Hyaluronic acid-conjugated polyamidoamine dendrimers for targeted delivery of 3,4-difluorobenzylidene curcumin to CD44 overexpressing pancreatic cancer cells

• Published in: Colloids and surfaces, B, Biointerfaces Vol. 136; pp. 413 - 423
• Main Authors: Kesharwani, Prashant, Xie, Lingxiao, Banerjee, Sanjeev, Mao, Guangzhao, Padhye, Subhash, Sarkar, Fazlul H., Iyer, Arun K.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.12.2015
• Subjects: 3, 4-Difluorobenzylidene curcumin; Cancer; CD44 targeting; Cell Line, Tumor; Cellular; Curcumin - administration & dosage; Curcumin - analogs & derivatives; Dendrimers; Dendrimers - chemistry; Drug delivery; Fluorescence; Formulations; Humans; Hyaluronan Receptors - immunology; Hyaluronic acid; Hyaluronic Acid - chemistry; Hydroxyapatite; Microscopy, Atomic Force; Microscopy, Fluorescence; Nanostructure; PAMAM dendrimer; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - immunology; Pancreatic Neoplasms - pathology; Receptors; Spectroscopy, Fourier Transform Infrared; Drug delivery; Hyaluronic acid; PAMAM dendrimer; Pancreatic cancer; CD44 targeting; 3, 4-Difluorobenzylidene curcumin
• ISSN: 0927-7765; 1873-4367
• DOI: 10.1016/j.colsurfb.2015.09.043

[Display omitted] •We developed a dendrimer based formulation of CDF for CD44 targeted therapy for pancreatic cancer.•The targeting ability of HA facilitated the accumulation of the CDF nanoformulation at the pancreatic cancer cells.•HA-PAMAM-CDF nanosystems portend to be highly effective for treating pancreatic cancers due to efficient cellular uptake in CD44 receptor-over expressing tumors.•This work offers the prospect of taking highly potent yet less toxic dendrimer nanosystems for clinical development. 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±1.5nm and −7.02±9.53mV, 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.