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Colloids Surf B Biointerfaces. 2015 Dec 1;136:413-23. doi: 10.1016/j.colsurfb.2015.09.043. Epub 2015 Sep 28.

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

Author information

1
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.
2
Department of Chemical Engineering and Materials Science, College of Engineering, Wayne State University, 5050 Anthony Wayne Drive, Detroit, MI 48202, USA.
3
Department of Pathology, Barbara Ann Karmanos Cancer Center, Wayne State University, School of Medicine, 740 HWCRC, Detroit, MI 48201, USA.
4
ISTRA, Department of Chemistry, MCE Society's Abeda Inamdar Senior College of Arts, Science and Commerce, University of Pune, Pune 411001, India.
5
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; Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University, School of Medicine, Detroit, MI 48201, USA. Electronic address: arun.iyer@wayne.edu.

Abstract

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.

KEYWORDS:

3, 4-Difluorobenzylidene curcumin; CD44 targeting; Drug delivery; Hyaluronic acid; PAMAM dendrimer; Pancreatic cancer

PMID:
26440757
DOI:
10.1016/j.colsurfb.2015.09.043
[Indexed for MEDLINE]

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