroit, MI 48201, USA.
Department of Chemical Engineering and Materials Science, College of Engineering, Wayne State University, 5050 Anthony Wayne Drive, Detroit, MI 48202, USA.
Colloids Surf B Biointerfaces. 2015 Dec 1;136:413-23. doi: 10.1016/j.colsurfb.2015.09.043. Epub 2015 Sep 28.
The current study was aimed to develop a targeted dendrimer formulation of 3, 4-difluorobenzylidene curcumin (CDF) and evaluate its potential in CD44 targeted therapy for pancreatic cancer. Using amine terminated fourth generation poly(amidoamine) (PAMAM) dendrimer nanocarrier and hyaluronic acid (HA) as a targeting ligand, we engineered a CD44-targeted PAMAM dendrimer (HA-PAMAM) formulation of CDF. The resulting dendrimer nanosystem (HA-PAMAM-CDF) had a particle size and surface charge of 9.3 ± 1.5 nm and -7.02 ± 9.53 mV, respectively. When CD44 receptor overexpressing MiaPaCa-2 and AsPC-1 human pancreatic cancer cells were treated with HA-PAMAM-CDF, a dose-dependent cytotoxicity was observed. Furthermore, blocking the CD44 receptors present on the MiaPaCa-2 cells using free excess soluble HA prior to treatment with HA-PAMAM-CDF nano-formulation resulted in 1.71 fold increase in the IC50 value compared to non-targeted formulation (PAMAM-CDF), confirming target specificity of HA-PAMAM-CDF. Additionally, HA-PAMAM-CDF formulation when compared to PAMAM-CDF, displayed higher cellular uptake in MiaPaCa-2 cancer cell lines as shown by fluorescence studies. In summary, the novel CD44 targeted dendrimer based nanocarriers appear to be proficient in mediating site-specific delivery of CDF via CD44 receptors, with an improved therapeutic margin and safety.
本研究旨在开发一种靶向性树枝状聚合物制剂，即3,4 - 二氟亚苄基姜黄素（CDF），并评估其在CD44靶向治疗胰腺癌中的潜力。我们使用胺端基第四代聚酰胺 - 胺（PAMAM）树枝状聚合物纳米载体和透明质酸（HA）作为靶向配体，设计了一种CD44靶向的PAMAM树枝状聚合物（HA - PAMAM）制剂来包裹CDF。所得的树枝状聚合物纳米系统（HA - PAMAM - CDF）的粒径和表面电荷分别为9.3±1.5 nm和 - 7.02±9.53 mV。当用HA - PAMAM - CDF处理过表达CD44受体的MiaPaCa - 2和AsPC - 1人胰腺癌细胞时，观察到剂量依赖性细胞毒性。此外，在用HA - PAMAM - CDF纳米制剂处理之前，使用游离过量的可溶性HA阻断MiaPaCa - 2细胞上存在的CD44受体，与非靶向制剂（PAMAM - CDF）相比，IC50值增加了1.71倍，证实了HA - PAMAM - CDF的靶向特异性。另外，荧光研究表明，与PAMAM - CDF相比，HA - PAMAM - CDF制剂在MiaPaCa - 2癌细胞系中表现出更高的细胞摄取。总之，新型的基于CD44靶向树枝状聚合物的纳米载体似乎能够通过CD44受体介导CDF的位点特异性递送，具有更高的治疗优势和安全性。
